tag:blogger.com,1999:blog-4716636313061407122024-03-23T03:13:26.840-07:00Prenatal Exposures Never DieThe blog about epigenetics, autism, and the multigenerational tragedy of prenatal pharmaceutical use.Unknownnoreply@blogger.comBlogger22125tag:blogger.com,1999:blog-471663631306140712.post-8561251917141870362014-03-10T07:23:00.005-07:002014-03-10T07:28:16.414-07:00Moving the ShopThanks to everyone who has followed this blog. In order to create a more robust (and more scientific and less ranty) repository of information about germline disruption, I have sponsored a new website, <a href="http://germlineexposures.org/">germlineexposures.org</a>.<br />
<br />
It will feature expert interviews, scientific information, and more. Given the amount of work I have on my plate doubt I will have time to keep up this blog, but please check in with the new site from time to time. Thanks!<br />
<br />
Jill Escher<br />
<br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjnVtN_u_R2fKd4LPVTp0ZUWy70zI1I8Zac8xXBQsPU0iAzEmXR5-ApRCp0P-kvJw9lsdcIFnYBih3DiIcHMBqLLlcEmRMnmC-fBuhbexh1NI5oVDbPTa6gWbEuuZxVtBHsimR3S7tk3CvU/s1600/Screen+shot+2014-03-10+at+7.21.47+AM.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjnVtN_u_R2fKd4LPVTp0ZUWy70zI1I8Zac8xXBQsPU0iAzEmXR5-ApRCp0P-kvJw9lsdcIFnYBih3DiIcHMBqLLlcEmRMnmC-fBuhbexh1NI5oVDbPTa6gWbEuuZxVtBHsimR3S7tk3CvU/s1600/Screen+shot+2014-03-10+at+7.21.47+AM.png" height="593" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">GermlineExposures.org</td></tr>
</tbody></table>
<br />Unknownnoreply@blogger.com9tag:blogger.com,1999:blog-471663631306140712.post-2337238236160001042013-12-15T18:31:00.001-08:002014-01-01T15:08:30.233-08:00Prenatal Drug Use in the 60s, Two Snapshots<div class="separator" style="clear: both; text-align: left;">
How pervasive was pregnancy drug use in the 1960s? We can look at two cohorts, the CHDS (Child Health and Development Study) and the Collaborative Perinatal Project to get a sense of this vast history. The top chart shows CHDS drug use throughout pregnancy, and the bottom two refer to drug CHDS and CPP drug use in roughly the first half of pregnancy.</div>
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Use of anti-nausea drugs, sedatives, hormones, painkillers and amphetamines were all common. Which of these abnormal exposures entered the womb and fetal tissue? All of them. Which of these affected fetal development? Most of them, though sometimes very subtly. Which of them affected fetal germline? Well, we hope to find out.</div>
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<br />Unknownnoreply@blogger.com22tag:blogger.com,1999:blog-471663631306140712.post-15117469097727984102013-12-12T18:26:00.004-08:002013-12-13T07:37:25.368-08:00On the Almost Two-Year Anniversary of the Germline Disruption Hypothesis of AutismNearly two years ago I sent the following email to a large group of researchers and autism leaders (including Tom Insel at NIMH, Autism Speaks, and noted scientists from UCLA to Texas to Hopkins) outlining for the first time the germline disruption hypothesis of autism.<br />
<br />
So much has happened since that time to confirm my suspicions — meeting many other autism parents with circa 1960s prenatal drug exposures just like mine, studies of multigenerational effects of endocrine disruptors and hypomethylation in animal models, findings of various multigenerational effects in human cohort studies, recognition of epigenetic involvement in some neurodevelopmental impairments, findings regarding <i>de novo</i> alterations in germline in autism, increasing recognition of gene-environment interaction in autism, to name a few — and as we head into the holiday season let us hope for a 2014 filled with long-overdue public awareness about this most urgent issue.<br />
<br />
Jill Escher<br />
----------------------------------------------------------- <br />
<br />
<b>Epigenetic Transgenerational Inheritance: How Old Pharmaceuticals May Be Contributing to the <span class="il">Autism</span> Epidemic Today</b><br />
<br />
<i><span class="il">Summary</span> Document, January 20, 2012</i><br />
<br />
<b><span class="il">Hypothesis</span></b><br />
<br />
That the increasing rate of ASDs stems in part from epigenetic disturbance of fetal germ cells caused by <i>in-utero </i>exposures
to various pharmaceuticals, including synthetic steroid hormones, used
in obstetric practice from roughly the 1950s to 1980s. In other words,
that gestating women given certain pharmaceutical drugs in roughly the
first half of pregnancy (likely window is weeks 6-18 of gestation) are
more likely to have neurologically impaired grandchildren, through the
action of epigenomic alterations of fetal germ cells.<br />
<br />
<b>Background</b><br />
<br />
From the 1950s through 1970s, and even
before, it was common in obstetric practice to prescribe various
pharmaceuticals to pregnant women, even in the first trimester. The
drugs included, among other things, hormone-like compounds,
barbiturates, and morning-sickness medications.<br />
<br />
In the post-war period chemists began synthesizing various
progesterone-like compounds. Based on theory that these compounds could
help prevent miscarriage or preterm birth, some obstetricians and early
fertility clinics began administering synthetic progestins to pregnant
women deemed to have at-risk pregnancies. Commonly, the patients had
suffered prior miscarriages or had complications such as bleeding. Use
of the compounds was relatively rare in the 1950s, but increased through
the 1960s and 70s, particularly in certain locales with a large
upper-middle class clientele who could afford the then-expensive
fertility treatments, including west Los Angeles and New Jersey, the
sites of cohort studies by Dr. June Reinisch.<br />
<br />
There was no standard practice for use of these compounds, according
to Reinisch, it was more of an art than a science. Some physicians
administered multiple hormones, some used hormones early in pregnancy,
some later. There was no standard dosing.<br />
<br />
Little thought was given to the impact of the various drugs,
including the progestins, on the exposed fetus. The progestins were
chemically similar to progesterone, except for a small “tail” or
“radical” hanging off the end of the molecule. They were not, like DES
(diethylstilbestrol), very chemically different from the natural
counterparts. While the idea of impact on fetal germ cells did come up,
it was thought at the time that the germ cells would be protected from
exogenous chemical exposures.<br />
<br />
Dr. Reinisch and a few others did perform research on
first-generation impact of prenatal exposure to synthetic steroid
hormones. Impacts on brain development were found, though subtle
compared to a neurodevelopmental disorder like <span class="il">autism</span>.
The impacts were primarily on personality traits. See, eg, Reinisch
and Karow,“Prenatal exposure to synthetic progestins and estrogens:
Effects on human development.” <a href="http://www.springerlink.com/content/k0552583r63776h2/" target="_blank">http://www.springerlink.com/<wbr></wbr>content/k0552583r63776h2/</a> and “Prenatal exposure to synthetic progestins increases potential for aggression in humans,” <a href="http://www.sciencemag.org/content/211/4487/1171.abstract?sid=792459ee-eacf-47d5-8dd3-9e5df26b6b85" target="_blank">http://www.sciencemag.org/<wbr></wbr>content/211/4487/1171.<wbr></wbr>abstract?sid=792459ee-eacf-<wbr></wbr>47d5-8dd3-9e5df26b6b85</a>.<br />
<br />
<b>Some of the pharmaceuticals used</b><br />
<br />
According to Prenatal
Exposure to Synthetic Progestins and Estrogens: Effects on Human
Development, Archives of Sexual Behavior, Vol 6, No. 4, 1977, p. 267,
the most common synthetic steroid hormones used in pregnancies deemed
at-risk appear to have been (progestins) Colprosterone, Delalutin,
Deluteval, Norlutin Acetate, Provera, Provest, and (additional
estrogens) Stilbestrol. Full list from that study:<br />
<br />
Progestins <br />
Broxorone (Squibb)<br />
Colprosterone (e)<br />
Deladroxate 110 (Squibb)<br />
Deladroxate 130 (Squibb)<br />
Deladroxate 150 (Squibb)<br />
Delalutin 142 (Squibb)<br />
Delaxadrone (Squibb)<br />
Deluteval (b) (Squibb)<br />
Depo-Provera (Upjohn)<br />
MK665(c) (Merck) ethymerone<br />
19NET, Norlutin (Syntex)<br />
Norlutin Acetate (Parke Davis)<br />
Norethynodrel (b) (Searle)<br />
Pranone (Schering)<br />
Provera (Upjohn)<br />
Provest (b) (Upjohn)<br />
RS1280 (c, e) (progestogen)<br />
SC4641 (c) (Searle) 19 NET<br />
SC4642 (c) (Searle) norethynodrel<br />
SC9022 (c) (Searle) methylnortestosterone<br />
SC10230 (c,g) (Searle) <br />
SC11800 (c) (Searle) ethyndiol <br />
1 142.53 (e) aqueous progesterone<br />
Additional estrogens (d)<br />
Allyl Estranol (Organon) <br />
Amestrogen (Squibb) <br />
Delestrogen (Squibb) <br />
Estrone (a)<br />
Hexestrol (e)<br />
Mestranol (e) <br />
Stilbestrol (e) <br />
Other drugs<br />
Thyroid (Armour) <br />
Cytomel (Smith, Klein& French) <br />
Methergine (Sandoz) <br />
Prednisone (McKesson)<br />
Proloid (Wamer-Chilcott) <br />
Sterane (Pfizer) <br />
Synthroid (Flint) <br />
<br />
Notes:<br />
a Many mothers received more than one drug.<br />
b Compounds that have estrogens included.<br />
C Experimental compounds.<br />
d Not including estrogen found in combination with progestin.<br />
e Company not identified.<br />
f Number of pregnancies in which medication was administered (omitted in this list, see article)<br />
g 21-Fluoro-17-hydr oxy-6-methylpregna-4,6-diene-<br />
<div id=":16l">
<wbr></wbr>3,20-dione acetate.<br />
<br />
Other
pharmaceuticals, such as the barbiturates and morning sickness
medications, were also prevalent, however I do not have a list of those
medications at this time.<br />
<br />
<b>The “Hidden History”</b><br />
<br />
Reinisch calls the past use of
these hormone-like pharmaceuticals, as well as the barbiturates and
morning sickness drugs, the “hidden” history for several reasons:<br />
--The records have largely been destroyed<br />
--The women who received the medications often did not know what they were getting<br />
--The women have largely forgotten taking the medications<br />
--The exposed children were never told of their exposure<br />
--The practice was very little studied, and has been forgotten by contemporary researchers and medical practitioners<br />
<br />
<b>Case Study</b><br />
<br />
By the end of 1964 a well-to-do 27 year-old
mother of one son in Los Angeles had suffered two miscarriages and
badly wanted another child. She sought treatment at a pioneering
private fertility clinic in west Los Angeles which was associated with
UCLA. She conceived after being given clomiphene and Pergonal to induce
ovulation. Through at least the first two trimesters, she was then
given regular doses of a synthetic progestin, Deluteval 2x, manufactured
by Squibb, for the ostensible prevention of miscarriage (these
compounds were never actually proven to promote gestation). It appears
Prednisone was also administered at some point. She delivered a healthy
baby girl in September 1965. <br />
<br />
This child now has three children of her own (“grandchildren”), two
of whom have markedly abnormal neurological development (label used is <span class="il">autism</span>).
All genetic tests have been negative, including tests for cnv’s and
microdeletions. All pregnancies and deliveries were normal, and Apgar
scores were high. The families of the grandchildren have no history of
neurological problems or mental illness. There were no unusual
exposures during the pregnancies. In spite of the very evident
neurological dysfunction, the children are robustly healthy and
normal-looking. <br />
<br />
The child born in 1965 also has a younger brother, born in 1968.
He, too, was exposed to exogenous synthetic steroid hormones. He is the
father of two children, one of whom has a mysterious neurological
disorder that is similar to NF1, though apparently not genetic in
origin. The older brother, unexposed to any hormones, has two normal
children. <br />
<br />
Several other <span class="il">autism</span> parents (both mothers and fathers) are also aware of their own in-utero exposures to synthetic steroid hormones: <b>symptoms reported in the offspring include Aspergers, <span class="il">autism</span>, sensory processing disorder, and learning disorders</b>. Many of these second-generation offspring also have no apparent, or very mild, symptoms. <br />
<br />
However, the vast majority of the parents who were exposed have no
idea about their prenatal histories--nearly all records have long ago
been destroyed, and it appears to have been uncommon for a mother to
think of the medication as worth mentioning to her offspring.<br />
<br />
<b>Background Research</b><br />
<br />
It has been postulated that common
pharmaceuticals could have epigenetic side-effects that appear only
years or decades after the exposure. See, eg, Szyf, M “Epigenetic
side-effects of common pharmaceuticals: A potential new field in
medicine and pharmacology.” <a href="http://www.medical-hypotheses.com/article/S0306-9877%2809%2900291-6/abstract" target="_blank">http://www.medical-hypotheses.<wbr></wbr>com/article/S0306-9877%2809%<wbr></wbr>2900291-6/abstract</a><br />
<br />
Researchers such as Michael Skinner, Andrea Gore, Moshe Szyf, and
Joseph Nadeau have looked into transgenerational epigenetic impact of
chemical exposures and have found early evidence for the phenomenon.
See, for example, Nadeau “Transgenerational genetic effects on
phenotypic variation and disease risk,” <a href="http://m.hmg.oxfordjournals.org/content/18/R2/R202.abstract" target="_blank">http://m.hmg.oxfordjournals.<wbr></wbr>org/content/18/R2/R202.<wbr></wbr>abstract</a>, Skinner et al, “Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease,” <a href="http://endo.endojournals.org/content/147/12/5515.short" target="_blank">http://endo.endojournals.org/<wbr></wbr>content/147/12/5515.short</a>, and Skinner, “Role of Epigenetics in Developmental Biology and Transgenerational Inheritance,” <a href="http://onlinelibrary.wiley.com/doi/10.1002/bdrc.20199/full" target="_blank">http://onlinelibrary.wiley.<wbr></wbr>com/doi/10.1002/bdrc.20199/<wbr></wbr>full</a>.<br />
<br />
New studies on endocrine disruptors, some yet unpublished, point to
differing epigenetic impacts on the F2 and F3 generations, likely due to
impact on developing germ cells. (Interviews with Szyf and Gore,
December 2011, and Skinner, January 2012.)<br />
<br />
There is broad agreement, even among traditional geneticists, that
it is biochemically plausible that the synthetic hormones, or their
metabolites, or other prenatal pharmaceuticals, could have had a
deleterious impact on germ cell reprogramming. Various theories were
espoused, including altered methylation patterns and impact on histone
tails during reprogramming. It is agreed that at a minimum, synthetic
steroid hormones would cross the placenta, enter fetal tissues, and
likely bind to receptors in ways that vary from natural, endogenous
steroids. The reasons for epigenetic alterations of germ cells to lead
specifically to a phenotype of abnormal neurodevelopment are unknown.<br />
<br />
Professor Skinner summarizes the core biochemical issue in his
article cited above, “Role of Epigenetics in Developmental Biology and
Transgenerational Inheritance” as follows (emphasis added):<br />
<br />
“<b>[T]he
basic mechanism of epigenetic transgenerational inheritance involves
the actions of an environmental factor (e.g., chemical or nutrition)
during germ line remethylation at gonadal sex determination to
permanently alter the germ line epigenome</b> (Anway et al., 2005;
Guerrero-Bosagna C et al., 2010; Skinner et al., 2010) to then transmit
this altered germ line epigenome to subsequent generations (Anway et
al., 2005; Anway et al., 2006a,b; Anway and Skinner, 2008;
Guerrero-Bosagna C et al., 2010; Skinner et al., 2010). As the embryonic
stem cell epigenome is altered due to this germ line transmission, all
cell populations and tissues will have an altered epigenome and
corresponding transcriptome (Anway et al., 2008; Skinner et al., 2010).
The germ line generated by the next generation will also have this
altered epigenome and transmit it to the subsequent generation
(Guerrero-Bosagna C et al., 2010; Skinner et al., 2010). Exposure to the
endocrine disruptors at other times of development do not appear to
have the capacity to permanently alter the germ line epigenome (Anway et
al., 2005; Anway and Skinner, 2008; Skinner et al., 2010). Of course,
the vast majority of exposures will alter the somatic cells at critical
periods of development to modify later cellular development and
potential adult onset disease, Figure 1, but this does not have the
capacity to become transgenerational as the germ line is not involved
(Skinner et al., 2010). Epigenetic transgenerational inheritance through
a permanently altered epigenome of the germ line has the capacity to
have a dramatic influence on developmental biology, as well as other
areas of biology such as evolution.<br />
<br />
“<b>In the event the base-line epigenome is altered, then the
cascade of epigenetic and genetic steps during development will be
altered and a modified differentiated or developmental state achieved</b>, Figure 1. <b>Therefore,
epigenetic transgenerational inheritance has a dramatic effect on the
developmental biology of all cells and tissues derived from the germ
line transmitting this modified baseline epigenome. Although not all
cell types or tissues will develop a disease state, those tissues that
have a sufficiently altered transcriptome will have a greater
susceptibility to develop disease</b> (Skinner et al., 2010). As all
development and differentiation processes involve a cascade of
epigenetic and genetic steps, alteration of the baseline epigenome,
similar to alteration in the genetic baseline, will have the capacity to
promote abnormal development which may lead to disease later in life.
For this reason, environmentally induced epigenetic transgenerational
inheritance through the germ line will have a significant impact on
developmental biology. This mechanism and consideration of the cascade
of integrated epigenetic and genetic events during development, Figure
1, will be an important factor in disease etiology not previously
considered (Skinner et al., 2010).”<br />
<br />
<b>What this <span class="il">hypothesis</span> might explain</b><br />
<br />
It goes without saying that there are many roads to the various phenotypes we lump together under the label of <span class="il">autism</span>.
Among them: genetic disorders, prenatal and perinatal complications,
prematurity and multiple birth, prenatal exposure to certain pathogens
or chemicals, and seizure disorders. However, it is worth noting that
the pharmaceutical/epigenetic <span class="il">hypothesis</span> is consistent with a great many research findings, as follows:<br />
<br />
--Abnormally high rates of <span class="il">autism</span> in west Los Angeles (the site of early, aggressive fertility and prenatal treatments beginning in the 50s)<br />
--Abnormally high rates of <span class="il">autism</span> in New Jersey (same)<br />
--Rising rates of <span class="il">autism</span>
diagnoses after about 1990 (the time when the early crop of
grandchildren of the growing number of women treated in the 1960s were
entering their preschool years)<br />
--Findings of certain epigenetic signatures in <span class="il">autism</span> brains<br />
--The lack of evidence for a genetic root of most cases of ASD<br />
--Findings implicating very early neurological development in ASDs<br />
--Certain
demographic patterns, eg, why certain religious or ethnic populations
that had little access to or interest in prenatal care have lower <span class="il">autism</span> rates<br />
--The vast heterogeneity of the ASD syndrome<br />
<br />
Some of the
researchers with whom I spoke agreed that pharmaceuticals could be
playing a role, but that other low-level environmental exposures such as
to plastics, endocrine disruptors, stress and hydrocarbons could also
be contributing. I feel the need for an editorial comment here: I
cannot fathom how ubiquitous and low-level exposures like those can
possibly compare to the sometimes huge direct doses of potent (though
forgotten) pharmaceuticals injected directly into our mothers during the
first half of pregnancy. The study of the pharmaceutical impacts
appears to be of much greater urgency.<br />
<br />
<b>Early Initiatives</b><br />
<br />
Various early initiatives have been proposed:<br />
<br />
<u>Epidemiology</u>.
There is broad agreement that epidemiological work should be done.
There exist at least four distinct cohorts of individuals known to have
been exposed to exogenous hormones in utero. It would be important to
do prospective studies (starting with obstetric records of the
grandmothers, and working downward), and not retrospective studies
(starting with autistic kids, and working up the family tree). This is
due to the absence of reliable information of past pharmaceutical use of
the grandmothers. To do meaningful epidemiological work, one would need
not only the basic knowledge of “exposure” but also the identities of
the drugs used, the dosages, and the timing.<br />
<br />
--Denmark (Dr. Reinisch is looking into the possibility of a
second-generation study on this cohort, which is part of the Prenatal
Development Project at Kinsey)<br />
--Finland (Dr. Brown is looking into
the possibility of a second-generation study on this cohort, which had
been identified by E Hemminki as part of a study into the fertility
rates in this cohort)<br />
--Los Angeles (Dr. Reinisch’s detailed files on individuals exposed in
utero to synthetic steroid hormones, in the 1960s and 70s, still exist,
in storage at the Kinsey Institute)<br />
--New Jersey (same as above)<br />
<br />
Quite possibly, with some sleuthing, cohorts exposed<i> in utero</i> to various pharmaceuticals could be found within initiatives at Kaiser and at Johns Hopkins as well.<br />
<br />
Broader epidemiological work, looking at data from several countries
at once, was also suggested. However, the integrity of the data
regarding the F1 (grandmother) pharmaceutical use is in question.<br />
<br />
<u>History</u>.
A few researchers suggested doing a basic history of past obstetric
pharmaceutical use around the world, since it is so poorly understood,
and attempting to make connections to the development of various
diseases, including ASDs, increasing in prevalence today.<br />
<br />
<u>Animal models</u>. A great many researchers suggested
three-generation animal modeling. This way, different compounds and
different timing of exposure could be tested for resulting changes in
behavior, brain morphology, and epigenetic changes.<br />
<br />
<u>Case studies</u>. A few researchers suggested doing direct
epigenetic studies on affected families. However, others cautioned that
such studies would be difficult owing to the complexity involved in
studying the epigenome.<br />
<br />
<b>In <span class="il">summary</span></b><br />
<br />
Long-forgotten pharmaceutical use may be playing a significant role in the <span class="il">autism</span>
epidemic today. If this is the case, there is urgent work to be done
in terms of prevention, family planning, changing fertility and
obstetric medical practice, reducing pharmaceutical use by women of
childbearing age by shifting emphasis to natural treatments of chronic
conditions, ensuring all prenatal medical records remain available and
never discarded, and possibly, finding targeted therapies for the many
disabled individuals suffering from artificially altered epigenomes.
Therefore, expediting research into this <span class="il">hypothesis</span> is critical.</div>
Unknownnoreply@blogger.com5tag:blogger.com,1999:blog-471663631306140712.post-20729922485366102432013-11-24T08:08:00.000-08:002013-12-12T18:09:48.660-08:00Germline Disruption Hypothesis of Autism in the NewsI've had quite a few requests for places people can go for news about the Germline Disruption Hypothesis of Autism. Here are some:<br />
<br />
<div class="post-header">
</div>
J<span style="font-size: small;">uly 2013, Environmental Health News: <b>Onslaught of autism: A mom's crusade could help unravel scientific mystery</b> <a href="http://www.environmentalhealthnews.org/ehs/news/2013/autism-epigenetics">http://www.environmentalhealthnews.org/ehs/news/2013/autism-epigenetics</a><br />
<br />
July 2013, NIH Interagency Autism Coordinating Committee: <b>Autism: Germline Disruption in Personal and Historical Context</b>, <a href="http://www.youtube.com/watch?v=8_0iMnxsKSo">http://www.youtube.com/watch?v=8_0iMnxsKSo</a> (15-minute video) <br />
<br />
</span><br />
<div class="headline">
<span style="font-size: small;"><span style="font-weight: normal;">August 2013, San Francisco Chronicle: <b>Mother's Quest Could Help Solve Autism Mystery</b>, <a href="http://www.sfchronicle.com/health/article/Mother-s-quest-could-help-solve-autism-mystery-4682498.php" target="_blank">http://www.sfchronicle.com/health/article/Mother-s-quest-could-help-solve-autism-mystery-4682498.php </a></span></span>
<span style="font-size: small;"></span><br />
<span style="font-size: small;"><br /></span>
<span style="font-size: small;"><span style="font-weight: normal;">August 2013, Autism Speaks Blog: <b>A Grandmotherly Clue in One Family's Autism Mystery</b>, </span></span>
<span style="font-size: small;"><span style="font-weight: normal;"><a href="http://www.autismspeaks.org/blog/2013/08/27/grandmotherly-clue-one-family%E2%80%99s-autism-mystery">http://www.autismspeaks.org/blog/2013/08/27/grandmotherly-clue-one-family%E2%80%99s-autism-mystery</a></span></span></div>
<span style="font-size: small;">
<br />
September 2013, Pittsburgh Post Gazette: <b>Can Autism Be Triggered in Future Generations? </b><a href="http://www.post-gazette.com/stories/news/health/can-autism-be-triggered-in-future-generations-706678/">http://www.post-gazette.com/stories/news/health/can-autism-be-triggered-in-future-generations-706678/</a></span><br />
<br />
<span style="font-size: small;">Also, many scientific presentations relating to the topic of epigenetics of germline disruption are archived at <a href="http://autismepigenetics.org/">AutismEpigenetics.org</a> </span>Unknownnoreply@blogger.com6tag:blogger.com,1999:blog-471663631306140712.post-19573420816082905662013-10-24T16:49:00.002-07:002013-10-24T16:50:18.137-07:00The FDA Responds to My Petition (by not responding)<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi7bEE0pyU_xCBvDF79B86KbuAty_uKiKvOCdrLWl3jEzr9wAmzX_W7zQmmvt4ovlBo3qvGisdD-bc2q3aPd3sJ-cWoHYo1W270xsc6t-tSXTObS_y5bJ6v-V21gU37uKoXx7cs4hq0veGd/s1600/FDALetterNov2013smaller.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi7bEE0pyU_xCBvDF79B86KbuAty_uKiKvOCdrLWl3jEzr9wAmzX_W7zQmmvt4ovlBo3qvGisdD-bc2q3aPd3sJ-cWoHYo1W270xsc6t-tSXTObS_y5bJ6v-V21gU37uKoXx7cs4hq0veGd/s640/FDALetterNov2013smaller.jpg" width="464" /></a></div>
<br />Unknownnoreply@blogger.com1tag:blogger.com,1999:blog-471663631306140712.post-20198723970075302612013-10-14T19:53:00.002-07:002013-10-14T19:54:55.102-07:00Letter to Ob/Gyn Leader Urging Clinicians to Protect Fetal Germ Cells from Pharmaceutical ExposureJill Escher<br />
Escher Fund for Autism<br />
<br />
Jeanne Conry, MD<br />
American Congress of Obstetricians and Gynecologists<br />
PO Box 70620<br />
Washington, DC 20024-9998<br />
<br />
October 14, 2013<br />
<br />
<b>Re: Urgent request to revise clinical practices to protect fetal germ cells from pharmaceutical exposure</b><br />
<br />
Dear Dr. Conry:<br />
<br />
I am writing with a most unusual request, as I realize it is not altogether common for a mother to advance a wholesale paradigm shift in the practice of obstetrics and gynecology, maternal-fetal medicine, and reproductive endocrinology. But in this case, the stakes are so high, the consequences so catastrophic, and the blind spot so glaring, I feel I have no choice but to speak up, and loudly.<br />
<br />
My appeal is both common-sense and grounded in science: that clinicians working with pregnant women take into consideration risks of pharmaceutical exposures to fetal germ cells, the delicate precursor cells to egg and sperm, before administering or recommending any drug before or during pregnancy. These all-important cells will confer the genetic and epigenetic material from which the following generation (the patients’ grandchildren) will spring. <b>But if these cells, which undergo rapid and environmentally vulnerable synthesis <i>in utero</i>, are genetically or epigenetically(fn) adulterated by exogenous exposures, abnormal development of the grandoffspring may result.</b><br />
<br />
It goes without saying that pregnancy exposure affects three generations simultaneously: the mother, her baby, and the baby’s germ cells. The medical profession has a laudable recent history of concern for the myriad proximal fetal effects of in utero chemical and drug exposure, but for reasons that are difficult to comprehend, thus far such concern has not extended to the fetal proto-gametes, which are arguably the most critical cells within the fetal body. <br />
<br />
Perhaps these third-generation tissues have not garnered the profession’s attention due to a faulty assumption that, short of outright mutagenesis of protein-coding sections of the genome, human germ cells, and the process of early oogenesis and spermatogenesis, are somehow immune to environmental influence. But we know this is not true: during certain windows of susceptibility, particularly the period of epigenetic germline reprogramming that occurs in weeks 6-18, abnormal exposures can exert strong influence on the molecular integrity of the germline. Aside from epimutagenesis, exposures can destabilize protein-coding or non-protein coding regions of the genome, damage DNA repair mechanisms, or provoke atypical transposon activity. Of particular relevance is research demonstrating marked germline effects of endocrine-disrupting substances that disrupt or augment hormone actions, which is not surprising in light of the density of hormone receptors populating the membranes of these precious cells.<br />
<br />
Germline development is a highly conserved, but dynamic and environmentally responsive process chaperoned by hormones, and choreographed with tremendous molecular precision over billions of years of evolution. Small perturbations in epigenetic marking can, for example, lead to imprinting disorders such as Prader-Willi or Angelman’s syndromes. Defects in epigenetic mechanisms are also implicated in Rett Syndrome, for example. Studies in animal models demonstrate that gestational chemicals can wreak multigenerational havoc, resulting in numerous pathologies, including behavioral abnormalities, defects in sexual development and fertility, metabolic disruptions, and cancer. In human epidemiology, we have observed third-generation effects of diethystilbestrol and nutritional stress.<br />
<br />
My interest in this area stems from personal experience. I was born in 1965 after having been exposed in utero to a cocktail of ob/gyn-administered chemicals, including ovulation-inducing drugs and seven months of various synthetic steroid hormones (progestins, glucocorticoids, and estrogens) that were fairly commonly used in the 1960s and intended at the time for the prevention of miscarriage. I know of my drug exposures in detail owing to the miracle of having recently obtained my prenatal medical records from a Los Angeles ob/gyn office where my mother had been a patient. Almost all such records have been destroyed; few of my generation know of their prenatal drug exposures in any detail.<br />
<br />
Ordinarily, such old records would be of little interest, but the concern runs not so much to my somatic cells, though my body and brain were certainly permanently altered by those early exposures. The concern runs to my ova, as my children, who are genetically normal and came from normal, healthy pregnancies with no risk factors, are idiopathically autistic.<br />
<br />
After connecting the dots between my endocrine-disrupting prenatal exposures, likely epigenetic perturbations during early oogenesis, studies showing autism risk genes “hotspots,” abnormal methylation in post-mortem autism brains, and my children’s mysteriously impaired neurodevelopment, I found family after family after family with the same story. In the course of my surveys of autism families, I found that about 30 percent of autistic children were born of parents who suffered substantial prenatal pharmaceutical drug exposures during the heyday of the prenatal pharmaceutical craze of the 1950s, 60s, and 70s. <br />
<br />
Those drug exposures include progestins, synthetic estrogens, glucocorticoids, sedatives (such as phenobarbital), anti-nausea medications, and psychoactive medications. The prevailing false belief in those decades regarding the protective “placental barrier,” combined with the explosion of new and heavily marketed synthetic drugs, <b>led to the unprecedented mass medicating of pregnant women in that era. This meant, of course, that three generations were medicated at once. </b><br />
Only the most vulnerable of those generations was not the mother or the fetus, but the relatively unadorned and unprotected germline; and the molecular-level birth defects to that generation would lay dormant for several decades. It is not a coincidence that the autism epidemic began in the 1980s, or that autism has been shown to be highly “heritable” among siblings, even without any autism in the family ancestry, or that a significant subset of autism appears to involve de novo changes in gene function involving hypermutable long genes on the genome.<br />
<br />
Distressingly, women’s use of medications before and during pregnancy seems to have abated little. Hormone drugs remain widely and intensively used in fertility practice, maternal antidepressant and ADHD drug use is rampant, anti-nausea drugs have drifted back into fashion, and, given the growing incidence of diabetes, PCOS, digestive problems, thyroid disease and hypertension, the use of many other drugs, many of them endocrine disruptors, has also climbed.<br />
<br />
In light of widespread gestational pharmaceutical use and the risks of perpetuating the horror of chemically induced fetal germline disruption, combined with your organization’s mission to promote patients’ and the public health, I ask your organization to please consider the following:<br />
<br />
<b>Publish this letter </b>in the ACOG Newsletter and other publications, both paper and online.<br />
<br />
<b>Support my petition to the FDA. </b>The Escher Fund for Autism has petitioned the FDA to consider potential impacts of prenatal pharmaceuticals on fetal germ cells, and to advise consumers of potential germline risks. In an unfathomable lapse in judgment, scientific understanding, and diligence, the FDA has never before considered fetal germline impacts of pharmaceutical drugs. Please find my petition, and submit comments online, by searching “Escher Fund for Autism FDA Petition.”<br />
<b><br />Warn all pregnant and pre-pregnant patients of potential dangers to fetal germline.</b> Systematically inform women who are pregnant or considering having a child of exposure risks to fetal germline posed by not just prescription pharmaceuticals, but also OTC drugs, smoking, drinking, recreational drugs, pesticides, endocrine disruptors, and poor nutrition. Of greatest concern, however, are the acute drug and pharmaceutical exposures.<br />
<br />
<b>Support full disclosure to exposed individuals. </b> Support a national policy requiring that all children born of medicated pregnancies, including all children resulting from fertility treatments, be advised in writing of their specific exposures, including timing, doses and identity of all drugs and manipulations used, and that these F1 offspring be counseled regarding the heightened risk of bearing F2 children with developmental impairments.<br />
<b><br />Support a policy requiring retention of all prenatal medical records indefinitely.</b> Because prenatal exposures can have lifelong health consequences, in addition to germline consequences, we must ensure that all prenatal medical records are kept in electronic media that can be accessed by all three generations directly exposed to the drugs.<br />
<b><br />Advocate for biologically conservative, and evolutionarily compatible, clinical practice.</b> Support clinical practice that refrains from prescribing any drug, particularly any drug with hormonal or endocrine-disrupting properties, unless absolutely necessary. For example, advocate for cessation of use of discretionary glucocorticoids, which have already been demonstrated to have adverse germ cell impacts, and minimize use of progesterone and progestins, particularly during weeks 6-18 of gestation when germline synthesis is at its height. Minimize, and attempt to eliminate, use of antidepressant drugs, which have endocrine-disrupting properties. And take extreme care to minimize periconceptional exposures, as that period presents another window of susceptibility to epigenetic derangement.<br />
<br />
<b>Advocate for clinical practice that emphasizes restoration of natural fertility and endogenous hormonal normalcy.</b> School your professionals in the principles of evolutionary medicine and ancestral health so they can expand their clinical toolbox to include reproduction-compatible interventions well beyond genotoxic approaches pharmaceutical companies are pitching. For example, focus on supporting women’s transitions to highly nutritious, low-inflammation diets free of sugar, grains, or processed food, but rich in healthy fats and dietary cholesterol, and dense with micronutrients and natural (not synthetic) folate and other methyl donors. Reduction of endocrine-disrupting compounds, whether natural or synthetic, is also essential. <br />
<br />
While we may be many decades away from fully understanding every mechanism of molecular genetics and epigenetics affected by every prenatal drug and chemical exposure, is beyond debate that xenobiotic in utero exposures can cause errors in germ cells. When in 1961 we perceived that thalidomide was causing horrific birth defects, no one said, “Let’s first ascertain the physiological mechanism before we issue a prudent warning.” Synthetic adulteration of germline, however inadvertent it may have been, represents the greatest medical disaster in history, having spawned a torrent of incapacitating disability among those born within the last three decades, and its catastrophic multigenerational effects will echo through the centuries. We can, however, stem further damage.<br />
<br />
Thank you for your prompt attention to this matter. Please feel free to contact me any time, I am at your disposal.<br />
<br />
Very truly yours,<br />
<br />
/s/<br />
<br />
Jill Escher<br />
<br />
cc: <br />
ACOG board members<br />
<br />
With similar letters to:<br />
Fertility and Sterility, editorial board members<br />
American Society for Reproductive Medicine, board members<br />
Society for Maternal-Fetal Medicine, board members<br />
Society for Reproductive Endocrinology, board members<br />
American Medical Association<br />
Rachel Turow, JD, Food and Drug Administration<br />
Margaret Hamburg, MD, Commissioner of the Food and Drug Administration<br />
<br />
(fn) In the event of unfamiliarity with epigenomics, epigenetic mechanisms refer to the many layers of molecular mechanisms that affect gene expression and regulate genome dynamics. Two of the major categories of epigenetic marks are DNA methylation and histone modifications. <br />
<br />Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-471663631306140712.post-42803203718045035532013-10-10T08:39:00.003-07:002013-10-10T09:14:18.147-07:00The Hidden History that Helped Trigger the Autism Epidemic, a Slide ShowI was invited to speak at two conferences recently, the Environmental Mutagenesis and Genomics Society annual meeting, a confab of top scientists who study how environmental exposures affect our genes, and the annual Morgan Autism Center Conference, an event aimed primarily at parents and teachers.<br />
<br />
I have received a number of requests to post my slides online, so I'll
post the Morgan Center presentation here and try to get to the Mutagenesis presentation soon. My main point at Morgan Center was that autism parents can (and must!) be much more active
participants in autism research, particularly in causation hypothesis hunting.
<b>Given what we now know about the vital importance of ancestral exposures
during windows of germline and fetal vulnerability, and that tens of millions of us had been prenatally exposed to powerfully genotoxic drugs (</b><b><b>I was exposed <i>in utero</i> to synthetic steroid hormone drugs in excess of the equivalent of 20,000 birth control pills!)</b>, our stories are
untapped goldmines of information that I believe will help solve many
mysteries of the horrible autism epidemic. WE JUST NEED TO CONNECT SOME PRETTY DARN OBVIOUS DOTS, PEOPLE!</b> <br />
<br />
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<br />Unknownnoreply@blogger.com5tag:blogger.com,1999:blog-471663631306140712.post-26575766242551558882013-10-08T14:14:00.000-07:002013-10-09T16:40:39.591-07:00The Pittsburgh Post-Gazette Tells My Story<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjZIiTPywZirtjjbtXuCMRUyQ_ABPwLEcgAr72Kpu_yN1TOd8YhFcZXE_c-1uRJI7VwwhHe_BfEh2CROvhx4UyuET5hsLpyEYsqhSVD99pUVQ_ICm-lDhIBzMSjILJIHFswozffR-uikjZ9/s1600/Screen+shot+2013-10-09+at+4.39.25+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="292" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjZIiTPywZirtjjbtXuCMRUyQ_ABPwLEcgAr72Kpu_yN1TOd8YhFcZXE_c-1uRJI7VwwhHe_BfEh2CROvhx4UyuET5hsLpyEYsqhSVD99pUVQ_ICm-lDhIBzMSjILJIHFswozffR-uikjZ9/s320/Screen+shot+2013-10-09+at+4.39.25+PM.png" width="320" /></a></div>
<br />
<a href="http://www.post-gazette.com/stories/news/health/can-autism-be-triggered-in-future-generations-706678/">http://www.post-gazette.com/stories/news/health/can-autism-be-triggered-in-future-generations-706678/</a><br />
<br />
Many thanks to science writer Mark Roth for his article today, "Can autism be triggered in future generations?" He opens with a brief description of my story and hypothesis and then delves into some of the new thinking about environmental exposures and germline epigenetics.<br />
<br />
The accompanying article features a family with multiple kids with ASD. That mom, like me, had been exposed <i>in utero</i> to "fertility" hormone drugs. Coincidence? Oh, I certainly do not think so.<br />
<br />
<a href="http://www.post-gazette.com/stories/news/health/one-family-four-children-two-forms-of-autism-706693/" target="_blank">http://www.post-gazette.com/stories/news/health/one-family-four-children-two-forms-of-autism-706693/ </a><br />
<br />
And did I mention that the last two autism moms I had coffee with both had similar prenatal exposures in the 1960s?<br />
<br />
Surely... just... one... giant... coincidence!Unknownnoreply@blogger.com1tag:blogger.com,1999:blog-471663631306140712.post-22268555319233470822013-08-28T16:58:00.005-07:002013-08-28T16:58:47.048-07:00The Escher Fund for Autism (A quickie post here about our charitable fund; in an effort to consolidate our ever-increasing number of websites and blogs, we are closing the Escher Fund website. For archival purposes, here's the info.)<br />
<br />
The Escher Fund for Autism funds cutting-edge autism research,
enrichment programs for children and adults, and efforts to increase
housing and programming for the skyrocketing population of adults with
autism. We regret that we do not accept grant applications or
solicitations.<br />
<br />
<u><b><i>Current areas of interest include:</i></b></u><br />
<br />
<span style="color: blue;"><b>Epidemiology</b></span>: Human studies to evaluate epigenetic germline effects of prenatal pharmaceuticals and smoking.<br />
<br />
<span style="color: blue;"><b>Germline protection</b></span>:
Efforts to enlighten the public, the medical profession, and regulatory
bodies, particularly the FDA, about the urgency of considering impacts
of prenatal pharmaceuticals and chemical exposures on the human
germline, the “weakest link” in the chain of life.<br />
<br />
<span style="color: blue;"><b>Symposia and conferences</b></span>:
Sponsorship of and appearances at meetings regarding the connection
between environmental epigenetics and abnormal neurodevelopment,
including autism.<br />
<br />
<span style="color: blue;"><b>Medical history</b></span>:
Research on one of the most toxic, but relatively unknown, events in
human history: the mass use of novel synthetic prenatal pharmaceuticals,
1950s-70s.<br />
<br />
<span style="color: blue;"><b>Medical record</b>s</span>: Efforts to allow all Americans full access to their prenatal exposure records.<br />
<span style="color: blue;"><br /></span>
<span style="color: blue;"><b>Laboratory studies</b></span>: Efforts to evaluate effects of drugs and chemicals on human germ cells.<br />
<span style="color: blue;"><br /></span>
<span style="color: blue;"><b>Housing and day programs</b></span>: Facilitating the creation of new housing opportunities and day programs for adults with autism.<br />
<br />
<br />
<b><i><u>In the media and online</u></i>: </b><br />
<br />
<span style="color: #666666;"><a href="http://www.environmentalhealthnews.org/ehs/news/2013/autism-epigenetics"><b>Onslaught of autism: A mom's crusade could help unravel scientific mystery</b></a>,</span> by Jane Kay, Environmental Health News, July 2013<br />
<br />
<span style="color: red;"><b><a href="http://prenatalexposures.blogspot.com/2013/07/we-must-be-much-better-caretakers-of.html">Mother's Quest Could Help Solve Autism Mystery</a></b></span>, San Francisco Chronicle, July 2013<br />
<br />
<span style="color: red;"><a href="http://www.youtube.com/watch?v=8_0iMnxsKSo"><b>Autism: Germline Disruption in Historical and Personal Context</b></a></span>, Presentation at the National Institutes of Health, Interagency Autism Coordinating Committee (15 minute video), July 9, 2013<br />
<br />
<span style="color: red;"><b><a href="http://www.autismspeaks.org/blog/2013/08/27/grandmotherly-clue-one-family%E2%80%99s-autism-mystery">A Grandmotherly Clue in One Family's Autism Mystery</a></b></span>, Autism Speaks Guest Blog, August 27, 2013 <br />
<br />
<span style="color: red;"><a href="http://autismepigenetics.org/"><b>Environmental Epigenetics: New Frontiers in Autism Research</b></a></span> symposium, sponsored by Autism Speaks, UC Davis MIND Institute, and Escher Fund for Autism, March 22-23, 2013<br />
<a href="http://www.regulations.gov/#%21documentDetail;D=FDA-2013-P-0522-0001"><br /></a>
<span style="color: red;"><a href="http://www.regulations.gov/#%21documentDetail;D=FDA-2013-P-0522-0001"><b>Escher Fund for Autism Citizen Petition to the FDA</b></a></span> requesting public disclosure of potential risks of prenatal drugs on fetal germ cells. <a href="http://www.regulations.gov/#%21documentDetail;D=FDA-2013-P-0522-0001">www.regulations.gov/#!documentDetail;D=FDA-2013-P-0522-0001</a><br />
<br />
“<span style="color: red;"><a href="http://prenatalexposures.blogspot.com/"><b>Prenatal Exposures Never Die</b></a></span>” Blog<br />
<br />
<br />
<a href="mailto:autismhormoneproject@gmail.com">Email: autismhormoneproject@gmail.com</a>.Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-471663631306140712.post-16956505185730020652013-07-25T10:06:00.000-07:002013-07-25T18:37:11.554-07:00"We must be much better caretakers of our genetic legacy"<h2 class="headline">
<span style="font-weight: normal;"><span style="font-size: small;">From the SF Chronicle yesterday. A shorter version of the story that appeared in Environmental Health News earlier this month.</span></span></h2>
<h2 class="headline">
<span style="font-weight: normal;"><span style="font-size: small;">--Jill Escher</span></span></h2>
<h2 class="headline">
-------------------------------------------<span style="font-weight: normal;"><span style="font-size: x-small;"> </span></span></h2>
<h2 class="headline">
<span style="font-weight: normal;"><span style="font-size: x-small;">http://www.sfchronicle.com/health/article/Mother-s-quest-could-help-solve-autism-mystery-4682498.php </span></span></h2>
<h2 class="headline">
Mother's quest could help solve autism mystery</h2>
<div class="wide-only">
<div class="byline">
Jane Kay</div>
<div class="timestamp">
8:23 AM</div>
</div>
<div class="img-wrap featured-photo p-feature ">
<div class="portrait-image">
<img height="200" src="http://ww4.hdnux.com/photos/22/67/55/4946771/3/rawImage.jpg" width="133" />
<br />
<div class="photo-cred">
<span style="font-size: xx-small;">Katy Raddatz, Katy Raddatz/Environmental Health</span></div>
<div class="photo-caption">
<i>Two of Jill Escher's three children are autistic, despite the low chances.</i><br />
<br /></div>
</div>
</div>
Jill Escher, a dark-haired dynamo
of smarts and stamina, was gently stopping her son, Jonny, 14, from
ripping up the mail. He had just emptied spice bottles on the table to
make finger paints.<br />
Upstairs, Escher's daughter,
Sophie, 7, was sending out incomprehensible cries. It could mean that
Sophie had opened a box of crayons, eaten some and rubbed the rest into
the carpet, or smeared a tube of toothpaste on the mirror. And while
Escher tried to calm Sophie, Jonny could be tossing his iPad over the
fence, tearing all the ivories off the piano, chewing the furniture or
wandering out into traffic.<br />
<br />
<div class="ad">
<div class="ad-inner" id="adMiddle">
</div>
</div>
For Escher, the anguish of
autism is doubled. Both Jonny and Sophie have been diagnosed with
autism, the fast-growing category of neurological disease afflicting 1
in every 88 U.S. children. The Escher children's intellectual
development is stalled at an early preschool level, and they need
constant care and protection.<br />
<br />
For years, Escher and her
husband worried about what could have gone wrong. Why would two of their
three children wind up autistic, defying the odds? Was it their genes?
Their environment? The San Jose couple tried to hunt down any health
problems in their lineage but found none. According to the Centers for
Disease Control and Prevention, parents who have a child with autism
have only a 2 to 18 percent chance of having a second autistic child.<br />
<br />
New studies appear with regularity, suggesting causes but offering no definitive answers for Escher.<br />
"To be perfectly honest, I
had given up trying to find out. I felt I would die never knowing what
happened to my children. No one could tell me," Escher said.<br />
<br />
<h3 class="subhead">
An idea is sparked</h3>
<h3 class="subhead">
</h3>
But
three years ago, Jill Escher had an epiphany, one that now subsumes her
waking hours and nighttime dreams. After prodding her mother for clues
from her past, Escher discovered some hidden history: Her mother had
sought help conceiving at a fertility clinic. As she grew in her
mother's womb, Escher was bombarded with synthetic hormones and other
drugs.<br />
<br />
Now Escher's dogged quest to
unravel why this happened to her children has drawn the attention of
scientists and may ultimately lead to a greater understanding of how
prescription drugs, and perhaps chemicals in the environment, may
secretly and subtly harm the health of generations to come.<br />
<br />
"The autism explosion has
been with us for more than two decades, and we have little to show about
what's causing it," Escher said. "We have many hundreds of thousands of
functionally disabled people who didn't exist before, and we have our
heads in the sand."<br />
<br />
<div class="img-wrap supporting-photo">
<img height="228" src="http://ww3.hdnux.com/photos/22/67/55/4946770/3/rawImage.jpg" width="320" />
<br />
<div class="photo-cred">
<span style="font-size: xx-small;">Katy Raddatz, Katy Raddatz/Environmental Health</span></div>
<div class="photo-caption">
<i>Jill Escher, who has a law degree, educated herself enough about autism to discuss research with experts.</i><br />
<br /></div>
</div>
Scientists know that some chemicals can alter developing embryos and fetuses, which can lead to disease later in life.<br />
<br />
But in recent years, they've
learned that the damage doesn't necessarily stop there. Something a
pregnant woman is exposed to may alter not just her children but also
her grandchildren and perhaps all subsequent generations.<br />
<br />
This is how the "germ line"
hypothesis works: Cells in what is called a germ line form eggs in the
female fetus and precursors to sperm in the male fetus. The germ line
establishes an unbroken link from generation to generation. But when a
pregnant woman is exposed to chemicals, the germ line may be altered.
That would mean that eggs developing in the fetus, the future third
generation, could be changed, leading to abnormalities or disease.<br />
<br />
<h3 class="subhead">
Pregnancy drug</h3>
<h3 class="subhead">
</h3>
The
power of pharmaceuticals to do just that came to light with a synthetic
estrogen called DES, or diethylstilbestrol, which was prescribed to up
to 10 million pregnant women from 1938 to 1971 in an effort to prevent
miscarriage and premature birth. DES daughters, exposed in the womb, are
at an increased risk for cancer of the vagina and cervix and other
reproductive disorders. Startling scientists, DES granddaughters turned
up with an increased incidence of reproductive abnormalities.<br />
These findings were
profound: A single exposure in the womb could induce defects that could
be transmitted to the next two generations.<br />
<br />
Now health experts probing
autism wonder: Could this be a clue? Could a pregnant woman's exposure
to something alter the brains of her grandchildren?<br />
<br />
"Twenty years ago,
the view in the field was that autism was totally a genetic disorder,
and if you could figure out which genes were involved, then you would
understand the cause of autism. Now we've gotten to the point where
we're saying environmental factors have just as much influence as
genetics," said neuroscientist David Amaral, research director at UC
Davis Mind Institute.<br />
With no scientific training,
Escher, 47, who has a law degree, has educated herself enough to
discuss new research with Amaral and other autism experts.<br />
<br />
"I was listening to a
podcast," Escher said, "and a health guru explained that a pregnant
woman's nutrition affects not only her fetus but also her grandchildren
because of exposure of the germ cells. I heard her say, 'A girl is born
with all her eggs.' "<br />
<br />
She was stunned. "Something's happened to my eggs," she thought.<br />
<br />
<h3 class="subhead">
Generational link</h3>
<h3 class="subhead">
</h3>
Millions
and millions of women who are now grandmothers took heavy doses of
drugs during their pregnancies in the '50s and '60s. Escher wondered:
Could the fertility, nausea and miscarriage drugs heavily prescribed in
the past decades alter the fetus and lead to lasting, transgenerational
abnormalities such as autism?<br />
<br />
One of the first scientists
she contacted was Michael Skinner at Washington State University.
Skinner laid out the shift in thinking that is setting off waves of
disagreement among geneticists. Scientists long believed that only
alterations in the DNA sequence could be passed on to subsequent
generations. Now there is evidence that the way in which normal genes
are expressed, or turned on and off, can be passed on, too. This is
called epigenetic inheritance.<br />
<br />
Many diseases have increased
faster than can be explained from normal genetic mechanisms. The
epigenetic phenomenon could be a reason.<br />
<br />
"If environmental factors influence gene expression, the risk of someone having autism could increase," Amaral said.<br />
<br />
One large study, published
earlier this year, reported that children of women who took valproate,
prescribed for epilepsy and psychiatric disorders, had a significantly
higher risk of autism spectrum disorders than other children.<br />
<br />
"There are many pieces of
information learned from more than a decade of study that need to be
connected before any conclusion can be made about autism," said Andrea
Gore, professor of pharmacology and toxicology at the University of
Texas at Austin.<br />
<br />
"We think most behavioral
disorders are a combination of genetic predisposition, natural
differences in reproductive hormones and differences in environmental
exposures."<br />
<br />
<h3 class="subhead">
Taking action</h3>
<h3 class="subhead">
</h3>
Two
months ago, Escher petitioned the FDA seeking revocation of Diclegis,
approved this year as the first antinausea drug for pregnant women,
until it is tested for effects on the fetus' developing germ cells. Her
cause is supported by some scientists.<br />
<br />
A representative of
Duchesnay Inc. said the Canadian pharmaceutical company worked with the
Food and Drug Administration in evaluating Diclegis. The drug has not
shown an increased risk to the fetus during pregnancy, according to an
e-mailed statement.<br />
<br />
FDA spokeswoman Andrea
Fischer said, "the science of epigenetics is new. ... As with all
emerging science, the FDA will review data and consider its potential
for impact on regulatory decisions." She said the agency is reviewing
Escher's petition.<br />
<br />
As for her own inspiration,
Escher said, "I love my kids. But I don't want this to happen to anyone
else. It's too hard. It's too damaging.<br />
<br />
"We have unwittingly
experienced this mass disruption in evolution. It has to stop. We have
to be much better caretakers of our genetic legacy."<br />
<br />
<br />
<div class="infobox">
</div>
<div class="dtlcomment">
Jane Kay is a writer for Environmental Health News. For a longer version of this story, go to <a href="http://bit.ly/15fjVMq">http://bit.ly/15fjVMq</a>.</div>
Unknownnoreply@blogger.com4tag:blogger.com,1999:blog-471663631306140712.post-19472178360438915222013-07-23T12:33:00.004-07:002013-07-25T18:24:46.102-07:00 Autism: Germline Disruption in Historical and Personal Context I had the privilege of sharing the podium with Autism Speaks' Dr. Alycia Halladay at the recent Interagency Autism Coordinating Committee (IACC) meeting at the NIH July 9, 2013, discussing our March 22-23, 2013 <a href="http://autismepigenetics.org/" target="_blank">symposium on the environmental epigenetics of autism</a>, held at the UC Davis MIND Institute.<br />
<br />
The presentation is 15 minutes and covers the history of germline-disrupting exposures, the emerging and established science raising red flags about the multigenerational effects of these exposures, including neurodevelopmental effects, and my own shocking story.<br />
<br />
Watch it here:<a href="https://www.youtube.com/watch?v=8_0iMnxsKSo"> https://www.youtube.com/watch?v=8_0iMnxsKSo</a><br />
<br />
<br />Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-471663631306140712.post-6287527284096292462013-07-20T08:46:00.000-07:002013-07-25T18:22:31.456-07:00 Onslaught of autism: A mom's crusade could help unravel scientific mystery <a href="http://www.environmentalhealthnews.org/ehs/news/2013/autism-epigenetics">http://www.environmentalhealthnews.org/ehs/news/2013/autism-epigenetics</a><br />
<i><br /></i>
<i>Editor's note: Early this week, Environmental Health News published a story about one mom's crusade (oh, that would be me) to unravel the mystery of her beautiful children's incapacitating neurodevelopmental disabilities. Here's the story, or see the link above. </i><br />
<br />
<i>Thanks to EHN for bravely sleuthing about my sleuthing. Every day I continue to be astonished at how ignorant the research and regulatory communities are about the concept of germline disruption. When I tell people I was exposed in utero to 90 times the amount of synthetic hormones found in a year's worth of birth control pills, that my eggs developed in utero, that hormones alter gene expression (epigenetics), and that brain development is strongly epigenetically controlled, at least some of them pause to think about how we might connect the dots.</i><br />
<i><br /></i>
<i>Worse, I was just one of countless tens of millions exposed to heavy doses of drugs in utero. I just happen to be the one who found the records.</i><br />
<br />
<h1 class="documentFirstHeading">
<span class="" id="parent-fieldname-title">
Onslaught of autism: A mom's crusa<span class="highlightedSearchTerm">d</span>e coul<span class="highlightedSearchTerm">d</span> help unravel scientific mystery
</span>
</h1>
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Jill Escher’s <span class="highlightedSearchTerm">d</span>ogge<span class="highlightedSearchTerm">d</span> quest to unravel why two of her chil<span class="highlightedSearchTerm">d</span>ren are autistic has <span class="highlightedSearchTerm">d</span>rawn the attention of scientists, an<span class="highlightedSearchTerm">d</span> may ultimately lea<span class="highlightedSearchTerm">d</span> to a greater un<span class="highlightedSearchTerm">d</span>erstan<span class="highlightedSearchTerm">d</span>ing of how prescription <span class="highlightedSearchTerm">d</span>rugs – an<span class="highlightedSearchTerm">d</span> perhaps chemicals in the environment – may secretly an<span class="highlightedSearchTerm">d</span> subtly harm the health of generations to come.
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<table class="FCKimagetableC" style="width: 100%px;"> <tbody>
<tr> <td style="text-align: center;"><img alt="" height="66" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/autismtop2.jpg" width="200" /></td> <td style="text-align: center;"></td> </tr>
<tr> <td class="FCKcredit" width="575"><a href="http://www.flickr.com/photos/wactout81/4846821544/"><span style="color: #999999; font-size: 75%;">Lance Neilson/flickr</span></a> </td> </tr>
<tr> <td class="FCKcaption"><span style="color: #555555; font-size: 85%;">One in every 88 ki<span class="highlightedSearchTerm">d</span>s in the Unite<span class="highlightedSearchTerm">d</span> States is <span class="highlightedSearchTerm">d</span>iagnose<span class="highlightedSearchTerm">d</span> with autism, a neurological <span class="highlightedSearchTerm">d</span>isease with unknown causes.<br /> </span></td> </tr>
</tbody> </table>
<br />
Jane Kay<br />
Environmental Health News<br />
July 16, 2013<br />
SAN JOSE, Calif. – Jill Escher, a <span class="highlightedSearchTerm">d</span>ark-haire<span class="highlightedSearchTerm">d</span> <span class="highlightedSearchTerm">d</span>ynamo of smarts an<span class="highlightedSearchTerm">d</span> stamina, was gently stopping her son, Jonny, 14, from ripping up the mail. He ha<span class="highlightedSearchTerm">d</span> just emptie<span class="highlightedSearchTerm">d</span> spice bottles on the table to make finger paints.<br />
Upstairs, her <span class="highlightedSearchTerm">d</span>aughter, Sophie, 7, was sen<span class="highlightedSearchTerm">d</span>ing out incomprehensible cries. It coul<span class="highlightedSearchTerm">d</span> mean that Sophie ha<span class="highlightedSearchTerm">d</span> opene<span class="highlightedSearchTerm">d</span> a box of crayons, eaten some an<span class="highlightedSearchTerm">d</span> rubbe<span class="highlightedSearchTerm">d</span> the rest into the carpet, or smeare<span class="highlightedSearchTerm">d</span> a tube of toothpaste on the mirror. An<span class="highlightedSearchTerm">d</span> while Escher trie<span class="highlightedSearchTerm">d</span> to calm Sophie, Jonny coul<span class="highlightedSearchTerm">d</span> be tossing his iPa<span class="highlightedSearchTerm">d</span> over the fence, tearing all the ivories off the piano, chewing the furniture, or wan<span class="highlightedSearchTerm">d</span>ering out into traffic.<br />
<table class="FCKimagetableR" style="float: right; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" height="317" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/jillescher.jpg" width="375" /></td> </tr>
<tr> <td class="FCKcredit"><span style="color: #999999; font-size: 75%;">Katy Ra<span class="highlightedSearchTerm">d</span><span class="highlightedSearchTerm">d</span>atz</span></td> </tr>
<tr> <td class="FCKcaption"><span style="color: #555555; font-size: 85%;">Jill Escher meets with Bra<span class="highlightedSearchTerm">d</span> Boar<span class="highlightedSearchTerm">d</span>man, executive <span class="highlightedSearchTerm">d</span>irector of the Morgan Autism Center, to <span class="highlightedSearchTerm">d</span>iscuss a grant from Escher's foun<span class="highlightedSearchTerm">d</span>ation.</span></td> </tr>
</tbody> </table>
For Escher, the anguish of autism is <span class="highlightedSearchTerm">d</span>ouble<span class="highlightedSearchTerm">d</span>. Both Jonny an<span class="highlightedSearchTerm">d</span> Sophie have been <span class="highlightedSearchTerm">d</span>iagnose<span class="highlightedSearchTerm">d</span> with autism, the fast-growing category of neurological <span class="highlightedSearchTerm">d</span>isease afflicting <a href="http://www.cdc.gov/features/countingautism/">one in every 88</a> U.S. chil<span class="highlightedSearchTerm">d</span>ren. The Escher chil<span class="highlightedSearchTerm">d</span>ren's intellectual <span class="highlightedSearchTerm">d</span>evelopment is stalle<span class="highlightedSearchTerm">d</span> at an early pre-school level, an<span class="highlightedSearchTerm">d</span> they nee<span class="highlightedSearchTerm">d</span> constant care an<span class="highlightedSearchTerm">d</span> protection.<br />
For years, Escher an<span class="highlightedSearchTerm">d</span> her husban<span class="highlightedSearchTerm">d</span>, Christopher, worrie<span class="highlightedSearchTerm">d</span> about what coul<span class="highlightedSearchTerm">d</span> have gone wrong. Why woul<span class="highlightedSearchTerm">d</span> two of their three chil<span class="highlightedSearchTerm">d</span>ren win<span class="highlightedSearchTerm">d</span> up autistic, <span class="highlightedSearchTerm">d</span>efying the o<span class="highlightedSearchTerm">d</span><span class="highlightedSearchTerm">d</span>s? Was it their genes? Their environment? Their foo<span class="highlightedSearchTerm">d</span>? The couple trie<span class="highlightedSearchTerm">d</span> to hunt <span class="highlightedSearchTerm">d</span>own any health problems in their lineage but foun<span class="highlightedSearchTerm">d</span> none. A glass of wine while pregnant? Paint fumes? Pollution from freeways?<br />
New stu<span class="highlightedSearchTerm">d</span>ies appear with regularity, suggesting causes but offering no <span class="highlightedSearchTerm">d</span>efinitive answers.<br />
“To be perfectly honest, I ha<span class="highlightedSearchTerm">d</span> given up trying to fin<span class="highlightedSearchTerm">d</span> out. I felt I woul<span class="highlightedSearchTerm">d</span> <span class="highlightedSearchTerm">d</span>ie never knowing what happene<span class="highlightedSearchTerm">d</span> to my chil<span class="highlightedSearchTerm">d</span>ren. No one coul<span class="highlightedSearchTerm">d</span> tell me,” Escher sai<span class="highlightedSearchTerm">d</span>.<br />
But three years ago, Jill Escher ha<span class="highlightedSearchTerm">d</span> an epiphany, one that now subsumes her waking hours an<span class="highlightedSearchTerm">d</span> nighttime <span class="highlightedSearchTerm">d</span>reams. After pro<span class="highlightedSearchTerm">d</span><span class="highlightedSearchTerm">d</span>ing her mother for clues from her past, Escher <span class="highlightedSearchTerm">d</span>iscovere<span class="highlightedSearchTerm">d</span> some hi<span class="highlightedSearchTerm">d</span><span class="highlightedSearchTerm">d</span>en history: Her mother ha<span class="highlightedSearchTerm">d</span> sought help conceiving at a fertility clinic. As she grew in her mother's womb, Escher was bombar<span class="highlightedSearchTerm">d</span>e<span class="highlightedSearchTerm">d</span> with synthetic hormones an<span class="highlightedSearchTerm">d</span> other <span class="highlightedSearchTerm">d</span>rugs.<br />
Now Escher’s <span class="highlightedSearchTerm">d</span>ogge<span class="highlightedSearchTerm">d</span> quest to unravel why this happene<span class="highlightedSearchTerm">d</span> to her chil<span class="highlightedSearchTerm">d</span>ren has <span class="highlightedSearchTerm">d</span>rawn the attention of scientists, an<span class="highlightedSearchTerm">d</span> may ultimately lea<span class="highlightedSearchTerm">d</span> to a greater un<span class="highlightedSearchTerm">d</span>erstan<span class="highlightedSearchTerm">d</span>ing of how prescription <span class="highlightedSearchTerm">d</span>rugs – an<span class="highlightedSearchTerm">d</span> perhaps chemicals in the environment – may secretly an<span class="highlightedSearchTerm">d</span> subtly harm the health of generations to come.<br />
“The autism explosion has been with us for more than two <span class="highlightedSearchTerm">d</span>eca<span class="highlightedSearchTerm">d</span>es, an<span class="highlightedSearchTerm">d</span> we have little to show about what's causing it,” Escher sai<span class="highlightedSearchTerm">d</span>. “We have many hun<span class="highlightedSearchTerm">d</span>re<span class="highlightedSearchTerm">d</span>s of thousan<span class="highlightedSearchTerm">d</span>s of functionally <span class="highlightedSearchTerm">d</span>isable<span class="highlightedSearchTerm">d</span> people who <span class="highlightedSearchTerm">d</span>i<span class="highlightedSearchTerm">d</span>n't exist before, an<span class="highlightedSearchTerm">d</span> we have our hea<span class="highlightedSearchTerm">d</span>s in the san<span class="highlightedSearchTerm">d</span>.”<br />
<span style="font-size: larger;"><b>From generation to generation</b></span><br />
Scientists know that some chemicals can alter <span class="highlightedSearchTerm">d</span>eveloping embryos an<span class="highlightedSearchTerm">d</span> fetuses, which can lea<span class="highlightedSearchTerm">d</span> to <span class="highlightedSearchTerm">d</span>isease later in life.<br />
But in recent years, they've learne<span class="highlightedSearchTerm">d</span> that the <span class="highlightedSearchTerm">d</span>amage <span class="highlightedSearchTerm">d</span>oesn't necessarily stop there. Something a pregnant woman is expose<span class="highlightedSearchTerm">d</span> to may alter not just her chil<span class="highlightedSearchTerm">d</span>ren, but also her gran<span class="highlightedSearchTerm">d</span>chil<span class="highlightedSearchTerm">d</span>ren – an<span class="highlightedSearchTerm">d</span> possibly even subsequent generations.<br />
<table class="FCKimagetableL" style="float: left; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/autism_full.jpg" /></td> </tr>
<tr> <td class="FCKcredit"><a href="http://www.nih.gov/about/discovery/allages/autism.htm"> <span style="color: #999999; font-size: 75%;">National Institutes of Health</span></a></td> </tr>
<tr> <td class="FCKcaption"><span style="color: #555555; font-size: 85%;">Autism affects normal <span class="highlightedSearchTerm">d</span>evelopment of communication an<span class="highlightedSearchTerm">d</span> social skills.<br /> </span></td> </tr>
</tbody> </table>
This is how the "germ line" hypothesis works: Cells in what is calle<span class="highlightedSearchTerm">d</span> a “germ line” form eggs in the female fetus an<span class="highlightedSearchTerm">d</span>
precursors to sperm in the male fetus. The germ line establishes an
unbroken link from generation to generation. But when a pregnant woman
is expose<span class="highlightedSearchTerm">d</span> to chemicals, the germ line may be altere<span class="highlightedSearchTerm">d</span>. That woul<span class="highlightedSearchTerm">d</span> mean that eggs <span class="highlightedSearchTerm">d</span>eveloping in the fetus – the future thir<span class="highlightedSearchTerm">d</span> generation – coul<span class="highlightedSearchTerm">d</span> be change<span class="highlightedSearchTerm">d</span>, lea<span class="highlightedSearchTerm">d</span>ing to abnormalities or <span class="highlightedSearchTerm">d</span>isease. Also, the <span class="highlightedSearchTerm">d</span>isrupte<span class="highlightedSearchTerm">d</span> programming in how genes are turne<span class="highlightedSearchTerm">d</span> on an<span class="highlightedSearchTerm">d</span> off – the very genes that instruct cell growth an<span class="highlightedSearchTerm">d</span> function – may be passe<span class="highlightedSearchTerm">d</span> on to more <span class="highlightedSearchTerm">d</span>escen<span class="highlightedSearchTerm">d</span>ants.<br />
<span style="border-left-color: rgb(140, 172, 187); border-left-style: solid; border-left-width: 4px; clear: right; color: #057234; float: right; font-weight: bold; line-height: 1.25em; margin: 0px 0px 1em 1em; padding: 0px 1em; width: 29%;"><span style="background-color: white;">“The autism explosion has been with us for more than two <span class="highlightedSearchTerm">d</span>eca<span class="highlightedSearchTerm">d</span>es, an<span class="highlightedSearchTerm">d</span> we have little to show about what's causing it. We have many hun<span class="highlightedSearchTerm">d</span>re<span class="highlightedSearchTerm">d</span>s of thousan<span class="highlightedSearchTerm">d</span>s of functionally <span class="highlightedSearchTerm">d</span>isable<span class="highlightedSearchTerm">d</span> people who <span class="highlightedSearchTerm">d</span>i<span class="highlightedSearchTerm">d</span>n't exist before, an<span class="highlightedSearchTerm">d</span> we have our hea<span class="highlightedSearchTerm">d</span>s in the san<span class="highlightedSearchTerm">d</span>.” </span>–<span style="background-color: white;"><i>Jill Escher</i> </span></span>The power of pharmaceuticals to <span class="highlightedSearchTerm">d</span>o just that came to light with a <a href="http://endo.endojournals.org/content/147/6/s11.long">synthetic estrogen</a> that harme<span class="highlightedSearchTerm">d</span> at least <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874639/">two generations</a> of offspring of women who took it. <span class="highlightedSearchTerm">D</span>ES, or <span class="highlightedSearchTerm">d</span>iethylstilbestrol, was prescribe<span class="highlightedSearchTerm">d</span> to up to 10 million pregnant women in the Unite<span class="highlightedSearchTerm">d</span> States an<span class="highlightedSearchTerm">d</span> the Unite<span class="highlightedSearchTerm">d</span> King<span class="highlightedSearchTerm">d</span>om from 1938 to 1971 in an effort to prevent miscarriage an<span class="highlightedSearchTerm">d</span> premature birth. <span class="highlightedSearchTerm">D</span>ES <span class="highlightedSearchTerm">d</span>aughters, expose<span class="highlightedSearchTerm">d</span> in the womb, are at an increase<span class="highlightedSearchTerm">d</span> risk for a rare form of cancer of the vagina an<span class="highlightedSearchTerm">d</span> cervix an<span class="highlightedSearchTerm">d</span> other repro<span class="highlightedSearchTerm">d</span>uctive <span class="highlightedSearchTerm">d</span>isor<span class="highlightedSearchTerm">d</span>ers, an<span class="highlightedSearchTerm">d</span> the sons have increase<span class="highlightedSearchTerm">d</span> risk for some repro<span class="highlightedSearchTerm">d</span>uctive problems. Startling scientists, <span class="highlightedSearchTerm">D</span>ES gran<span class="highlightedSearchTerm">d</span><span class="highlightedSearchTerm">d</span>aughters turne<span class="highlightedSearchTerm">d</span> up with an increase<span class="highlightedSearchTerm">d</span> inci<span class="highlightedSearchTerm">d</span>ence of urinary an<span class="highlightedSearchTerm">d</span> genital malformations, irregular menstrual cycles an<span class="highlightedSearchTerm">d</span> other abnormalities.<br />
These fin<span class="highlightedSearchTerm">d</span>ings were profoun<span class="highlightedSearchTerm">d</span>: A single exposure of a pregnant woman seeme<span class="highlightedSearchTerm">d</span> to in<span class="highlightedSearchTerm">d</span>uce <span class="highlightedSearchTerm">d</span>efects in her fetus's eggs, triggering health effects in the next generation.<br />
Now health experts probing autism won<span class="highlightedSearchTerm">d</span>er: Coul<span class="highlightedSearchTerm">d</span> this be a clue? Coul<span class="highlightedSearchTerm">d</span> a pregnant woman’s exposure to something alter the brains of her gran<span class="highlightedSearchTerm">d</span>chil<span class="highlightedSearchTerm">d</span>ren?<br />
<span style="font-size: larger;"><b>A personal quest</b></span><br />
When Escher’s first chil<span class="highlightedSearchTerm">d</span>, Evan, was born in 1997, he met his <span class="highlightedSearchTerm">d</span>evelopmental markers. Two years later came Jonathan. “He was really colicky, an<span class="highlightedSearchTerm">d</span> always seeme<span class="highlightedSearchTerm">d</span> to be in some pain that we coul<span class="highlightedSearchTerm">d</span>n't soothe. He woul<span class="highlightedSearchTerm">d</span> sit in the backyar<span class="highlightedSearchTerm">d</span> an<span class="highlightedSearchTerm">d</span> pick up rocks an<span class="highlightedSearchTerm">d</span> <span class="highlightedSearchTerm">d</span>irt,” she sai<span class="highlightedSearchTerm">d</span>.<br />
She saw the ominous signs: no eye contact, no babbling as a baby. The Eschers took him for an assessment. As soon as the <span class="highlightedSearchTerm">d</span>octor walke<span class="highlightedSearchTerm">d</span> into the waiting room, he suspecte<span class="highlightedSearchTerm">d</span> autism.<br />
<span style="border-right-color: rgb(140, 172, 187); border-right-style: solid; border-right-width: 4px; clear: left; color: #057234; float: left; font-weight: bold; line-height: 1.25em; margin-bottom: 1em; margin-right: 1em; padding: 0px 1em; width: 35%;">Jill Escher saw the ominous signs in her son Jonny: no eye contact, no babbling as a baby. As soon as a <span class="highlightedSearchTerm">d</span>octor walke<span class="highlightedSearchTerm">d</span> into the waiting room, he suspecte<span class="highlightedSearchTerm">d</span> autism. Then when Sophie was born seven years later, she showe<span class="highlightedSearchTerm">d</span> similar signs.</span>“Jonny
is a brick. Nothing permeates his skull. He was just impervious to what
we were trying to teach him. He was an affectionate little boy an<span class="highlightedSearchTerm">d</span> remains so to<span class="highlightedSearchTerm">d</span>ay,” Escher sai<span class="highlightedSearchTerm">d</span>.<br />
Then when Sophie was born seven years after Jonathan, she showe<span class="highlightedSearchTerm">d</span> similar signs. She <span class="highlightedSearchTerm">d</span>i<span class="highlightedSearchTerm">d</span>n't play or make eye contact. Her <span class="highlightedSearchTerm">d</span>iagnosis came soon after. Genetic testing reveale<span class="highlightedSearchTerm">d</span> no known abnormalities in either chil<span class="highlightedSearchTerm">d</span>, an<span class="highlightedSearchTerm">d</span> no clinician coul<span class="highlightedSearchTerm">d</span> think of any reason for two chil<span class="highlightedSearchTerm">d</span>ren with such severe <span class="highlightedSearchTerm">d</span>isabilities.<br />
Accor<span class="highlightedSearchTerm">d</span>ing to the Centers for <span class="highlightedSearchTerm">D</span>isease Control an<span class="highlightedSearchTerm">d</span> Prevention, parents who have a chil<span class="highlightedSearchTerm">d</span> with autism have only a 2 to 18 percent chance of having a secon<span class="highlightedSearchTerm">d</span> autistic chil<span class="highlightedSearchTerm">d</span>.<br />
In 2000 an<span class="highlightedSearchTerm">d</span> 2002, <a href="http://www.cdc.gov/features/countingautism/">one in every 150</a> U.S. chil<span class="highlightedSearchTerm">d</span>ren was <span class="highlightedSearchTerm">d</span>iagnose<span class="highlightedSearchTerm">d</span> with autism spectrum <span class="highlightedSearchTerm">d</span>isor<span class="highlightedSearchTerm">d</span>ers, which affect the brain’s normal <span class="highlightedSearchTerm">d</span>evelopment of social an<span class="highlightedSearchTerm">d</span> communication skills. But the rate climbe<span class="highlightedSearchTerm">d</span> to <a href="http://www.cdc.gov/features/countingautism/">one in 88 in 2008</a>, accor<span class="highlightedSearchTerm">d</span>ing to the C<span class="highlightedSearchTerm">D</span>C. Many experts believe the rise is <span class="highlightedSearchTerm">d</span>ue to a combination of a real increase in prevalence plus improve<span class="highlightedSearchTerm">d</span> <span class="highlightedSearchTerm">d</span>iagnoses.<br />
“We <span class="highlightedSearchTerm">d</span>on't know why the numbers are increasing, an<span class="highlightedSearchTerm">d</span> we <span class="highlightedSearchTerm">d</span>on't know which portions of the brain are affecte<span class="highlightedSearchTerm">d</span> when a person has autism,” sai<span class="highlightedSearchTerm">d</span> neuroscientist <span class="highlightedSearchTerm">D</span>avi<span class="highlightedSearchTerm">d</span> Amaral, research <span class="highlightedSearchTerm">d</span>irector at the University of California, <span class="highlightedSearchTerm">D</span>avis, MIN<span class="highlightedSearchTerm">D</span> Institute.<br />
<table class="FCKimagetableR" style="float: right; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" height="326" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/chartpage.jpg" width="300" /></td> </tr>
<tr> <td class="FCKcaption"><span style="color: #555555; font-size: 85%;">Source: Centers for <span class="highlightedSearchTerm">D</span>isease Control an<span class="highlightedSearchTerm">d</span> Prevention</span></td> </tr>
</tbody> </table>
“Twenty years ago, the view in the fiel<span class="highlightedSearchTerm">d</span> was that autism was totally a genetic <span class="highlightedSearchTerm">d</span>isor<span class="highlightedSearchTerm">d</span>er, an<span class="highlightedSearchTerm">d</span> if you coul<span class="highlightedSearchTerm">d</span> figure out which genes were involve<span class="highlightedSearchTerm">d</span>, then you woul<span class="highlightedSearchTerm">d</span> un<span class="highlightedSearchTerm">d</span>erstan<span class="highlightedSearchTerm">d</span>
the cause of autism. Now we've gotten to the point where we're saying
environmental factors have just as much influence as genetics,” he sai<span class="highlightedSearchTerm">d</span>.<br />
With no scientific training, Escher, 47, has e<span class="highlightedSearchTerm">d</span>ucate<span class="highlightedSearchTerm">d</span> herself enough to <span class="highlightedSearchTerm">d</span>iscuss new research with Amaral an<span class="highlightedSearchTerm">d</span> other autism experts. She has a law <span class="highlightedSearchTerm">d</span>egree from the University of California, Berkeley, an<span class="highlightedSearchTerm">d</span> five years' experience as a clerk in the U.S. <span class="highlightedSearchTerm">D</span>istrict Court in San Jose. Five years ago, Escher an<span class="highlightedSearchTerm">d</span> her husban<span class="highlightedSearchTerm">d</span> foun<span class="highlightedSearchTerm">d</span>e<span class="highlightedSearchTerm">d</span> a small family fun<span class="highlightedSearchTerm">d</span> that first finance<span class="highlightedSearchTerm">d</span> school recreational activities for autistic chil<span class="highlightedSearchTerm">d</span>ren, then research into its causes.<br />
To her horror, she learne<span class="highlightedSearchTerm">d</span> that researchers ha<span class="highlightedSearchTerm">d</span> <span class="highlightedSearchTerm">d</span>iscovere<span class="highlightedSearchTerm">d</span> an <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961977-0/fulltext">autism cluster</a> in West Los Angeles, where she grew up. In her search for answers, Escher came across a Tel Aviv University stu<span class="highlightedSearchTerm">d</span>y linking in vitro fertilization with increase<span class="highlightedSearchTerm">d</span> risk of autism.<br />
“That's when it hit me that I might have been a fertility ki<span class="highlightedSearchTerm">d</span>,” she sai<span class="highlightedSearchTerm">d</span>. She remembere<span class="highlightedSearchTerm">d</span> a scrap of information tucke<span class="highlightedSearchTerm">d</span> away. At 13, the cover of Time magazine feature<span class="highlightedSearchTerm">d</span> a test tube to illustrate creating a baby with the ai<span class="highlightedSearchTerm">d</span> of science. Someone – she thinks it was her <span class="highlightedSearchTerm">d</span>a<span class="highlightedSearchTerm">d</span> – sai<span class="highlightedSearchTerm">d</span> to her, “You were just like that baby. You were a miracle chil<span class="highlightedSearchTerm">d</span>. You were wante<span class="highlightedSearchTerm">d</span> very ba<span class="highlightedSearchTerm">d</span>ly.” She wasn’t a test tube baby, but she won<span class="highlightedSearchTerm">d</span>ere<span class="highlightedSearchTerm">d</span> if her mother ha<span class="highlightedSearchTerm">d</span> taken fertility <span class="highlightedSearchTerm">d</span>rugs.<br />
Escher calle<span class="highlightedSearchTerm">d</span> her mother, an<span class="highlightedSearchTerm">d</span> aske<span class="highlightedSearchTerm">d</span>. “They gave me a whole bunch of stuff. I <span class="highlightedSearchTerm">d</span>on't know what it was,” her mother sai<span class="highlightedSearchTerm">d</span>.<br />
At Escher's request, her mother calle<span class="highlightedSearchTerm">d</span> her former obstetrician. Four pages of recor<span class="highlightedSearchTerm">d</span>s, store<span class="highlightedSearchTerm">d</span> on microfilm, were sent to Escher. Scrawle<span class="highlightedSearchTerm">d</span> over the pages was a list of synthetic hormone <span class="highlightedSearchTerm">d</span>rugs that her mother took. Over an<span class="highlightedSearchTerm">d</span> over, she saw steroi<span class="highlightedSearchTerm">d</span> hormones: <span class="highlightedSearchTerm">D</span>eluteval (a progestin with estra<span class="highlightedSearchTerm">d</span>iol) an<span class="highlightedSearchTerm">d</span> pre<span class="highlightedSearchTerm">d</span>nisolone. Escher learne<span class="highlightedSearchTerm">d</span> that her mother ha<span class="highlightedSearchTerm">d</span> gone to a West Los Angeles fertility clinic run by <span class="highlightedSearchTerm">D</span>r. E<span class="highlightedSearchTerm">d</span>war<span class="highlightedSearchTerm">d</span> Tyler, who ha<span class="highlightedSearchTerm">d</span> prescribe<span class="highlightedSearchTerm">d</span> Pergonol an<span class="highlightedSearchTerm">d</span> Clomi<span class="highlightedSearchTerm">d</span> to in<span class="highlightedSearchTerm">d</span>uce ovulation to help her conceive. An<span class="highlightedSearchTerm">d</span> it was Tyler who ha<span class="highlightedSearchTerm">d</span> prescribe<span class="highlightedSearchTerm">d</span> a continuing regimen of hormones an<span class="highlightedSearchTerm">d</span> steroi<span class="highlightedSearchTerm">d</span>s, inclu<span class="highlightedSearchTerm">d</span>ing weekly injections, as a way to prevent miscarriage <span class="highlightedSearchTerm">d</span>uring the pregnancy.<br />
Escher aske<span class="highlightedSearchTerm">d</span> some autism researchers about the fertility <span class="highlightedSearchTerm">d</span>rugs, but got no encouragement, so she set the recor<span class="highlightedSearchTerm">d</span>s asi<span class="highlightedSearchTerm">d</span>e.<br />
But when the sister of a frien<span class="highlightedSearchTerm">d</span> who ha<span class="highlightedSearchTerm">d</span> been expose<span class="highlightedSearchTerm">d</span> to <span class="highlightedSearchTerm">D</span>ES in the womb <span class="highlightedSearchTerm">d</span>ie<span class="highlightedSearchTerm">d</span> of breast cancer, she realize<span class="highlightedSearchTerm">d</span> that the effects of some <span class="highlightedSearchTerm">d</span>rugs coul<span class="highlightedSearchTerm">d</span> last for generations. “<span class="highlightedSearchTerm">D</span>ES was a real eye opener in terms of transgenerational effects of prenatal exposure to <span class="highlightedSearchTerm">d</span>rugs,” she sai<span class="highlightedSearchTerm">d</span>.<br />
<table class="FCKimagetableL" style="float: left; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/skinner.jpg" /></td> </tr>
<tr> <td class="FCKcredit"><a href="http://researchnews.wsu.edu/environment/139.html"> <span style="color: #999999; font-size: 75%;">Washington State University</span></a></td> </tr>
<tr> <td class="FCKcaption"><span style="color: #555555; font-size: 85%;">Michael Skinner is a pioneer in environmental epigenetics.</span></td> </tr>
</tbody> </table>
“I was listening to a po<span class="highlightedSearchTerm">d</span>cast, an<span class="highlightedSearchTerm">d</span> a health guru explaine<span class="highlightedSearchTerm">d</span> that a pregnant woman's nutrition affects not only her fetus but also her gran<span class="highlightedSearchTerm">d</span>chil<span class="highlightedSearchTerm">d</span>ren because of exposure of the germ cells. I hear<span class="highlightedSearchTerm">d</span> her say, 'A girl is born with all her eggs.'”<br />
She was stunne<span class="highlightedSearchTerm">d</span>. “Something's happene<span class="highlightedSearchTerm">d</span> to my eggs,” she thought.<br />
<span style="font-size: larger;"><b>Searching the epigenome for answers<br /> </b></span><br />
Millions an<span class="highlightedSearchTerm">d</span> millions of women who are now gran<span class="highlightedSearchTerm">d</span>mothers took heavy <span class="highlightedSearchTerm">d</span>oses of <span class="highlightedSearchTerm">d</span>rugs <span class="highlightedSearchTerm">d</span>uring their pregnancies in the '50s an<span class="highlightedSearchTerm">d</span> '60s. Escher won<span class="highlightedSearchTerm">d</span>ere<span class="highlightedSearchTerm">d</span>: Coul<span class="highlightedSearchTerm">d</span> the fertility, nausea an<span class="highlightedSearchTerm">d</span> miscarriage <span class="highlightedSearchTerm">d</span>rugs heavily prescribe<span class="highlightedSearchTerm">d</span> in the past <span class="highlightedSearchTerm">d</span>eca<span class="highlightedSearchTerm">d</span>es alter the fetus an<span class="highlightedSearchTerm">d</span> lea<span class="highlightedSearchTerm">d</span> to lasting, transgenerational abnormalities such as autism?<br />
So far, no one has looke<span class="highlightedSearchTerm">d</span>, although one ambitious stu<span class="highlightedSearchTerm">d</span>y is about to be launche<span class="highlightedSearchTerm">d</span> in Europe.<br />
“Right now research looks at environment an<span class="highlightedSearchTerm">d</span> it looks at genetics. But it <span class="highlightedSearchTerm">d</span>oesn't
look at the environmental effects on the germ line. These are critical
questions. So far we're silent on them,” Escher sai<span class="highlightedSearchTerm">d</span>.<br />
Science is very compartmentalize<span class="highlightedSearchTerm">d</span>, she sai<span class="highlightedSearchTerm">d</span>.<br />
“We alrea<span class="highlightedSearchTerm">d</span>y have all the pieces. We just nee<span class="highlightedSearchTerm">d</span> to put them in or<span class="highlightedSearchTerm">d</span>er. But you <span class="highlightedSearchTerm">d</span>on't have one person stringing it all together,” she sai<span class="highlightedSearchTerm">d</span>.<br />
Escher is trying to be the one to <span class="highlightedSearchTerm">d</span>o that.<br />
One of the first scientists she contacte<span class="highlightedSearchTerm">d</span> was Michael Skinner, a professor in the School of Molecular Biosciences at Washington State University.<br />
<span style="border-right-color: rgb(140, 172, 187); border-right-style: solid; border-right-width: 4px; clear: left; color: #057234; float: left; font-weight: bold; line-height: 1.25em; margin-bottom: 1em; margin-right: 1em; padding: 0px 1em; width: 35%;">“The majority of brain <span class="highlightedSearchTerm">d</span>isease has been shown not to be genetically base<span class="highlightedSearchTerm">d</span>, an<span class="highlightedSearchTerm">d</span> autism is likely environmentally in<span class="highlightedSearchTerm">d</span>uce<span class="highlightedSearchTerm">d</span> <span class="highlightedSearchTerm">d</span>uring some perio<span class="highlightedSearchTerm">d</span> of <span class="highlightedSearchTerm">d</span>evelopment.” –<i style="color: #057234; font-weight: bold; line-height: 15px;">Michael Skinner, Washington State University</i></span>Skinner lai<span class="highlightedSearchTerm">d</span> out the shift in thinking that is setting off waves of <span class="highlightedSearchTerm">d</span>isagreement among geneticists. For more than a century, scientists believe<span class="highlightedSearchTerm">d</span> that only alterations in the <span class="highlightedSearchTerm">D</span>NA sequence coul<span class="highlightedSearchTerm">d</span> be passe<span class="highlightedSearchTerm">d</span> on to subsequent generations. Now they are consi<span class="highlightedSearchTerm">d</span>ering a change in that thinking: The way in which normal genes are expresse<span class="highlightedSearchTerm">d</span>, or turne<span class="highlightedSearchTerm">d</span> on an<span class="highlightedSearchTerm">d</span> off, may be passe<span class="highlightedSearchTerm">d</span>
on, too. An abnormal exposure to a pregnant woman – a toxicant or
smoking, for instance – might change the genetic switching that controls
the <span class="highlightedSearchTerm">d</span>evelopment of a fetus. These alterations then may be passe<span class="highlightedSearchTerm">d</span> on to multiple generations.<br />
This is calle<span class="highlightedSearchTerm">d</span> <a href="http://www.ncbi.nlm.nih.gov/pubmed/21970811">epigenetic inheritance.</a><br />
<a href="http://www.environmentalhealthnews.org/ehs/news/2013/http-www.environmentalhealthnews.org-ehs-news-2013-autism-epigenetics-2"><b><i>Continue rea<span class="highlightedSearchTerm">d</span>ing on Page </i></b><b><i>2</i></b></a><br />
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Onslaught of autism. Page 2
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(<b><i>Continued from </i></b><a href="http://www.environmentalhealthnews.org/ehs/news/2013/autism-epigenetics"><b><i>Page 1</i></b></a>)<br />
Scientists
believe that molecules called the “epigenome” modify a person's
instruction-giving genome in a way that tells it what to do, where to do
it and when to do it. Environmental factors can more easily interact
with the epigenome than the genome, and these changes can be passed on
from cell to cell as cells divide.<br />
Skinner explained it to Escher this way: “Think of the genome as the computer, and the epigenome as the software.”<br />
<table class="FCKimagetableR" style="float: right; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/mice.jpg" /></td> </tr>
<tr> <td class="FCKcredit" style="font-size: 11.818181991577148px;"><span style="font-size: 9.090909004211426px;"><a href="http://epigenome.eu/en/2,48,873">Epigenome NoE</a></span></td> </tr>
<tr> <td class="FCKcaption" style="font-size: 13.63636302947998px;"><span style="font-size: 11.818181991577148px;">A
mouse's color can change in future generations by how its genes are
expressed, or turned on and off, even if its DNA sequence isn't altered.</span></td> </tr>
</tbody> </table>
The
hypothesis is that if the germ cells are affected in the fetus,
disruptions in signals can be transmitted to subsequent generations,
without affecting the DNA sequence. If at least three generations of
offspring are affected, Skinner calls it "<a href="http://www.ncbi.nlm.nih.gov/pubmed/15933200">transgenerational</a>."<br />
“In
essence, what your grandmother was exposed to when she was pregnant may
cause disease in you and your grandchildren. Therefore, the potential
hazard of environmental toxicants is dramatically increased, in
particular for pregnant women in mid-gestation, six to 18 weeks,”
Skinner said at a <a href="http://autismepigenetics.org/">symposium on epigenetics and autism</a> at UC Davis in March, partly supported by a grant from the Escher Fund for Autism.<br />
In lab animals, Skinner and other scientists have linked a dozen chemicals – including <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055387">bisphenol A</a>, which is an ingredient of polhycarbonate plastics, <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055387">phthalates </a>used as plasticizers, the insecticide DEET and <a href="http://endo.endojournals.org/content/147/12/5515.short">a fungicide</a> –
to transgenerational epigenetic changes that have led to tumors,
prostate disease, reproductive problems and other problems in at least
three generations of offspring.<br />
Environmental epigenetics may
have an important role in the origins of autism, Skinner said. “The
majority of brain disease has been shown not to be genetically based,
and autism is likely environmentally induced during some period of
development,” he said.<br />
However, study of possible links between
autism and multigenerational effects of environmental exposures is in
the early stages, and the links remain a topic of debate among
scientists.<br />
"So far there are only a handful of gene mutations
that are found in the human autism population. For the majority of
patients we know something else is going on, and that might be
epigenetic changes,” said <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=22707478">Emilie Rissman</a>, professor of biochemistry and molecular genetics at the University of Virginia School of Medicine.<br />
Many
diseases have increased faster than can be explained from normal
genetic mechanisms. The epigenetic phenomenon could be a reason.<br />
“If
environmental factors influence gene expression, the risk of someone
having autism could increase,” said Amaral of the University of
California, Davis.<br />
But Amaral said more basic science is needed
to figure out the possible effects of environmental toxicants and
pharmaceuticals. “Not enough is being done,” he said.<br />
One large study, published earlier this year, reported that children of women who took <a href="http://jama.jamanetwork.com/article.aspx?articleid=1681408">valproate</a>,
prescribed for epilepsy and psychiatric disorders, had a significantly
higher risk of autism spectrum disorders than other children.
The study didn't look at epigenetic effects, however.<span style="font-family: "Times New Roman"; font-size: 12.0pt; mso-bidi-font-size: 10.0pt;"><br /> </span><br />
<table class="FCKimagetableL" style="float: left; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" height="279" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/DirectExposureGraphic.jpg" width="375" /></td> </tr>
<tr> <td class="FCKcredit" style="font-size: 11.818181991577148px;"><a href="http://learn.genetics.utah.edu/content/epigenetics/inheritance/"><span style="color: #999999; font-size: 9.090909004211426px;">University of Utah</span></a></td> </tr>
<tr> <td class="FCKcaption" style="font-size: 13.63636302947998px;"><span style="font-size: 11.818181991577148px;">A pregnant woman's exposures may harm not just her fetus but the fetus's developing reproductive cells.</span></td> </tr>
</tbody> </table>
“There
are many pieces of information learned from more than a decade of study
that need to be connected before any conclusion can be made about
autism,” said Andrea Gore, professor of pharmacology and toxicology at
the University of Texas at Austin. Gore was one of the first to show in
lab animals that prenatal exposure to hormone-like chemicals interfered
with development of the neurological and reproductive systems, leading
to abnormalities, including social and neurobehavioral disorders.<br />
“It's
too soon to make a direct connection between exposure to synthetic
reproductive hormones and autism,” Gore said. “We think most behavioral
disorders are a combination of genetic predisposition, natural
differences in reproductive hormones and differences in environmental
exposures.”<br />
University of California, Davis, autism researcher <a href="http://www.ncbi.nlm.nih.gov/pubmed/23677056">Janine M. LaSalle</a>
said human studies over many generations would be needed to determine
whether genomes and epigenomes may be increasingly susceptible to autism
due to a multitude of environmental factors.<br />
With lab animals,
Gore and her colleagues will conduct transgenerational studies of
hormone-mimicking chemicals to try to understand molecular changes in
the brain and the connection between nerve cells and behavior.<br />
“The
caveat is that animals don't get autism spectrum disorders. All we can
do is look at perturbations of normal behavior in ways that we believe
may mimic some aspects of autism,” she said.<br />
“The human is very
special. We are different from other species… When it comes to these
really complicated neurological biological disorders, we have to
interpret the animal results in that context.”<br />
<span style="font-size: larger;"><b>Antidepressants under the microscope</b></span><br />
Escher
started doing some sleuthing of her own. Suspicious of links between
pharmaceuticals and autism, she surveyed other autism families to ferret
out exposures during pregnancy. Over months, she communicated with 70
parents, mostly mothers. Nine women told her they had taken
antidepressants, including drugs known as SSRIs.<br />
“The stories
were the same again and again and again. The mother was mildly
depressed. The doctor would always say it's more important for you to
stay on the drug, and there is no sign of risk to the fetus,” Escher
said.<br />
<table class="FCKimagetableR" style="float: right; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" height="223" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/antidepressants1.jpg" width="500" /></td> </tr>
<tr> <td class="FCKcredit" style="font-size: 11.818181991577148px;"><a href="http://www.cdc.gov/ncbddd/autism/data.html"><span style="color: #999999; font-size: 9.090909004211426px;">Centers for Disease Control and Prevention</span></a></td> </tr>
<tr> <td class="FCKcaption" style="font-size: 13.63636302947998px;"> <span style="font-size: 11.818181991577148px;">About 1 in 9 people 12 years and older in the United States takes antidepressants.</span></td> </tr>
</tbody> </table>
Prenatal
use of SSRIs, or selective serotonin reuptake inhibitors such as Prozac
and Zoloft, have surged since their introduction in the late 1980s.<br />
She
came across a post by Dr. Adam Urato, assistant professor and clinician
at Tufts University School of Medicine, saying that there was a body of
science linking SSRIs to autism, birth defects and other effects.<br />
“If
you look at the DES tragedy, you see many of the same hallmarks that
you see today. I'm concerned that the warning voices aren't being heard,
and the evidence of harm is being drowned out,” Urato said.<br />
Antidepressants
are believed to block serotonin, which is essential for brain growth,
from being taken up by neurons, the basic cells of the brain. Autism is
characterized by changes in the serotonin system.<br />
<span style="border-left-color: rgb(140, 172, 187); border-left-style: solid; border-left-width: 4px; clear: right; color: #057234; float: right; font-weight: bold; line-height: 1.25em; margin: 0px 0px 1em 1em; padding: 0px 1em; width: 226.8607940673828px;">“I'm concerned that the warning voices aren't being heard, and the evidence of harm is being drowned out.” –<i style="line-height: 1.25em;">Dr. Adam Urato, Tufts University</i><span style="line-height: 1.25em;"> </span></span><a href="http://www.ncbi.nlm.nih.gov/pubmed/15514160">Studies in animals</a> and
humans suggest that fetal exposure to SSRIs may be linked to
neurological and developmental disorders, including an increased risk
for autism syndrome disorders, Urato said.<br />
For example, researchers in Sweden reported a link between <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630989/">antidepressants and autism</a>. Pregnant women taking SSRIs showed a more-than-triple increase in risk of offspring with autism spectrum disorder.<br />
Other
researchers in the San Francisco Bay Area examined the association
between autism and antidepressants during pregnancy. In a study
published last year, they found a more than two-fold <a href="http://archpsyc.jamanetwork.com/article.aspx?articleid=1107329">increased risk of autism</a> associated with SSRIs with the strongest effect found in the first trimester.<br />
One research group concluded that “fetal and infant <a href="http://www.pnas.org/content/108/45/18465.full">exposure to SSRIs</a> should be examined in humans, particularly those with developmental dysfunction, such as autism.“<br />
When
asked about any ongoing studies by the U.S. Food and Drug
Administration, spokeswoman Andrea Fischer responded: “The FDA is not
aware of any studies demonstrating that antidepressant use causes
autism.”<br />
<span style="border-right-color: rgb(140, 172, 187); border-right-style: solid; border-right-width: 4px; clear: left; color: #057234; float: left; font-weight: bold; line-height: 1.25em; margin-bottom: 1em; margin-right: 1em; padding: 0px 1em; width: 226.8607940673828px;">Today,
prenatal use of SSRIs, or selective serotonin reuptake inhibitors such
as Prozac and Zoloft, have surged since their introduction in the late
1980s.</span>There have been no studies on the epigenetic or germ line effects of SSRIs.<br />
Skinner
is intrigued, and wants to study germ line changes related to
pharmaceuticals but says the research funds aren't there. “In my
opinion, it's a Catch-22. If we can't find research money to do the
studies, then the medical community is not going to pay attention. All
it would take is a few good publications to raise the red flag. Then the
industry would respond accordingly, and the FDA would respond,” he
said.<br />
Escher is impatient with the FDA, saying it is missing an
opportunity to explore a hypothesis that autism researchers call viable.<br />
“We
know pregnant women are taking SSRIs. We know that SSRIs have
endocrine-disrupting effects. We know that endocrine-disrupting
chemicals can disrupt germ line development. It only stands to reason
that SSRIs can have transgenerational effects.<br />
“It makes sense on paper. But nobody's asking the question,” she said.<br />
<span style="font-size: larger;"><b>FDA petitioned, NIH involved</b></span><br />
Two months ago, Escher <a href="http://www.environmentalhealthnews.org/ehs/news/2013/pdf-links/Escher%20Letter.pdf">petitioned the FDA</a>.
She is seeking revocation of the first anti-nausea drug approved for
pregnant women, Diclegis, until it is tested for effects on the fetus's
developing germ cells.<br />
Escher also wants wording on drug labels
that alerts pregnant women that the medication has not been tested for
damage to the baby's vulnerable egg or sperm precursors, and bears the
risk of causing disease or developmental disorders in the next
generation.<br />
“I chose Diclegis as a poster child because it had
been approved as though there are no risks to the fetus,” she said. She
is particularly concerned that it is prescribed during the first half of
pregnancy, when germ lines develop.<br />
<table class="FCKimagetableR" style="float: right; width: 150pxpx;"> <tbody>
<tr> <td><img alt="" height="312" src="http://www.environmentalhealthnews.org/ehs/images/2013/ehn/july/autism/Epigenetic_mechanisms.jpg" width="450" /></td> </tr>
<tr> <td class="FCKcredit" style="font-size: 11.818181991577148px;"><a href="http://en.wikipedia.org/wiki/File:Epigenetic_mechanisms.jpg"><span style="color: #999999; font-size: 9.090909004211426px;">Wikipedia</span></a></td> </tr>
</tbody> </table>
Her cause is supported by some scientists, including Tel Aviv University theoretical biologist <a href="http://www.ncbi.nlm.nih.gov/pubmed/22975443">Eva Jablonka</a>, who has been studying transgenerational epigenetic effects for years.<br />
Jablonka
wrote a letter to the FDA saying the understanding of epigenetic
inheritance and fetal vulnerability “should alert us and urge us to take
cautionary measures until research reveals whether or not the drugs
affect the relevant grand-offspring generation.”<br />
A representative
of Duchesnay Inc. said the Canadian pharmaceutical company worked
closely with the FDA in evaluating Diclegis. The drug has not shown an
increased risk to the fetus during pregnancy, according to an emailed
statement. The drug maker didn't respond to questions about possible
effects on the fetal germ line.<br />
At the FDA, Fischer said the
combination of active ingredients in Diclegis – doxylamine succinate and
pyridoxine hydrochloride – has been the subject of many epidemiological
studies designed to detect the potential to cause birth defects in the
fetus. Based on these and other studies, “there are <a href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm347087.htm">no concerns</a> for an increased risk for malformations from first trimester exposure to these ingredients,” Fischer said.<br />
But
Jablonka and other scientists say the testing of drugs should not be
stopping with the exposed fetus, because perhaps only the subsequent
generations are harmed. Asked about that, Fischer said, “the science of
epigenetics is new, and initial work in animal models suggests it may
provide additional approaches to better understand environmental
influences for human health. As with all emerging science, the FDA will
review data and consider its potential for impact on regulatory
decisions.” She said the agency is reviewing Escher’s petition.<br />
Earlier this month, Escher, along with Alycia Halladay of the national nonprofit <a href="http://www.autismspeaks.org/what-autism">Autism Speaks</a>,
presented the germ line disruption hypothesis to a committee of the
National Institute of Mental Health, which is congressionally mandated
to deal with the autism crisis.<br />
The National Institutes of Health has begun funding some epigenetics studies related to autism and prescription drugs.<br />
<span style="border-right-color: rgb(140, 172, 187); border-right-style: solid; border-right-width: 4px; clear: left; color: #057234; float: left; font-weight: bold; line-height: 1.25em; margin-bottom: 1em; margin-right: 1em; padding: 0px 1em; width: 226.8607940673828px;">"The
science of epigenetics is new, and initial work in animal models
suggests it may provide additional approaches to better understand
environmental influences for human health." - Andrea Fischer, FDA</span>A
large study in Europe, led by the Mount Sinai School of Medicine, is
looking at medications taken by mothers and the health of their
offspring. University of California, Davis, researchers are examining
links between exposure to air pollution and pesticides, epigenetic
changes and autism. Johns Hopkins University researchers are testing for
epigenetic changes in autistic children associated with prenatal
exposures to environmental chemicals. The National Institute of Mental
Health is financing some studies on pharmaceuticals, including an
investigation of whether antidepressants are causing epigenetic changes.<br />
Also,
an ambitious, first-of-its kind study of 8,000 people in Denmark,
partially paid for by Escher’s fund, will look for connections between
any pharmaceuticals they were exposed to in the womb and neurological
disorders in their children.<br />
Scientists, Escher said, have access to a treasure trove: the parents and grandparents of autistic children.<br />
“Most
autism families can generate very strong clues about what could have
happened with their children. But it requires probing deep into
ancestral exposures. The clues are there,” she said.<br />
As for her own inspiration, “I love my kids. But I don't want this to happen to anyone else. It's too hard. It's too damaging.<br />
"We
have unwittingly experienced this mass disruption in evolution. It has
to stop. We have to be much better caretakers of our genetic legacy.”Unknownnoreply@blogger.com1tag:blogger.com,1999:blog-471663631306140712.post-27341988810625334102013-06-23T20:31:00.004-07:002013-06-25T08:26:43.511-07:00Prenatal Exposures: Should You Be Worried?<i>by Jill Escher (@Autism_Exposed)</i><br />
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<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZw68G_NpDcLnbxW0rxRhWzSMGdhh6IjtX7ELszSTXLECKYBK61UyjQY00D5gt-v01ewvoo3__zocc6YKcWTUWMugQ5v5K-5ko8QGXid0oIPGDZoF2LR3XiYkY5oyDXbnCAIVyk1wx5m8n/s1600/jony+ipod+in+sf.jpg" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZw68G_NpDcLnbxW0rxRhWzSMGdhh6IjtX7ELszSTXLECKYBK61UyjQY00D5gt-v01ewvoo3__zocc6YKcWTUWMugQ5v5K-5ko8QGXid0oIPGDZoF2LR3XiYkY5oyDXbnCAIVyk1wx5m8n/s200/jony+ipod+in+sf.jpg" width="150" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><i>My 14 year-old son Jonny, in SF today. Like all of us, Jonny developed from a single egg and single sperm. But something very odd happened to the JonnyEgg, before I was even born—evolutionarily unprecedented bombardment by synthetic hormone drugs that, unbeknownst to anyone at the time, impaired epigenetic synthesis of the all-important germ cell. Now, having differentiated into 100 trillion cells or so, Jonny is so handsome, and, with a brain that really does not know how to connect, so autistic. Gee, thanks, docs! Thanks epigenetics!</i></td></tr>
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With more people learning about the potential connections between my own prenatal drug exposures and my children's autism (via unintended epigenetic damage to my eggs), I'm hearing many worried, no, <i>panicked</i>, questions from a number of corners. <br />
<br />
I'd like to try to address some of these questions, knowing that my hypothesis has profound practical implications, but with the caveat that these responses are based on the "as far as I can tell from the research" basis, and that I do not speak with any sense of perfect authority on the subject. So here goes.<br />
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<b>Q: My husband and I used IVF to get pregnant with twins, and the fertility clinic gave me several medications both before and after conception. Should I worry that any of these medications may have damaged the eggs of my daughter and sperm of my son?</b><br />
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I recommend that you contact the fertility clinic as soon as possible to obtain all records, both written and electronic, of your medication use, both before and during pregnancy. The people who will most benefit from these documents are your son and daughter, who should at some point be given the opportunity to know of their prenatal pharmaceutical exposures, particularly before they contemplate having children of their own.<br />
<br />
Depending on the drugs used, dosages, and timing, you and your children should have some level of concern about the impact of the drug exposures on their germ cells, and therefore, your future grandchildren. That said, most of the drugs used in an IVF cycle address the pre-ovulation and early implantation stages, so to the extent they have adverse impacts (and many, including myself, believe they do), those impacts would be seen in the health and development of your children themselves.<br />
<br />
Early IVF cycle drugs include a wide variety of chemicals to facilitate production and retrieval of eggs. Commonly used drugs include agonists and antagonists like Lupron, Synarel, Antagon, Cetrotide, gonadotropins such as Gonal F,
Bravelle, Follistim, Menopur, Pergonal and Repronex, HCGs such as Pregnyl, Profasi, Ovidrel and Novarel, corticosteroids such as Medrol, and antibiotics such as doxycycline. It is worth noting that <i>corticosteroids are known to have epigenetic effects on DNA, yet early embryos are routinely exposed to these very genotoxic drugs</i>.<br />
<br />
However, your children's primordial germ cells (future gametes) develop from the cluster of cells exposed to the various early-IVF drug regimen, and may be further affected by exposures to drugs, such as hormone preparations, given during the first half of pregnancy. Progesterone is often given from the beginning of pregnancy, under the belief that additional progesterone will encourage implantation and prevent miscarriage. There is extremely little data to support this contention, however, but since the 1950s it has remained an unshakeable myth perpetuated by the drug companies and a subset of medical doctors. Administration is via vaginal
suppositories, intramuscular injections or by mouth.<br />
<br />
I was exposed in utero to heavy doses of synthetic progesterones (along with other hormones), via injection of my mother, throughout the first two trimesters of my gestation. <i> I advise strongly against the prenatal use of most exogenous hormones, including progesterone, as excess hormones can not only affect the physical and behavioral sexual development of the exposed individual, they can affect epigenetic synthesis of the baby's germline, which can lead to developmental abnormalities in the grandchild generation.</i><br />
<br />
One notable exception, where benefit certainly appears to outweigh risk, is thyroid hormone where mother or baby are hypothyroid and require supplementation to reach normal levels to facilitate healthy fetal brain development.<br />
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<b>Q: I took antidepressants (20 mg of Paxil per day) throughout my pregnancy. My son seems to be okay, but is there a risk of permanent damage to his sperm?</b><br />
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Antidepressants such as SSRIs have been shown to elevate the risk for autism in an exposed fetus, so your son is fortunate to have escaped damage. As for the next generaion, a male fetus develops his spermatogonial stem cells (SSCs) while <i>in utero</i>, cells that go through additional processes of division and maturation, resulting in mature sperm beginning at the time of puberty. Sperm continue to develop from the SSCs throughout the male's life, spermatogenesis taking about 2 months time.<br />
<br />
So the question is, can the <i>in utero</i> exposure to SSRI chemicals impair epigenetic synthesis of the SSCs? Animal models have repeatedly shown epigenetic changes, such as reduced methylation of DNA, in response to exposure to endocrine disrupting chemicals. SSRI drugs are known to interfere with normal hormonal functioning and should be considered endocrine disrupting chemicals. So, though no study has ever been conducted to examine the question directly, the research suggests a possible connection between SSRI exposure and epigenetic fetal gamete impairments. <i>I strongly urge precaution and recommend against any use of antidepressant drugs during (or several months before) pregnancy.</i><br />
<br />
As an alternative to drugs to elevate mood, women should consider natural alternatives, including a mood-boosting <a href="http://robbwolf.com/what-is-the-paleo-diet/" target="_blank">Paleo-type diet</a> packed with micronutrients and healthy fats, and free of processed food, sugars, and inflammation-causing grains. What causes depression in the first place? Often hormone disruption caused by birth control pills, impaired neurological function caused by low-fat diets (tragically, the misguided nutrition advice for the past half-century), and impaired blood sugar control and neurotransmitter function caused by high-carb and processed food diets.<br />
<br />
Exercise and talk therapy have also shown to be helpful. But food makes mood, and <i>women should strive to adopt a highly nutritious mood-boosting diet, free of low-fat and processed crap, well before becoming pregnant</i>. <br />
<br />
Distressingly, many women report staying on SSRIs during pregnancy because they had become chemically dependent on them over the years and feared suffering through withdrawal. This represents a dramatic side effect of the drug that is never disclosed or reported. It underscores the importance of resisting all temptation to start taking these drugs if you think you might ever choose to have children.<br />
<br />
Again, it is urgent that you obtain copies of all medical records from your pregnancy, so that your son can later have the opportunity to learn of his <i>in utero </i>drug exposures.<br />
<br />
<b>Q: Diclegis, a drug to prevent morning sickness, was just approved as a Category A drug for pregnancy by the FDA. Are there risks the FDA has not disclosed?</b><br />
<br />
Category A drugs are described as drugs that have been tested and shown to be safe during pregnancy. However, while Diclegis has not demonstrated increased risk for fetal malformations, <i>it has <u>never</u> been tested for potential impacts to fetal germ cells, which, though subtle and submicroscopic, could result in subtle or catastrophic disability in the next generation</i>. Please do not consider taking Diclegis or any other morning sickness medication until such epigenetic germline testing has been completed. Details on the topic can be found in my <a href="http://www.regulations.gov/#!documentDetail;D=FDA-2013-P-0522-0001" target="_blank">Citizen's Petition to the FDA</a>.<br />
<br />Unknownnoreply@blogger.com2tag:blogger.com,1999:blog-471663631306140712.post-35516736697667717402013-05-22T12:22:00.001-07:002013-05-24T10:37:10.090-07:00Videos from Environmental Epigenetics: New Frontiers in Autism Research<b>Environmental Epigenetics: New Frontiers
in Autism Research was a groundbreaking symposium that took place March 22-23, 2013 at the UC Davis MIND
Institute in Sacramento, California, co-sponsored by Autism Speaks, the
MIND Institute, and the Escher Fund for Autism. The meeting brought
together leading scientists from multiple disciplines to consider how
environmental epigenetics may play a role in the causes of some forms of
neurodevelopmental disability, including ASD. There was much emphasis on germline disruption effects of pharmaceuticals and chemicals.</b><br />
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If you want the brightest clues about what's causing a good portion of the autism epidemic, set aside a few hours and watch these. More info on the conference is at the event website, <a href="http://autismepigenetics.org/">autismepigenetics.org</a>.<br />
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<b><a href="http://media.mindinstitute.org/video/epigenetics/escher_epigenetics_2013_web.mov" target="_blank">An autism mom asks: Who says you can’t have a genetic epidemic?</a> </b></div>
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<b>Presenter:</b> Jill Escher</div>
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<b>Affiliation:</b> Escher Fund for Autism</div>
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<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 13:04</div>
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<b>Summary:</b> A mother of two
children with autism poses the question whether past exposures,
particularly prenatal exposures to popular mid-20th century prenatal
pharmaceutical drugs, such as synthetic steroid hormones and sedatives,
may have impacted vulnerable fetal germline epigenetics, resulting in a
surge of developmental abnormalities in the grandchild generation.</div>
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<img alt="Jill Escher" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/escher_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="Epigenetics Symposium 2013"><img alt="Flash Media" border="0" src="http://www.ucdmc.ucdavis.edu/mindinstitute/images/logos/adobe_flash_logo.png" style="border-bottom: medium none; border-left: medium none; border-right: medium none; border-top: medium none; margin: 3px;" title="Flash Media" /></a></div>
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/escher_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="MIND Institute Media Player">Play in Media Player<br /> 71.2MB</a></div>
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<a href="http://media.mindinstitute.org/video/epigenetics/woodruff_epigenetics_2013_web.mov"><b>Environment, neurodevelopment, and opportunities for prevention</b></a></div>
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<b>Presenter:</b> Tracey Woodruff, Ph.D., MPH</div>
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<b>Affiliation:</b> Program on Reproductive Health and the Environment, UCSF</div>
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<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 22:47</div>
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<b>Summary:</b> We are experiencing a
sharp upward trend in autism that cannot be fully explained by factors
such as younger ages at diagnosis, migration patterns, changes in
diagnostic criteria. Interaction among environmental factors,
including a glut of novel and untested synthetic chemicals known to
cause disturbances in CNS development, may be contributing to the
problem. Dr. Woodruff explains the history of environmental chemical
exposures and efforts that were successful in reducing exposures and
improving child health.</div>
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<img alt="Tracey Woodruff, PhD, MPH" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/woodruff_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="Epigenetics Symposium 2013"><img alt="Flash Media" border="0" src="http://www.ucdmc.ucdavis.edu/mindinstitute/images/logos/adobe_flash_logo.png" style="border-bottom: medium none; border-left: medium none; border-right: medium none; border-top: medium none; margin: 3px;" title="Flash Media" /></a></div>
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/woodruff_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="MIND Institute Media Player">Play in Media Player<br /> 123.5MB</a></div>
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<a href="http://media.mindinstitute.org/video/epigenetics/dolinoy_epigenetics_2013_web.mov"><b>Perinatal environmental exposures and lifecourse health effects </b></a></div>
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<b>Presenter:</b> Dana Dolinoy, Ph.D.</div>
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<b>Affiliation:</b> University of Michigan School of Public Health</div>
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<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 30:00</div>
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<b>Summary:</b> Molecular level
epigenetic “switches” can influence the expression of protein-coding
genes. Periods of particular epigenetic susceptibility include
gametogenesis, pre-implantation stage of embryogenesis, fetal and
neonatal periods of development, puberty, ad old age. Lab studies have
shown endocrine-disrupting chemicals can have non-monotonic effects,
differentially methylate DNA (both hyper- and hypo), and have different
effects in different succeeding generations. Epigenomic studies can
decipher the role of the environment on the epigenome, identify
epigenetically labile genes, and link epigenetically labile loci with
biological pathways and phenotypes/human health outcomes.</div>
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<img alt="Dana Dolinoy, PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/dolinoy_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="Epigenetics Symposium 2013"><img alt="Flash Media" border="0" src="http://www.ucdmc.ucdavis.edu/mindinstitute/images/logos/adobe_flash_logo.png" style="border-bottom: medium none; border-left: medium none; border-right: medium none; border-top: medium none; margin: 3px;" title="Flash Media" /></a></div>
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/dolinoy_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="MIND Institute Media Player">Play in Media Player<br /> 141.1MB</a></div>
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<a href="http://media.mindinstitute.org/video/epigenetics/crews_epigenetics_2013_web.mov"><b>Evolutionary implications for a new world of contamination </b></a></div>
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<b>Presenter:</b> David Crews, Ph.D.</div>
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<b>Affiliation:</b> Section of Integrative Biology, University of Texas at Austin</div>
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<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 27:45</div>
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<b>Summary:</b> As an evolutionary
biologist, Dr. Crews’ research focuses on how exposures change
adaptation across generations in a sex-dependent way. He describes two
types of ways in which the environment sculpts the phenotype of
individuals: 1) context dependent which is due to a direct exposure and
manifests in each generation and 2) germline dependent. This manifests
in the absence of a causative agent since it is cumulative across
generations. He describes experiments where changes to the environment
can affect social and sexual behavior, as well as response to stress,
when the exposures was ancestral.</div>
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<img alt="David Crews, PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/crews_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="Epigenetics Symposium 2013"><img alt="Flash Media" border="0" src="http://www.ucdmc.ucdavis.edu/mindinstitute/images/logos/adobe_flash_logo.png" style="border-bottom: medium none; border-left: medium none; border-right: medium none; border-top: medium none; margin: 3px;" title="Flash Media" /></a></div>
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/crews_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="MIND Institute Media Player">Play in Media Player<br /> 127.4MB</a></div>
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<a href="http://media.mindinstitute.org/video/epigenetics/skinner_epigenetics_2013_web.mov"><b>Environmental induced epigenetic transgenerational inheritance of disease </b></a></div>
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<b>Presenter:</b> Michael Skinner, Ph.D.</div>
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<b>Affiliation:</b> Washington State University</div>
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<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 40:32</div>
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<b>Summary:</b> Biological science is
undergoing a paradigm shift away from the fixed genetic determinism of
the 20th century and toward an understanding that environmental factors
can alter gene expression and activity. Genetics works together with the
environment to contribute to disease risk. In some cases, changes to
gene expression in future generations can occur when the germ cell
(sperm or egg) is reprogrammed via an abnormal exposure such as an
endocrine-disrupting compound, and these alterations may persist for
generations. This transgenerational exposure to environmental factors
represents an example of epigenetic inheritance. Various pathologies
may result from certain germline exposures, including cancer,
infertility, polycystic ovary disease, obesity, and behavioral
abnormalities. Assays find clusters of altered gene expression dependent
on the original exposure, or dependent on the generation studied.</div>
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<img alt="Michael Skinner, PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/skinner_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="Epigenetics Symposium 2013"><img alt="Flash Media" border="0" src="http://www.ucdmc.ucdavis.edu/mindinstitute/images/logos/adobe_flash_logo.png" style="border-bottom: medium none; border-left: medium none; border-right: medium none; border-top: medium none; margin: 3px;" title="Flash Media" /></a></div>
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/skinner_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="MIND Institute Media Player">Play in Media Player<br /> 130.2MB</a></div>
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<b><a href="http://media.mindinstitute.org/video/epigenetics/clark_epigenetics_2013_web.mov">A remodeled germline epigenome: the ultimate gift to our children and grandchildren</a> </b></div>
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<b>Presenter:</b> Amander Clark, Ph.D.</div>
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<b>Affiliation:</b> UCLA</div>
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<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 19:12</div>
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<b>Summary:</b> During pregnancy,
three generations of DNA coexist in the woman’s body: hers, that of her
fetus, and the primordial germ cells growing within the fetus. Those
germ cells decades later contribute to the grandchild generation. Human
gametogeneis begins in early gestation, with the male fetus’s germline
developing differently than the female fetus’s germline. The proper
reprogramming of the germline is essential for proper child development,
and molecular perturbations can lead to developmental disorders.
Environmental exposures can interfere with the molecular process of
germline programming.</div>
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<img alt="Amander Clark, Ph.D." border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/clark_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="Epigenetics Symposium 2013"><img alt="Flash Media" border="0" src="http://www.ucdmc.ucdavis.edu/mindinstitute/images/logos/adobe_flash_logo.png" style="border-bottom: medium none; border-left: medium none; border-right: medium none; border-top: medium none; margin: 3px;" title="Flash Media" /></a></div>
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<a class="option" href="http://media.mindinstitute.org/video/epigenetics/clark_epigenetics_2013_web.mov" rel="shadowbox;width=640;height=360" title="MIND Institute Media Player">Play in Media Player<br /> 71.2MB</a></div>
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<a href="http://media.mindinstitute.org/video/epigenetics/fallin_epigenetics_2013_web.mov" target="_blank"><b>How might epigenetics relate to the etiology of ASD? </b></a></div>
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<b>Presenter:</b> M. Danielle Fallin, Ph.D.</div>
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<b>Affiliation:</b> Johns Hopkins Bloomberg School of Public Health</div>
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<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 26:24</div>
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<b>Summary:</b> Various epigenetic
mechanisms may contribute to ASD traits and there is growing evidence
for environmental susceptibility of epigenetic marks. Studies show that
phenotype and epigenetic marks can be modified by factors such as
maternal diet, pharmaceuticals, and smoking, and metals and behavior.
The epigenome may be the intermediary between genetics and the
environment, mediating disease outcome. Existing research supports a
role for epigenetics in ASD etiology, for example with ASD-related
disorders with known epigenetic mechanisms, parent-of-origin effects,
differences of expression in ASD-related genes, and differences in
methylation patterns.</div>
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<img alt="M. Danielle Fallin, PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<b> <a href="http://media.mindinstitute.org/video/epigenetics/mansuy_epigenetics_2013_web.mov" target="_blank"> Epigenetic inheritance of complex behaviors and their alteration by traumatic stress in mammals </a></b><br />
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<b>Presenter:</b> Prof. Isabelle Mansuy</div>
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<b>Affiliation:</b> Brain Research Institute, University of Zurich</div>
<div style="margin: 10px;">
<b>Date:</b> March 22, 2013</div>
<div style="margin: 10px;">
<b>Length:</b> 30:34</div>
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<b>Summary:</b> Disease arises via a
combination of genotype and epigenotype. Over the human lifecycle, there
are different environmental influences on epigenotype. Early trauma is a
risk factor for psychiatric and cognitive disorders, and involve
epigenetic factors. Animal studies show early trauma can alter social
behavior across generations. Multiple molecular mechanisms appear to be
involved with the induced differences in gene expression, including DNA
methylation, histone/protamines posttranslational modifications, and
small noncoding RNAs.</div>
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<img alt="Prof. Isabelle Mansuy" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a href="http://media.mindinstitute.org/video/epigenetics/gore_epigenetics_2013_web.mov" target="_blank"><b>Neuroendocrine disruptors, epigenetics and neurodevelopment</b></a></div>
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<b>Presenter:</b> Andrea Gore, Ph.D.</div>
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<b>Affiliation:</b> University of Texas at Austin</div>
<div style="margin: 10px;">
<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 43:34</div>
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<b>Summary:</b> Hormones play a
critical role in sculpting the entire nervous system and brain.
Endocrine disrupting chemicals can adversely affect fetal brain
development and may have lifelong consequences. Psychiatric disorders
are influenced by gonadal steroid hormones. EDCs perturb hypothalamic
development and therefore hormonal regulation. Studies of PCBs, which
persist in the environment and bioaccumulate in tissue demonstrate
lifelong changes in physiology, brain development and behaviors.
Multigenerational adverse impacts of exposure to the antimiscarriage
synthetic hormone DES is also discussed.</div>
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<img alt="Andrea Gore, PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a href="http://media.mindinstitute.org/video/epigenetics/reinisch_epigenetics_2013_web.mov" target="_blank"><b>Prenatal exposures: An unrecognized multigenerational epidemic</b></a></div>
<div style="margin: 10px;">
<b>Presenter:</b> June Reinisch, Ph.D. and Erik L. Mortensen, CanD</div>
<div style="margin: 10px;">
<b>Affiliation:</b> University of Copenhagen Prenatal Development Project</div>
<div style="margin: 10px;">
<b>Date:</b> March 22, 2013</div>
<div style="margin: 10px;">
<b>Length:</b> 31:39</div>
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<b>Summary:</b> Historically, the
placenta was viewed as a barrier preventing passage of harmful
substances to the fetus. However, today we know that organ acts more
like a sieve, with most maternally ingested substances reaching fetal
tissues. Prenatal use of synthetic medications goes back a century,
beginning with barbiturates and then synthetic hormones, including
synthetic estrogens (including the catastrophic drug DES) progesterones,
and corticosteroids. In the mid 20th century, synthetic hormone drugs
were widely used in pregnancies deemed to be “at risk,” and as a result
millions of offspring were exposed to augmented levels of synthetic or
natural hormones. The exposures are associated with a variety of
disruptions of typical development; however, drug impacts on fetal germ
tissues (grandchild, or F2, generation) have not yet been assessed. A
study using the Danish Prenatal Development Project, which is unusually
rich with prenatal exposure data, will be the first to examine potential
germline/F2 impacts of prenatal drug use.</div>
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<img alt="June Reinisch" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<b><a href="http://media.mindinstitute.org/video/epigenetics/weksberg_epigenetics_2013_web.mov" target="_blank">A role for assisted reproduction technology (ART) in the etiology of ASD?</a> </b></div>
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<b>Presenter:</b> Rosanna Weksberg, M.D., Ph.D.</div>
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<b>Affiliation: </b>University of Toronto</div>
<div style="margin: 10px;">
<b>Date:</b> March 22, 2013</div>
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<b>Length:</b> 23:58</div>
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<b>Summary:</b> Exposures are most
likely to have a significant impact only during certain stages of
development, including gamete development and early embryonic
development. Assisted reproduction, such as ovulation stimulation, in
vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI),
expose gametes and the early embryo to unusual environmental factors
coinciding in time with critical windows of epigenetic programming.
Exposures that may cause epigenetic perturbations include: ovulation
stimulation (FSH/clomid) (causing maturation and ovulation of oocytes
with incomplete/aberrant DNA methylation); IVF (in vitro embryo
culturing may disrupt proper imprinting maintenance in oocyte and embryo
during global genome demethylation); ICSI (sperm with
incomplete/aberrant methylation bypass natural selection). The increased
incidence of imprinting disorders associated with ART appears to arise
from epigenetic rather than genetic defects. Methylation patterns in ART
children appear to be slightly but significantly reduced. Study of
children conceived through ART offer a unique opportunity to study
exposure and epigenetic factors in development.</div>
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<img alt="Rosanna Weksberg, MD PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a href="http://media.mindinstitute.org/video/epigenetics/rissman_epigenetics_2013_web.mov" target="_blank"><b>BPA, social behavior, and epigenetics in juvenile mice</b></a></div>
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<b>Presenter:</b> Emilie Rissman, Ph.D.</div>
<div style="margin: 10px;">
<b>Affiliation:</b> University of Virginia</div>
<div style="margin: 10px;">
<b>Date:</b> March 22, 2013</div>
<div style="margin: 10px;">
<b>Length:</b> 23:58</div>
<div style="margin: 10px;">
<b>Summary:</b> Studies on
exposure-induced changes in social behavior in mice may shed light on
human neurobehavioral disorders. A study found that low-dose endocrine
disrupting chemical BPA changes juvenile interactions in female mice;
some changes in gene expression were also found. Multigenerational
effects were identified, with different effects in different
generations. Environmentally induced epigenetic modification of the X
chromosome may have implications for the sex difference seen in ASD.</div>
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<img alt="Emilie Rissman, PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a href="http://media.mindinstitute.org/video/epigenetics/lasalle_epigenetics_2013_web.mov" target="_blank"><b>PBDE exposure, sex differences and epigenetics in an animal model of ASD</b></a></div>
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<b>Presenter:</b> Janine LaSalle, Ph.D.</div>
<div style="margin: 10px;">
<b>Affiliation:</b> Medical Microbiology and Immunology, UC Davis School of Medicine</div>
<div style="margin: 10px;">
<b>Date:</b> March 22, 2013</div>
<div style="margin: 10px;">
<b>Length:</b> 30:21</div>
<div style="margin: 10px;">
<b>Summary:</b> A study on PBDEs
(flame retardant chemical) and PCBs (industrial chemical) examined the
effects of environmental pollutants on epigenetics of neurodevelopment
in both a mouse model and with human brain tissue. Perinatal BDE-47
exposure adversely affected reproductive success in this genetically
susceptible mouse model, consistent with adverse effects on human
fecundity. PBDE exposure adversely affected two measurements of social
behavior in the mouse model, and resulted in reduced global DNA
methylation in the adult brain specifically in females, correlating with
deficits in sociability. Gene by environment interactions at the
epigenetic interface are complex, involving sexual dimorphism,
epigenetic dysregulation, compensatory molecular mechanisms, and
specific behavioral deficits. The study of PCBs in human brain samples
suggested a possible environmental contributor to 15q duplications
through an epigenetic mechanism. An integrative approach to
understanding environmental impacts on the brain methylome is suggested.</div>
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<img alt="Janine LaSalle, PhD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<a href="http://media.mindinstitute.org/video/epigenetics/urato_epigenetics_2013_web.mov" target="_blank"><b>Counseling the pregnant woman: Focus on SSRI antidepressants</b></a></div>
<div style="margin: 10px;">
<b>Presenter:</b> Adam Urato, M.D.</div>
<div style="margin: 10px;">
<b>Affiliation:</b> Chairman, Dept. of OB/GYN, MetroWest Medical Center, Assistant Professor, Tufts Medical Center</div>
<div style="margin: 10px;">
<b>Date:</b> March 23, 2013</div>
<div style="margin: 10px;">
<b>Length:</b> 29:23</div>
<div style="margin: 10px;">
<b>Summary:</b> Medication use during
pregnancy is common and has been steadily increasing since the 1970s;
typical pharmaceuticals include antidepressants, anti-nausea drugs, and
heartburn medications. This represents a dramatic change in the chemical
environment from the perspective of evolutionary biology: mammals have
evolved for 200 million years without the interference of synthetic
drugs in gestation. In spite of clear warning signs, the synthetic
estrogen drug DES was used on pregnant women for 33 years before the
harmful effects were acknowledged. Today, prenatal use of SSRI drugs has
surged since their introduction in the 1980s. Studies in animal models
and human cohorts suggest that fetal SSRI exposure may long-term
neurodevelopmental outcome, including reports of an increased risk for
ASD.</div>
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<img alt="Adam Urato, MD" border="1" src="http://media.mindinstitute.org/video/epigenetics/epigenetics_web.jpg" style="margin: 0px 0px 10px;" />
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<div style="align: top; margin: 3px;">
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-471663631306140712.post-49697140385895506802013-05-15T08:01:00.002-07:002013-06-05T19:37:52.588-07:00Worse than thalidomide? The consequences of mass prenatal progestin exposure, 1950s-70s<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjh4kIYV3rqQftfnZn1dfG3raZ_mz4aieFcMxgcyCXAX-7K1BJqz-XKKujATCodD1h3_HqHlPnQd82yofxE5p-R_-7ah48k252r41wj5ztDN1VdzT4Sa4o7ectZ72Pt3b9TDZojZCbWTrkW/s1600/ImagesHandler.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjh4kIYV3rqQftfnZn1dfG3raZ_mz4aieFcMxgcyCXAX-7K1BJqz-XKKujATCodD1h3_HqHlPnQd82yofxE5p-R_-7ah48k252r41wj5ztDN1VdzT4Sa4o7ectZ72Pt3b9TDZojZCbWTrkW/s1600/ImagesHandler.png" /></a></div>
<i>by Jill Escher (Follow me on Twitter @autism_exposed)</i><br />
<br />
When we think of prenatal drug disasters, we usually think of the sedative thalidomide, which caused horrific birth defects, and synthetic estrogen DES, which caused cancer and infertility in offspring, among other horrors.<br />
<br />
Ignored, however, have been the downstream effects of the extensive use of progestin drugs in obstetric and fertility practice from the late 1950s through today. Progestins, not estrogens, were the most widely used anti-miscarriage drugs during several decades of practice that placed near-unquestioning faith in modern pharmaceuticals combined with near-nonexistent concern about impacts on the fetus.<br />
<br />
These potent pseudo-hormones were given to countless millions of women who were deemed to be “at-risk” for miscarriage or who were termed “habitual aborters,” defined very liberally at the time as women who had suffered two or three prior miscarriages. The most common synthetic progestins administered in these protocols appear to have been Colprosterone, Delalutin, Deluteval, Norlutin Acetate, Provera, and Provest. (Reinisch and Karow, Prenatal Exposure to Synthetic Progestins and Estrogens: Effects on Human Development, Arch. Sex. Behav. 6:4 1977).<br />
<br />
A 1969 medical text, “The Use of Progestins in Obstetrics and Gynecology,” by RW Kistner explained to physicians the then-standard of care for treatment of the “habitual aborters.” Please note the acute nature of the timing and dosage; the old practices resulted in massive fetal exposure to high doses of potent endocrine disrupting chemicals.<br />
<blockquote class="tr_bq">
<b>Provera</b>: ... 10 mg daily, orally, during the first trimester of pregnancy; then 20 mg daily, orally, during the second trimester and 30 mg, daily, orally, during the third trimester.<br />
<br />
<b>Delalutin</b>: (hydroxyprogesterone caproate) 375-500 mg (3-4 cc., intramuscularly) every week, starting as soon as pregnancy is confirmed and continuing to fetal viability.<br />
<br />
<b>Deluteval</b> (hydroxyprogesterone caproate plus estradiol valerate): 500 mg. Delalutin plus 10 mg Delestrogen, intramuscularly, every week from the time of confirmation of pregnancy until fetal viability.”<br />
<br />
If progesterone is administered, it is best started before conception and continued during pregnancy.... Progesterone, hydroxyprogesterone caproate and oral medroxyprogesterone acetate may be used in the prophylatic management of the habitual aborter.</blockquote>
Kistner, pp 112-13.<br />
<br />
Nine years earlier, Dr. Edward Tyler, founder of the Tyler Medical Clinic in Los Angeles, had published his influential 1960 book, “Sterility: Office Management of the Infertile Couple,” (available online free at <a href="http://catalog.hathitrust.org/Record/001566807">http://catalog.hathitrust.org/Record/001566807</a>) which touted the use of the new synthetic hormones for a variety of fertility and other obstetric problems. <br />
<br />
Dr. Tyler also endorsed large doses of synthetic progestins for miscarriage prevention:<br />
<blockquote class="tr_bq">
A new injectable progestogen, 17a-hydroxyprogesterone caproate (17-AHPC) [note: this is Delalutin, which had been approved by the FDA for miscarriage prevention in 1956], differs from progestone in two major respects: large doses, for example, 250 mg per injection, can be given with relative freedom from local reactions; and, the therapeutic effect of each injection is prolonged so that a single injection produces progestational activity for 8 to 10 days. These qualities of prolonged action and relative freedom from local reactions make 17-AHPC a generally more desirable therapeutic agent than progesterone for intramuscular use, but dosage must be controlled carefully.</blockquote>
Sterility, pp. 253-56. Tyler's colleague, Dr. M Edward Davis, contributed a chapter concerning endocrine therapy for threatened miscarriage, explaining the theoretical basis for such intervention.<br />
<blockquote class="tr_bq">
Progesterone is the pregnancy hormone and the logical substance to use in threatened abortion. If it can be demonstrated that the pregnancy is still viable, this hormone can be administered in moderately large doses. This key steroid may compensate for inadequate production of hormones by the corpus luteum or early chorion. Temporary supplementation of this vital steroid may bridge the gap during the transition from corpus luteum to chorionic hormonal support of the pregnancy. </blockquote>
<blockquote class="tr_bq">
It has been argued by some authors that no therapy is indicated in patients who threaten to abort, for in more than one-half of these women threatening symptoms will subside and the pregnancies will culminate successfully. Furthermore, the high incidence of ovular defects decreases tremendously the number of pregnancies that are worth salvaging. <b>However, such an attitude of defeat and resignation does not conform with modern dynamic medicine. If only 5 or 10 per cent of patients in whom the threatened abortion would have become inevitable can be helped to carry their pregnancies by intelligent therapy it is worthwhile</b>.</blockquote>
Sterility, pp. 326-27 (emphasis mine). Dr. Davis continues his enthusiastic endorsement of the "over-abundant" clinical use of synthetic progesterones in “modern dynamic medicine” as follows:<br />
<blockquote class="tr_bq">
Until the last two years, 100 mg of progesterone in oil was administered intramuscularly to the patient four or five times each week. This was continued until she felt life at about 16 to 18 weeks if on previous occasions she belonged to the group who aborted early in pregnancy. If the pattern for previous abortions indicated that the terminations occurred most often at midpregnancy, however, the medication was continued until the baby reached a safe period of viability, about 6 weeks from term. No other steroids were administered.</blockquote>
<blockquote class="tr_bq">
The frequency of the intramuscular administration and the occasional discomfort they induced interfered to some extent in the above regimen. Unfortunately, progesterone is metabolized rapidly, for the administration of 50 mg per day to the patient who is not pregnant produces no holdover effects for longer than 48 hours. The introduction of 17a-hydroxyprogesterone caproate (Delalutin) provided a long-acting progestational agent. Although its metabolism differs from crystalline progesterone, its biologic action is similar. The length of its action is dependent on an adequate supply of estrogens. It is possible that additional estrogens may be indicated in some cases. The habitual aborter can now receive 250 mg of 17a-hydroxyprogesterone caproate intramuscularly twice a week, or even 500 mg once a week. There have been no undesirable sequelae following the administration of this new progestational agent. The administration of crystalline progesterone and 17a-hydroxyprogesterone caproate during pregnancy has not resulted in virilism in the newborns in our experience.<br />
[...]<br />
[A]n overabundance of [progesterone] may improve the uterine environment of the conceptus and result in a more adequate circulation, a more substantial implantation, and a quiescent abode for the embryo.</blockquote>
Sterility, pp. 332-333.<br />
<br />
It is very important to note that in a subset of infertility patients, the use of corticosteroids such as prednisolone was also advised. These cases included women with adrenogenital syndrome, women with amenorrhea, or infrequent menses, and with no signs of masculinization, patients with fallopian tube obstruction, patients with long- standing infertility, and a group of husbands showing oligospermia. Sterility pp. 381-82. Tyler described the clinical use of prednisolone for fertility as follows:<br />
<blockquote class="tr_bq">
Patients were given 5 mg four times daily for 2 days, then 5 mg three times daily for 2 days, and then were placed on a maintenance dosage of 5 mg twice daily for 12 weeks, or slightly longer. When therapy was to be discontinued the dosage was tapered off gradually, so that during one week 5 mg was administered daily, and the dose decreased to 5 mg every other day the following 2 weeks, then 5 mg twice a week for 2 weeks, at which time the medication was then stopped.</blockquote>
Sterility, p. 382.<br />
<br />
In sum, the literature reflects a once widespread medical practice of prophylactically drugging pregnant women who had suffered more than one previous miscarriage with heavy doses of synthetic hormones, particularly progestins, and to a lesser extent estrogens and corticosteroids, sometimes in combination with each other. This practice was particularly prevalent among somewhat upper income women who could afford the expensive therapies.<br />
<br />
I am a perfect example of a child exposed in utero to these synthetic chemicals in the 1960s. As fate would have it, I was the subject of the study, "Prenatal Exposure to Synthetic Progestins and Estrogens: Effects on Human Development," by Dr. June Reinish. Thanks to meticulous record-keeping by Dr. Reinisch and the Kinsey Institute, where she had served as director, I just recently obtained the records of my own exposures. They were:<br />
<br />
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<br />
<br />
<b>Deladroxate</b> (dihydroxyprogesterone acetophenide enanthate, maybe
combined with 10-mg <b>estradiol</b>) by injection for 7 weeks, 100
mg once a week (first trimester);<br />
<br />
<b>Deluteval</b>
(hydroxyprogesterone caproate (also known as Delalutin) plus <b>estradiol
valerate</b>) by injection 250 mg every week, for 19 weeks (second
and third trimesters); and<br />
<br />
<b>Prednisolone</b>, oral, preconception through first trimester, approx. 35 mg for 10 weeks.<br />
<br />
A birth control pill has about .2 mg of synthetic hormones. I was exposed to about 6,000 mg [note: at first I thought it was about half that] of these chemicals <i>in utero</i>, most during the first half of pregnancy, the very period during which my eggs developed. As far as I can tell, although millions of us were exposed to these insane and genotoxic anti-miscarriage protocols, I'm the only one who has recovered her prenatal records.<br />
<br />
The heavy use of synthetic hormones for anti-miscarriage began to fade in the 1970s, first with the revelations about DES toxicity in 1971, and then with the publication of various studies beginning to question the fetal impacts of these exposures, including, notably, the aforementioned 1977 study of developmental effects by June Reinisch, in which she found distinct personality differences in the exposed children, as compared to their unexposed siblings. The differences can be summed up this way: we were a bit “Aspie,” that is more independent and less groupish, and somewhat gender-bended. Reinisch and others later found prenatal corticosteroid exposure to have teratogenic effects on the fetus, including fetal growth retardation.<br />
<br />
<span style="color: red;"><b>OH DEAR, you are thinking, WHY DOES ANY OF THIS MATTER? I TURNED OUT OKAY, RIGHT?</b></span><b><span style="color: red;"></span></b><br />
<b><span style="color: red;"><br /></span></b>
<span style="color: red;">Yes,
I turned out okay, but my children are not. They are autistic. Their brains do not
work. They cannot talk. They cannot learn. They spend their days
engaged in constant stims, like shredding paper or chewing on toys. They will never have jobs. They will require tens of millions of dollars in 24/7 support over their lifetimes. And now, seemingly out of the blue, there are hundreds of thousands of others just like them.</span><br />
<br />
<b>You see, the drugs screwed up my eggs. The process of fetal germline (egg or sperm) development depends on the appropriate delivery of precise chemical messages, including hormonal molecules. Impostor hormones such as progestins, estrogens or corticosteroids, singularly and in combination, can hijack a fragile and unfathomably complex system that evolved over billions of years, upsetting the normal molecularly-controlled developmental processes necessary for normal sperm and egg development.</b> This process has been demonstrated in a great many studies over the past decade. [FN1] In addition, as mentioned above, the use of these novel synthetic medications was particularly intense in
the first half of pregnancy, which is precisely the timeframe of
epigenetic programming of the vulnerable fetal germline.<br />
<br />
<b>Did progestins, with or without combined estrogens and corticosteroids scramble the intracellular signals needed for normal epigenetic
synthesis, resulting in developmental abnormalities in our egg and sperm, and therefore in our progeny, our children? </b>In
light of the vast exposure history, what we know about germline
disruption caused by impostor hormones, and the strongly epigenetic
nature of neurodevelopment, it is more than plausible, it is indeed highly likely. Already I have found many autism families with prenatal exposure histories just like mine.<br />
<br />
It
is time for the “hidden history” of mass use of progestins and other
endocrine-disrupting synthetic steroid hormone drugs in pregnancy to
come out of the closet. Researchers are almost totally ignorant about what occurred in countless doctor's offices over several decades, resulting in one of the greatest toxic events in the history of humanity. No doubt, it will explain a portion of
the glut of quasi-genetic disorders in the generation born 1980s to
today, a generation rife with autism, ADHD, mental disorders, learning
disabilities, and other “idiopathic” public health mysteries of our era.
If there is a connection, and of course there is, the implications are vast and of profound
importance. <br />
<br />
<i><br /></i>
<i>FN1 Endocrine disrupting compounds have repeatedly been shown to induce epimutations and impact gene expression profiles of germ cells, at both low and high doses. See, eg, Manikkam et al, Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations, PLOS One 8(1): e55387. doi:10.1371/journal.pone. 0055387 (2013); Crews, Epigenetic transgenerational inheritance of altered stress responses, PNAS USA. 2012 doi: 10.1073/pnas.1118514109; Susiarjo et al 2013, Bisphenol A Exposure Disrupts Genomic Imprinting in the Mouse, PLoS Genet 9(4): e1003401. doi:10.1371/journal.pgen.1003401; Walker and Gore, Transgenerational neuroendocrine disruption of reproduction, Nature Reviews Endocrinology 7, 197-207 2011. Doyle et al. (2013), Transgenerational Effects of Phthalate on Male Germ Cells, BOR Papers in Press Published on March 27, 2013 as DOI:10.1095/biolreprod.112.106104; Manikkam et al, Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations, PLoS ONE 7(9): e46249. doi:10.1371/journal.pone.0046249 (2012); Del Mazo et al, The effects of different endocrine disruptors defining compound specific alterations of gene expression profiles in the developing testis, Reproductive Toxicology 33:1, 106–115 (2012).</i><br />
<br />Unknownnoreply@blogger.com49tag:blogger.com,1999:blog-471663631306140712.post-89820553568840759752013-05-10T15:47:00.000-07:002013-05-10T17:41:30.125-07:00Now for some good news: the NIEHS seeks input on multigenerational consequences of exposures<div class="separator" style="clear: both; text-align: center;">
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<br />
Kudos to the NIEHS (National Institute for Environmental Health Sciences)! They seem to be sensing that something is going on with multigenerational consequences of chemical, pharmaceutical and other exposures, and ... they want to hear from us about it. Responding to their <a href="http://ntp.niehs.nih.gov/?objectid=86D060C9-060B-A580-7FB68D3F8243F240">Request for Information (RFI): Input on a Literature Review Approach “Evaluation of the State of the Science for Transgenerational Inheritance of Health Effects”</a>, I penned the following letter.<br />
<br />
Let's hope this nascent effort on their part opens new doors to understanding autism etiology and the hidden sources of other raging public health disasters.<br />
Jill E<br />
-------------------------------------------<br />
<br />
Jill Escher<br />
Escher Fund for Autism<br />
jill.escher@gmail.com<br />
<br />
Vickie R. Walker <br />
Health Scientist <br />
Office of Health Assessment and Translation <br />
Division of the National Toxicology Program <br />
National Institute of Environmental Health Sciences<br />
111 TW Alexander Dr., PO Box 12233 MD: K2-04<br />
Durham, NC 27709 <br />
<br />
<br />
May 10, 2013<br />
<b><br /> Re: Input on “Evaluation of the State of the Science for Transgenerational Inheritance of Health Effects”</b><br />
<br />
Dear Dr. Walker and OHAT,<br />
<br />
I appreciate this opportunity to respond to the RFI on multigenerational impacts of ancestral exposures. Based on personal experience, as well as interviews with more than 70 autism families and the extant scientific literature, I share the concern that certain chemical and pharmaceutical exposures, given in certain timeframes of susceptibility, can, via molecular epigenetic impact on germline, adversely affect the health and developmental integrity of subsequent generations, sometimes dramatically.<br />
<br />
I am grateful that the NIEHS is exploring this urgent question, and would like to provide the following comments. As background to my involvement in this field (as it’s not common for a non-scientist to take such a keen interest), please see a short video regarding my personal story at <a href="http://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_es.html">http://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_es.html</a>. Simply scroll down to the top video, called, “An autism mom asks: Who says you can’t have a genetic epidemic?”<br />
<br />
<b>A. Comments on the proposed approach for exploratory screening: (1) importance of direct germline impacts, (2) targeting highly impactful exposures, and (3) adding additional relevant search terms</b><br />
1. <b>Direct germline (in F1 or F2) exposure effects are of utmost importance, and should be central to OHAT’s inquiry.</b><br />
<br />
As the NIEHS evaluates the state of the science in this area, it should involve a strong focus on the health and developmental effects of direct germline exposures, in other words, exposures that directly affect the molecular genetic integrity of the sperm, egg, or their precursors. These direct germline exposures can occur in at least three ways:<br />
<br />
(1) Exposure of fetal germ cells, affecting F2 health. In a gestating female (F0), the fetus would be F1, and the fetal germ cells F2. If the F0 female takes a pharmaceutical or drug, smokes cigarettes, or is otherwise exposed to a stressor, that stressor may impact the F1 fetus as well as the fetal germline (F2), which is highly epigenetically vulnerable to exogenous exposures during the first half of gestation. F2/fetal germline exposures were rampant in the mid-20th century, with almost unrestrained prenatal pharmaceutical use, widespread maternal smoking, the use of potent endocrine disruptors such as dioxin, flame retardants, PCBs and DDT, and even air pollution.<br />
<br />
(2) Exposure of the very early embryo, affecting F1 health. At around the time of fertilization, abnormal exposures can affect the germline epigenome. As the embryonic stem cell epigenome is altered due to this germ line transmission, all the resulting organismʼs cell populations and tissues will have an altered epigenome and corresponding transcriptome. Although not all cell types or tissues will develop a disease state, those tissues that have a sufficiently altered transcriptome will have a greater susceptibility to abnormal development. Two examples of abnormal exposures that could affect the F1 early embryo are:<br />
<br />
--IVF and assisted fertility: Assisted reproductive technology (ART) may play a role in the etiology of some cases of ASD through epigenetic perturbations, particularly loss of DNA methylation in the early embryo. Various ART factors contributing to epigenetic disturbance include artificial ovulation induction, culturing of cells in certain media, and the physical manipulation of germ cells and early embryos.<br />
<br />
--Oral contraceptive pills: Although birth control pills are generally effective at preventing pregnancy, many women continue, unaware, to take the pills post-conception. These pills are made from synthetic hormones, which are likely to have epigenetic impacts on the egg and early embryo.<br />
<br />
(3) Exposure of the post-natal gametes, affecting F1 health. In the male, for example, it takes two months for a spermatozoa to mature from the spermatogonial stem cells. During this time, the developing sperm are vulnerable to exogenous exposures, and paternal drug or pharmaceutical use or smoking, for example, may impair the proper synthesis of the germline epigenome. Unlike other cells, sperm are lacking in internal mechanisms that repair DNA.<br />
<br />
The idea that exposures to the germ cells can impact health and development of the later-resulting organism is largely noncontroversial. Unfortunately, however, these impacts are ignored almost entirely in the FDA and EPA safety review processes, and have not been evaluated in NIH studies apart from some study of the DES third generation. Moreover, these exposures are likely extremely relevant to many of today’s public health challenges, including skyrocketing rates of neurodevelopmental disability (autism spectrum disorders included), asthma, diabetes, autoimmune disease, and obesity. <br />
<br />
In sum, while “transgenerational” effects that do not stem from direct exposures are also extremely important, OHAT’s present inquiry should begin with the more fundamental and relevant (yet under-explored) question of direct germline effects of xenobiotic exposure, since that is where ancestral exposures are likely to have greatest effect, and where all multigenerational consequences on gene expression begin.<br />
<br />
<b>2. Stressors to be studied. I would like to suggest four particular categories for ancestral stressors for study. </b><br />
<br />
a. Gestational exposures: Historic prenatal pharmaceutical use of the 1950s-70s, plus current prenatal pharmaceutical use<br />
<br />
The Prenatal Pharmaceutical Craze of the 1950s, 60s and 70s – though largely forgotten by the public, historians, and researchers – ranks among the most toxic events in human history, as it placed acute doses of potent synthetic chemicals and endocrine disruptors directly into the bodies of pregnant women, and therefore, their fetuses and germline. Countless millions of us were exposed.<br />
<br />
In the decades after the war, chemical and drug companies produced an explosion of novel synthetic pharmaceutical products, and the medical profession, intoxicated by the same boundless faith in the progress of science that gripped the rest of the country, was eager to administer the new concoctions to its patients, including pregnant women. An excerpt from the book, “Origins,” by Annie Murphy Paul (2010) summarizes the history, beginning with the medical profession's early views regarding the risks of alcohol:<br />
<br />
Doctors' confidence in the harmlessness of alcohol was based on their beliefs about the placenta. This organ, which implants itself in the uterus soon after conception to form a way station between woman and fetus, was thought to provide seamless protection from harmful substances. Medical historian Ann Dally traces this sanguine notion back to the attitudes of the late nineteenth century. "The Victorian tendency to put woman on a pedestal led to the idealization of the woman as well as of the woman," she writes, and to 'a belief in the placenta as a perfect barrier against damaging influences." This conviction was still current in the 1950s, when Dally attended medical school; there she was taught that a toxin would affect the fetus only if it actually killed the mother. Pregnant women were not counseled about the dangers of medications or alcohol, Dally notes, and new drugs were not thoroughly tested for their safety during pregnancy.<br />
<br />
And new drugs there were in abundance. The middle of the twentieth century was a golden age of pharmaceutical innovation, a time when serene sleep and steady nerves and a slim figure could be found inside the medicine cabinet. Pregnant women, too, were promised relief from all the complaints, small and large, of their condition: sleeplessness, morning sickness, miscarriage. The remedies were touted by advertisers in women's magazines, and by the publications' writers and editors themselves; an article about miscarriage in the November 1950 issue of Women's Home Companion celebrated "the miracle drugs that have tumbled from the laboratories in such heartening profusion recently." The sales job worked: those who gave birth in the postwar years, writes one chronicler of the period, "were among the most medicated women in history." Between 1958 and 1965, according to one study, half of all new mothers took two to four pharmaceutical products while pregnant.<br />
<br />
Origins, pp 79-80.<br />
<br />
What have been the germline effects of this unprecedented mass use of gestational synthetic pharmaceuticals? We don’t know. No one has yet asked the question. The pharmaceutical exposures of concern include synthetic hormones (progestins, estrogens, corticosteroids, thyroid hormones), barbiturates and other sedatives, psychoactive drugs, amphetamines, anti-nausea medications, and anti-hypertensives, among others.<br />
<br />
As for the synthetic hormones, this information from a 1969 medical text, “The Use of Progestins in Obstetrics and Gynecology,” by RW Kistner explains the old standard of care for “habitual aborters,” defined as women who had two or more miscarriages, and the acute nature of the timing and dosage:<br />
<br />
Provera: ... 10 mg daily, orally, during the first trimester of pregnancy; then 20 mg daily, orally, during the second trimester and 30 mg, daily, orally, during the third trimester.<br />
<br />
Delalutin: (hydroxyprogesterone caproate) 375-500 mg (3-4 cc., intramuscularly) every week, starting as soon as pregnancy is confirmed and continuing to fetal viability.<br />
<br />
Deluteval (hydroxyprogesterone caproate plus estradiol valerate): 500 mg. Delalutin plus 10 mg Delestrogen, intramuscularly, every week from the time of confirmation of pregnancy until fetal viability.”<br />
<br />
“If progesterone is administered, it is best started before conception and continued during pregnancy.... Progesterone, hydroxyprogesterone caproate and oral medroxyprogesterone acetate may be used in the prophylatic management of the habitual aborter.”<br />
<br />
Also advised, for example by Edward Tyler in his influential 1960 book, “Sterility: Office Management of the Infertile Couple,” was the use of prednisolone very early in the at-risk pregnancy.<br />
<br />
It is worth noting that no evidence shows these old enhanced hormonal methods (which continue to various degrees in some assisted fertility practice) were effective at sustaining pregnancy or reducing miscarriage rates. The old practices were based purely on hypothesis and conjecture and not empirical data.<br />
<br />
b. Gestational and non-gestational exposure case study: Flame retardant disaster of Jackson County, Michigan<br />
<br />
In 1973, it was discovered that Michigan Chemical had accidentally used the flame retardant chemical PBB instead of a vitamin additive for cattle feed.<br />
That contaminated feed was then fed to cattle, pigs, and chickens throughout Michigan. It's estimated that nine out of 10 Michiganders consumed contaminated meat, dairy, or poultry during the two years it took to discover the human error.<br />
For the past 40 years, the Michigan Department of Community Health and now Emory University have been involved in studying the effects that consumption of PBB-contaminated food has had on human health. Research found an increase in breast cancer, thyroid disease, and early puberty in girls, as well as infertility in women born to mothers who consumed the PBB-contaminated food. Phase II of the research is now looking at additional cancers, Alzheimer's, Parkinson's, and fertility problems in males born to mothers who consumed the PBB-contaminated food. <br />
As this is among largest studies of human chemical contamination in the world, I suggest OHAT’s evaluation look closely at the data for germline and multigenerational effects.<br />
c. Non-gestational exposures: Dioxin and DDT<br />
<br />
Both dioxin and DDT are potent endocrine disruptors to which people, particularly in certain localities, suffered acute exposures in the mid 20th century. Both chemicals accumulate in fatty tissue and persist in the body for many years. Therefore, a fetus and its germline can be considered “exposed” to these chemicals many years after the parental contact with the chemicals, owing the parental body burden.<br />
<br />
These compounds should be of particular concerns, for reasons expressed so well in the landmark book, “Our Stolen Future.”<br />
<br />
“Hormonally active synthetic chemicals are thugs on the biological information highway that sabotage vital communication. They mug the messengers or impersonate them. They jam signals. The scramble messages. They sow disinformation. They wreak all manner of havoc. Because hormone messages orchestrate many critical aspects of development, from sexual differentiation to brain organization, hormone-disrupting chemicals pose a particular hazard before birth and early in life.” (Pp 263-64.)<br />
<br />
I would suggest reviewing the literature on multigenerational effects of Agent Orange, PCBs, and DDT. With respect to Agent Orange I would suggest partnering with the military to access their studies and files. Agent Orange was tested domestically before it was used in Vietnam, but finding data from those exposed in Vietnam, whether US soldiers or native Vietnamese, is exceedingly important. It is worth noting that autism rates among both the US military and the Vietnamese (families of immigrants to the US, and in Vietnam itself) have skyrocketed.<br />
<br />
d. Non-gestational exposures: paternal pre-conception smoking, drug or pharmaceutical use, ionizing radiation<br />
<br />
In the male, for example, it takes two months for a spermatozoa to mature from the spermatogonial stem cells. During this time, the developing sperm are vulnerable to exogenous exposures, and paternal drug or pharmaceutical use or smoking, for example, may impair the proper synthesis of the germline epigenome. Unlike other cells, sperm are without internal mechanisms that repair DNA.<br />
<br />
Men are not warned about the risks to their sperm integrity caused by pre-conception exposures. Yet, there is literature to suggest this is occurring.<br />
<br />
<b>3. Additional search terms.</b><br />
<br />
The approach to conduct the exploratory screening of the literature should include these additional search terms, in various combinations as may be appropriate: “germline,” “germ cell,” “primordial germ cell,” “spermatogonial stem cell,” “epigenetic,” “methylation,” “histone,” “in utero,” “intrauterine,” “prenatal,” and “gestational.” <br />
<br />
<b>B. identification of scientists with knowledge or expertise relevant to this topic. </b><br />
<br />
The following is a list of scientists of whom I am aware, who are involved in this or closely related areas of research.<br />
<br />
[omitted from blog]<br />
<br />
<b>C. Unpublished, ongoing, or planned studies related to transgenerational inheritance</b><br />
<br />
In many ways, experiments in multigenerational experiments on human subjects have already been done, as acute gestational exposures to synthetic chemicals, given in the form of pharmaceutical drugs, were widespread after World War II, particularly in the 1950s, 60s, and into the 70s. In an effort to look at F2 outcomes of these historic exposures, I have been working with epidemiologists to locate cohorts for which there are both F0 reliable gestational exposure records and a good likelihood of obtaining F2 health and developmental outcomes. As you can imagine, this is not an easy task.<br />
<br />
That said, one such epidemiological study is in the works, funded by our fund and Autism Speaks. It is a first-of-its-kind three-generation study based on Denmark’s Prenatal Development Project Cohort, a cohort of women who gave birth in about 1960 at a Copenhagen hospital. Thanks to Denmark’s system of health registries, the researchers, Reinisch and Mortensen, hope to be able to cross reference the F0 exposures to the F2 grandchildren. The F0 exposures are primarily synthetic hormone drugs, barbiturates, other drugs common in that era, and cigarette smoking. You can learn details about this new study in a video posted here: <a href="http://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_es.html">http://www.ucdmc.ucdavis.edu/mindinstitute/videos/video_es.html</a> (scroll down to video featuring Reinisch and Mortensen).<br />
<br />
Other cohorts being investigated for possible grandchild-effect studies include the CHDS, the CPP, and a cohort in Israel. Of personal interest are smaller cohorts, for which there are outstandingly detailed prenatal drug exposure records, from Los Angeles in New Jersey. The F1 offspring of these pregnancies were studied by Reinisch in the 1970s (as a child, I was a subject in her 1977 Los Angeles study). However, these studies are not yet underway.<br />
<br />
<br />
In closing, the process of germline development depends on the appropriate delivery of precise chemical messages, including hormonal molecules. Impostor hormones and other synthetic chemicals can hijack a fragile and unfathomably complex system that evolved over billions of years, upsetting the normal molecularly-controlled developmental processes necessary for normal sperm and egg development. And these perturbations may have multigenerational consequences.<br />
<br />
Thank you for your interest in multigenerational impacts of exposures and for your consideration of these comments.<br />
<br />
<br />
Respectfully submitted,<br />
<br />
Jill EscherUnknownnoreply@blogger.com4tag:blogger.com,1999:blog-471663631306140712.post-75451594883057633552013-05-04T08:02:00.000-07:002013-05-04T09:25:08.592-07:00The Autism Epidemic: How Hormone Disruptors Blindsided Us Again<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgdGx5ma1b4PxwXO1zmphXn8TmsCvyiCJVkgyKllXmd687Ck8NthILHNLq8TKfFN3v0-rNi84Z4w0hnmWeTsATiyWLTSRNWU0_1CJx6Z3-U5xoZbitVkPNES5iZsV6ktslEUR18iTcwUbu9/s1600/our-stolen-future1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgdGx5ma1b4PxwXO1zmphXn8TmsCvyiCJVkgyKllXmd687Ck8NthILHNLq8TKfFN3v0-rNi84Z4w0hnmWeTsATiyWLTSRNWU0_1CJx6Z3-U5xoZbitVkPNES5iZsV6ktslEUR18iTcwUbu9/s200/our-stolen-future1.jpg" width="135" /></a><br />
<br />
<i>by Jill Escher</i><br />
<br />
I’m a mom, investor, philanthropist, volunteer, ex-lawyer, Jewish girl from Beverly Hills, landlady, wife, mild shopaholic, disability housing advocate, Stanford alum, Cal alum, walk-lover, writer about nutrition, and I wear many other hats, but there are two things for present purposes that loom above all others: first, I was endocrine-disrupted <i>in utero</i> via intense doses of synthetic hormone drugs, and second, I am mother to two mysteriously neurodevelopmentally disabled (autistic) children.<br />
<br />
And one more thing: <a href="http://prenatalexposures.blogspot.com/2013/04/autism-genetic-epidemic.html">my prenatal drug exposures</a>, which were well intended by the pharma-happy medical establishment of the 1960s, but wildly reckless and foolhardy in hindsight, affected not just me but also my little tiny developing eggs, most likely causing my children’s bizarre and unprecedented abnormalities. How? By dysregulating the programming of my germ cells’ epigenome. The epigenome comprises all the countless millions of little chemical switches that provide the instruction book for the underlying DNA. In interfering with a highly conserved evolutionary process based on signaling by natural hormones with very particular chemical structures, those exposures shredded those instruction books.<br />
<br />
These acute endocrine-disrupting drug exposures, which were common in the latter half of the 20th century in the form of countless prenatal pharmaceutical drugs, smoking, and persistent environmental chemicals like PCBs, DDT, and dioxin, <i>affected untold tens of millions of fetuses</i>. And their <i>eggs</i>. And their <i>sperm</i>. And therefore, <i>the development of their later-conceived children</i>. Children born roughly from the 1980s through today. The precise period coinciding with the epidemics of autism and related neurodevelopmental disorders.<br />
<br />
The only difference between me and millions of others is that I have my prenatal records, and they don’t. Almost no one has seen the records of what drugs they were exposed to in utero, even though the scientific community is in broad agreement that fetal exposures can and often do have lifelong health consequences, for ourselves and for our children. The lack of records is in itself a massive tragedy.<br />
<br />
IMFAR, the world’s largest conference about autism, took place this week. Thousands of researchers trying their darndest to figure out autism all converged in one place. Lots of papers about genetics, some about environment, loads on early identification (who cares, it hardly matters), early intervention (in truth, it barely helps), brain scanning (won’t tell you much), but almost nothing on gene-environment interaction. Almost nothing on epigenetics. And absolutely nothing on what could be causing so much de novo havoc in our kids’ genomes, or the horrible history of prenatal exposures of the 20th century.<br />
<br />
Now, I know next year will be different. Slowly researchers are waking up to the idea that something weird is happening to our genes (and though I sound frustrated at the slow pace of progress, trust that I am exceedingly grateful to the many enlightened researchers with whom I have been working). And environmental epigenetics is bit by bit emerging as a likely culprit. But, unfortunately, the vast majority of autism research remains blinded by the passe, discredited view of genetics in which the genome is essentially imperturbable and protected from environmental influence. Indeed, the vast majority of autism research funding goes towards projects based on the broken, old, Mendellian genetic point of view.<br />
<br />
As I think about my own synthetic chemical history, I wonder, “Couldn’t anyone have seen this coming? Isn’t is obvious that fake hormones would f*ck our egg and sperm and give rise to a generation of developmentally disfigured children?"<br />
<br />
Well, I guess not. No one saw it coming. No one wanted to think about the germline. Not the FDA, not the EPA, not the drugmakers, not the physicians. And while the catastrophic autism epidemic rages unabated, threatening to overwhelm our educational and social services systems, and imposing incalculable misery and cost on a mystified and burdened populace, it will take years to advance these ideas into the mainstream. <br />
<br />
On the other hand, maybe someone did see it coming. In 1996, Colborn, Dumanoski and Myers published their landmark book on the immense and irreversible damage caused by endocrine disrupting chemicals, “<a href="http://www.amazon.com/Our-Stolen-Future-Threatening-Intelligence/dp/0452274141">Our Stolen Future</a>.” Though they do not directly address autism or the germline, they issue this prescient warning about the unpredictable and devastating effects of hormone-disrupting chemicals:<br />
<blockquote>
“Judging from past experience, it may take a generation for the next nasty surprise to emerge. When it comes it will show up where we least expect it.... The safer bet, however, is that the surprise will be something never even considered. If anything is certain, it is that <b>we will be blindsided again</b>.” (See p 242 paperback edition (emphasis mine).)</blockquote>
While the authors focus on the deleterious impacts on somatic cells, they perfectly characterize germline havoc as well, that hidden history precipitating today’s "nasty surprise."<br />
<blockquote class="tr_bq">
“Hormonally active synthetic chemicals are thugs on the biological information highway that sabotage vital communication. They mug the messengers or impersonate them. They jam signals. The scramble messages. They sow disinformation. They wreak all manner of havoc. Because hormone messages orchestrate many critical aspects of development, from sexual differentiation to brain organization, hormone-disrupting chemicals pose a particular hazard before birth and early in life.” (Pp 263-64.)</blockquote>
The process of germline development depends on the appropriate delivery of precise chemical messages, including hormonal molecules. Impostor hormones hijack a fragile and unfathomably complex system that evolved over billions of years. Synthetic chemicals have derailed human evolution, upsetting the normal molecularly-controlled developmental processes necessary for normal sperm and egg development, and have invisibly unleashed an epidemic that threatens not only our budgets and culture, but also the very foundations of our humanity.<br />
<br />
We've been blindsided, yes, but for how much longer must we remain blind? <br />
<br />Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-471663631306140712.post-84793782127716341572013-05-02T08:20:00.002-07:002013-05-02T21:17:49.352-07:00The Federal Response to the Autism Epidemic: Unforgivable Shoulder Shrugging and Denial<div class="separator" style="clear: both; text-align: center;">
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<br />
<br />
<i>by Jill Escher</i><br />
<br />
Today we are faced with one of the greatest catastrophes in the history of humanity -- the soaring rates of devastating, disabling neurodevelopmental abnormalities among our children. Children who will often need lifelong care, who will not work, pay taxes, be able to help defend our country, or bear children. We call the spectrum of abnormalities "autism," a condition that, under any label, barely existed even several decades ago.<br />
<br />
While our schools overflow with jumping, flapping, darting, cognitively impaired, nonverbal kids in rapidly proliferating special needs classrooms, while our already-stressed developmental services agencies get flooded daily with new clients needing therapy, programs, housing, and intensive lifelong care, while states report 10 and 20-fold increases in autism rates, while the CDC itself admits the numbers are 1 in 88, or maybe even 1 in 50, and while the costs to society are predicted to run into the hundreds of billions of dollars per year, what is the federal response?<br />
<br />
<i>"What autism epidemic?"</i><br />
<br />
In what must be one of the most shameful chapters in public health history, or perhaps in history, <i>period</i>, our government officials seem to have made the decision to stick their collective heads in the sand about the scope and devastation of this horrible epidemic. <br />
<br />
Baffled by the reports of skyrocketing numbers, and unable to make sense of it based on the science with which they are familiar, they say again and again that the rates must be due to better detection and awareness. They say, as was a theme at the last IACC meeting, that rates can't be increasing because, as we all know, autism is "genetic."<br />
<br />
If you don't understand something (and our federal staffers are clearly insufficiently schooled about environmental epigenetics), the easiest route is denial it exists. <b>Where is a federal champion expressing urgency about this catastrophe? </b>Are they all too spineless and gutless to speak the obvious for fear of some sort of reprimand or scar on their reputations? I, for one, cannot comprehend the silence and shoulder shrugging from our officials, who must be smart enough to know better. Well, one would hope.<br />
<br />
I possess a bit of discretion and will therefore not repeat publicly some of the discussions I have had with various federal staffers about finding the causes of the autism epidemic. Suffice it to say that what they tell me in private differs markedly from the "we just don't know" meme they repeat endlessly in public.<br />
<br />
Where, oh where, is the urgency? If the brains of 1 or 2 of every 100 kids in America was sprayed with bullets, or if a million kids came down with mental retardation-causing brain disease, we would respond with the utmost astonishment, horror and vigor. But that is pretty much exactly what's happening, and the response is so timid as to almost not exist. Shame on them. Shame on our country. Shame.<br />
<br />
<br />Unknownnoreply@blogger.com1tag:blogger.com,1999:blog-471663631306140712.post-62806741767737013782013-04-25T20:02:00.000-07:002013-05-02T07:51:55.342-07:00Dear FDA, Stop overlooking the worst birth defect of all<br />
<div class="separator" style="clear: both; text-align: center;">
<b><i><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEirXPicPWztizOW58oMpfWuhpS_kewC1cJ8zyfX40V0gHmRM6mlkusuR9g3NrCoZ16YCts8wo7YslpTQzWATyiEoxVSdlcJDm-HesB47oH8ENUoy2BhRm5vNvvTScTqOVTBzbCOgiWu4swa/s1600/Tank-Man.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="180" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEirXPicPWztizOW58oMpfWuhpS_kewC1cJ8zyfX40V0gHmRM6mlkusuR9g3NrCoZ16YCts8wo7YslpTQzWATyiEoxVSdlcJDm-HesB47oH8ENUoy2BhRm5vNvvTScTqOVTBzbCOgiWu4swa/s320/Tank-Man.jpg" width="320" /></a></i></b></div>
<b><i> </i></b><br />
<b><i>In the face of a gargantuan bureaucracy that really does not want to be bothered, can one person possibly make a difference? </i></b><br />
<br />
<b><i>Today I submitted a Citizens Petition to the FDA regarding fetal germline impacts of prenatal pharmaceutical exposures. The petition, below, is rather long, so here's a summary:</i></b><br />
<br />
<span style="color: red;">• Babies are born with their eggs or proto-sperm (germline) largely developed.</span><br />
<span style="color: red;">• The germline develops, for the most part, in the first half of pregnancy.</span><br />
<span style="color: red;">• During that period, the DNA programming ("epigenome") is exposed and vulnerable to damage by chemicals and drugs.</span><br />
<span style="color: red;">• Everybody (but the FDA, it appears) knows about germline epigenetic susceptibility.</span><br />
<span style="color: red;">• The FDA assesses drug impacts on fetal somatic tissues, but not germline cells.</span><br />
<span style="color: red;">• This is a catastrophic omission. </span><br />
<span style="color: red;">• When the germline is damaged, the resulting pathologies in the subsequent generation can be devastating.</span><br />
<span style="color: red;">• It is irrational and unconscionable for the FDA to continue to ignore fetal germline impact caused by gestational drug exposures.</span><br />
<span style="color: red;">• Americans and their medical providers deserve to know of potential germline risks.</span><br />
<br />
<b><i>Will common sense prevail? Or will the FDA continue to sail against the scientific winds? Stay tuned for their response.</i></b><br />
_____________________________________________________________________________<br />
<br />
<br />
Division of Dockets Management<br />
Food and Drug Administration<br />
Department of Health and Human Services<br />
5630 Fishers Lane, rm. 1061<br />
Rockville, MD 20852<br />
<br />
April 26, 2013<br />
<br />
<b>Re: Citizen Petition to: (1) Revoke Approval for Diclegis (doxylamine succinate and pyridoxine hydrochloride) Pending Fetal Germline Safety Assessment; and (2) Revise Pregnancy Drug Labeling Rules to Alert Consumers to Potential for Fetal Germ Cell Perturbation</b><br />
<br />
To the Commissioner of the Food and Drug Administration:<br />
<br />
The undersigned respectfully submits this petition in accordance with 21 C.F.R. 10.30, and pursuant to the written suggestion of Nancy Hayes, Acting Director, Office of Regulatory Policy, Center for Drug Evaluation and Research (letter to Escher dated April 16, 2013), to request that the Commissioner of Food and Drugs revoke approval for the drug Diclegis (doxylamine succinate and pyridoxine hydrochloride) pending fetal germline impact assessment, and to issue additional pregnancy label warnings for all drugs regarding potential for fetal germ cell perturbation.<br />
<br />
<b>A. Action requested</b><br />
<br />
This petition requests that the Commissioner take the following actions:<br />
<br />
(1) Revoke the March 2013 order approving Diclegis as a Category A drug for pregnancy and require the drugmaker/applicant to conduct thorough safety testing regarding fetal germline impact of continuous gestational exposure to the drug prior to any subsequent FDA consideration of approval or labeling; or, at a minimum, re-categorize Diclegis as a category “C” pregnancy drug pending adequate testing; and<br />
<br />
(2) Revise regulation of OTC and prescription drug labeling to expressly include potential for fetal germline perturbation among enumerated pregnancy medication risks. Pending appropriate testing of individual drugs, both individually and in combination with other drugs, a blanket warning should be added to all medications, as follows: <br />
<br />
“Fetal Risk. A potential risk of taking a medication during pregnancy includes damage to the baby’s vulnerable germ cells (egg or sperm precursors), which may cause disease or developmental disorders in the next generation, your grandchildren. This drug has not yet been tested for fetal germline impact. Because of potential for multigenerational impacts, you are advised to use caution before taking this drug in pregnancy.”<br />
<br />
<b>B. Statement of grounds</b><br />
<br />
This petition is made pursuant to 21 U.S.C. Sec. 355-1(b)(3) to present to the FDA “new safety information” regarding both a particular drug and a class of drugs in general. Under that statute, new safety information may include “scientific data deemed appropriate by the Secretary about a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved.”<br />
<br />
The term “serious risk” means a risk of a serious adverse drug experience. 21 U.S.C. Sec. 355-1(b)(5). A “serious adverse drug experience” is defined an adverse drug experience that results in, among other things, “a congenital anomaly or birth defect.” 21 U.S.C. Sec. 355-1(b)(4).<br />
<br />
This petition presents a new analysis of existing information that calls out the increased risks of serious birth defects caused by exposure to Diclegis and other gestational drugs in the form of impaired development of fetal germline, the delicate and submicroscopic genetic and epigenetic material within germ cells (egg and sperm precursors) that gives rise to the subsequent generation. Impairment of the molecular programming of a baby’s germline represents a harrowing paradox: minute, invisible, latent birth defects, but with potentially catastrophic consequences that appear in greatly magnified form only many decades after the initial exposure, and in separate and distinct organisms, that is, the children of exposed fetuses.<br />
<b><br /> 1. Overview: environmentally induced fetal germline impairment</b><br />
<br />
Comprehension of the petitioner’s request must begin with the understanding that gestational drug exposures affect three generations at once: the mother, her fetus (child), and the fetal germ cells (child’s future children). The fetal germ cells, sometimes called stem cells, are the precursors to the baby’s egg or sperm, containing both the genetic and epigenetic material, together providing the complicated instruction book for the development of the next generation. Although it is textbook knowledge that prenatal exogenous exposures can permanently perturb the epigenetic programming of the germline, to date the FDA has not made any attempt to ascertain fetal germline impacts of any drug taken by pregnant women or to warn women and their partners, or even their medical providers, of this vast dimension of profound risk. <br />
<br />
Complicating matters, and therefore the relevant adverse drug effect information that tends to reach FDA staff, people who have been exposed in utero to gestational drugs lack access to the medical or other records showing the nature and extent of their prenatal exposures, leaving them without knowledge of silent insults which may have triggered lifelong consequences for themselves and/or their children. Lack of information does not equate to lack of impact, however; and most assuredly many mysterious and increasingly prevalent pathologies suffered today are at least in part the result of germline havoc wreaked by long-forgotten prenatal drug exposures of a previous era.<br />
<br />
It is well known that fetal germline epigenetic reprogramming is vulnerable to damage by exogenous compounds, particularly man-made, synthetic “Franken-molecules” that mimic natural biochemistry and hormones, but disrupt the very precise biochemical process of germline development which was forged over millions of years of mammalian evolution. The germ cells are not only the most vulnerable of all human tissues during early embryonic development, and they are of course also the most important in the child’s body, assuming that child desires to reproduce upon reaching maturity. Submicroscopic molecular disturbance of the germline, whether considered mutation or epimutation, could, during development of the resulting child, become magnified as a subtle, moderate or severe developmental abnormality or disease. This is owing to abnormal gene expression caused by permanent de novo aberrations affixed during germline construction.<br />
<br />
<b> 2. Scientific support for fetal germline impairment and pathology in successive generation</b><br />
<br />
Far from being inert marbles of immutable DNA sequences, our germ cells are highly vulnerable to environmental interference, particularly during susceptible periods of development. The epigenome of the germ cell is known to be susceptible to environmental influences. (Skinner, Birth Defects Research (Part C) 93:51–55 (2011).) Indeed, because of the inherent lability of the epigenome, this represents a primary target for environmentally induced disruption. (See, eg, McCarrey, The epigenome as a target for heritable environmental disruptions of cellular function, Molecular and Cellular Endocrinology, Volume 354, Issues 1–2, 9-15, 2012.) Petitioner will briefly address three points relevant to in utero exposures of the fetal germline: (1) the particular vulnerability of the fetal germline; (2) sources of germline epigenetic perturbation; and (3) evidence for resulting neurodevelopmental pathologies.<br />
<br />
But first, a note. While some may protest, “most germline impairment research examines effects of ambient environmental chemicals, not pharmaceutical drugs,” the biochemistry of the body and its component cells does not distinguish between chemicals marketed as therapeutic agents and other chemicals marketed for other purposes, such as the killing of vermin or the softening of plastics. What matters is the timing, dose and nature of compound, its chemistry and metabolites, and not how it is packaged and marketed to the public. Indeed, for the vast majority of people, their most acutely toxic, high-dose abnormal, xenobiotic and/or endocrine-disrupting environmental exposures come in the form of drugs and pharmaceuticals, not pesticides, fungicides, smog, smoking or water pollution. This is especially true for fetuses.<br />
<br />
<b> a. The germline reprogramming window of susceptibility</b><br />
<br />
It is well established that the epigenome is inherently more susceptible to environmental disruption than the genome. (See McCarrey 2012.) The idea that the human germline epigenome is particularly sensitive to derangement by exogenous exposures during certain windows of susceptibility, including early fetal development, is, likewise, non-controversial. (Skinner, Birth Defects Research 2011.) The timeframe of greatest concern is the period of gonadal development during early gestation, approximately weeks 6-18 in humans. Ibid.<br />
<br />
The vulnerability stems from the fact the fetal germline epigenome is denuded of most existing epigenetic tags and dynamically remodeled in a sex-specific manner during that timeframe. In human fetuses of both genders, primordial germ cells enter genital ridges, and then enter a premeiotic stage and undergo rapid DNA demethylation followed by sex-specific de novo methylation. (Durcova- Hills et al., Influence of sex chromosome constitution on the genomic imprinting of germ cells, PNAS 2006 Jul 25;103(30); Anway et al., Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308:1466–1469 2005; Guerrero-Bosagna C et al., Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE 5:e13100 (2010).; Anway et al., Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147:5515–5523 2006; Anway et al., Transgenerational effect of the endocrine disruptor vinclozolin on male spermatogenesis, J Androl 27:868–879 2006; Anway and Skinner, Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease. Prostate 68:517–529 2008; Chamorro-Garcia, Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal obesogen tributyltin in mice, Environ Health Perspect (2013): .doi:10.1289/ehp.1205701 (2013).) Methylation is only one of the epigenetic processes affected by in utero exposures. Histone modification, among other molecular modifications to DNA, can also be affected. (Walker and Gore, Transgenerational neuroendocrine disruption of reproduction, Nature Reviews Endocrinology 7, 197-207 2011.)<br />
<br />
In the female fetus, germ cells mature before birth, whereas in males these cells develop after the onset of puberty, allowing for additional susceptibility to environmental insults. Prenatal exposures have been demonstrated to impact fetal oogenesis at the onset of meiosis in the fetal ovary and the formation of follicles in the perinatal ovary. (Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey Hunt et al., doi: 10.1073/pnas.1207854109 PNAS September 24, 2012.) Transmission of DNA methylation occurs mainly through maternal gametes. (De Assis, High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring, Nat Commun. 2012; 3: 1053.) In theory, this means that dysregulation of a female fetus’s germ cells may cause greater impairment in subsequent offspring than in utero insults to the male.<br />
<br />
As the embryonic stem cell epigenome is altered due to this germ line transmission, all the resulting organism’s cell populations and tissues will have an altered epigenome and corresponding transcriptome. (Anway et al., 2008; Skinner et al., 2010.) Although not all cell types or tissues will develop a disease state, those tissues that have a sufficiently altered transcriptome will have a greater susceptibility to abnormal development. (Skinner et al., 2010. Furrow et al, Environment-sensitive epigenetics and the heritability of complex diseases. Genetics 189:1377–87 (2011).) Normal epigenetic gene regulation is essential for normal development, and consequently, environmentally induced dysregulation of the epigenome will promote abnormal development. Epigenetic changes to somatic cells, such as those triggering various forms of cancer, are often reversible, but altered epigenetic markers of germline are not; they are fixed through the development of the organism and are irreversible.<br />
<br />
<b> b. Sources of epigenetic perturbation</b><br />
<br />
The character, dose, and duration of the in utero exposures will affect the extent of epigenetic disfigurement of the fetal germline. Endocrine disrupting compounds, for example, have repeatedly been shown to induce epimutations and impact gene expression profiles of germ cells, at both low and high doses. (See, eg, Manikkam et al, Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations, PLOS One 8(1): e55387. doi:10.1371/journal.pone.0055387 (2013); Crews, Epigenetic transgenerational inheritance of altered stress responses, PNAS USA. 2012 doi: 10.1073/pnas.1118514109; Susiarjo et al 2013, Bisphenol A Exposure Disrupts Genomic Imprinting in the Mouse, PLoS Genet 9(4): e1003401. doi:10.1371/journal.pgen.1003401; Walker and Gore, Transgenerational neuroendocrine disruption of reproduction, Nature Reviews Endocrinology 7, 197-207 2011. Doyle et al. (2013), Transgenerational Effects of Phthalate on Male Germ Cells, BOR Papers in Press Published on March 27, 2013 as DOI:10.1095/biolreprod.112.106104; Manikkam et al, Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations, PLoS ONE 7(9): e46249. doi:10.1371/journal.pone.0046249 (2012); Del Mazo et al, The effects of different endocrine disruptors defining compound specific alterations of gene expression profiles in the developing testis, Reproductive Toxicology 33:1, 106–115 (2012).)<br />
<br />
However, EDCs are not the only exposures that impair germline development. For example, a recent study has revealed that fetal exposure to nicotine due to maternal smoking has multigenerational effects on rat offspring. (Rehan et al, Perinatal nicotine exposure induces asthma in second generation offspring, BMC Medicine 2012, 10:129; See also Linschooten, et al., Paternal lifestyle as a potential source of germline mutations transmitted to offspring, FASEB J. 2013 Mar 28. (paternal smoking can affect the chance of heritable mutations in unstable repetitive DNA sequences in sperm). Hydrocarbons also have been shown to have germline effects. (Tracey et al 2013, Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations.) These are just examples of the many environmental factors that manipulate or influence germline development.<br />
<br />
<b> c. Resulting neurodevelopmental pathology in germline offspring</b><br />
<br />
As we have seen, a transient in utero exposure to a xenobiotic compound may permanently alter the epigenetic programming of the germline, resulting in pathologies in offspring. While many pathologies related to compromised robustness of the human germline have been demonstrated, including metabolic disorders, infertility, follicle loss and polycystic ovary disease, kidney disease, pubertal abnormalities in females, and several forms of cancer, a particular concern is impaired neurodevelopment of resulting offspring. (See Walker and Gore 2011.) Studies have shown neurodevelopmental and behavioral abnormalities connected to impaired germline synthesis. (See, eg, Rissman et al., Gestational Exposure to Bisphenol A Produces Transgenerational Changes in Behaviors and Gene Expression, Endocrinology 1195 (2012); Skinner et al., Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior, PLoS ONE 3(11): e3745. doi:10.1371/journal.pone.0003745 2008.)<br />
<br />
Exposure even to common chemicals, such as a common fungicide, has been show to promote an epigenetic reprogramming of the male fetal germline, causing changes in the brain transcriptome of subsequent offspring. (Skinner et al. 2008.) Several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation. (Ibid.) In a separate study, a single exposure to the fungicide, vinclozolin, three generations removed altered the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress. (Crews et al. 2012.) This alteration of baseline brain development promotes a change in neural genomic activity that correlates with changes in physiology and behavior, revealing the interaction of genetics, environment, and epigenetic transgenerational inheritance in the shaping of the adult phenotype. Ibid.<br />
<br />
Also alarming is that an accumulation of epimutations can ultimately influence the genome itself. Epigenetic alterations such as methylation deserts or increased retrotransposition can influence genetics (mutations) via weakening of the epigenome, which may increase the risk for copy number variations, including duplications and deletions. (LaSalle, A genomic point-of-view on environmental factors influencing the human brain methylome, Epigenetics 2011;6:862-869.) Human neurodevelopment appears to be particularly sensitive to alterations in epigenetic pathways; neuronal development and functioning may be particularly impacted by even subtle alterations to DNA methylation. Ibid.<br />
<b><br /> 3. Because of the timing of administration and the receptor-blocking nature of the drug, Diclegis may pose a significant risk to the epigenetic synthesis and integrity of fetal germline</b><br />
<br />
In March of 2013, the FDA approved the drug Diclegis for nausea and vomiting of pregnancy (NVP). While testing of Diclegis revealed no increase in obvious somatic birth defects caused by fetal exposure to the drug, neither the FDA nor the drugmaker made any attempts to ascertain whether continuous, daily fetal exposure during the first half of pregnancy (as per dosing instructions) can compromise the synthesis and integrity of the delicate fetal germline.<br />
<br />
The process of fetal germline reprogramming occurs during precisely the time period of morning sickness experienced by most pregnant women. Indeed, it is likely that morning sickness — wherein a pregnant woman becomes exceedingly sensitive to her environment — evolved at least in part as a mechanism to protect the exposed and sensitive germline from potentially harmful exposures. Yet, administration of Diclegis is expressly targeted at this known window of epigenetic susceptibility. <br />
<br />
Doxylamine, the medicinal ingredient in Diclegis, is a synthetic molecule invented in the 1950s. It crosses the placenta and enters fetal tissues. It is a competitive agonist of the histamine-1 (H1) receptors, and by design interferes with the normal binding of cellular receptors and intracellular signaling. The action of H1 receptors are implicated in neurogenesis, learning, and memory. Doxylamine is a CNS depressant.<br />
<br />
Per the dosing instructions, 10mg of the antihistamine may be taken up to 4 times daily, for 40 mg daily. It is reasonably foreseeable that many consumers will continue use for about three months, or 90 days, for a total of 3600 mg of foreseeable fetal germline exposure to a synthetic molecule that interferes with receptor activity and intracellular signaling. It is reasonable to assume this exposure could therefore interfere with normal synthesis of the germline epigenome. This does not even take into account the synergistic, cumulative effects of other drugs also taken by the patient, which may include fertility treatment hormones, antidepressant drugs, antihypertensives, diabetes drugs, PPIs and others. <br />
<br />
What is the effect of this massive quantity of receptor-disrupting “Franken-molecules” on the cellular receptors of the germ cell, which provide direction to the epigenome under development? Given what evolutionary biology now teaches us about the epigenetic susceptibilities of the early germline, it is shocking that the FDA has never even asked the question.<br />
<br />
If the FDA is unwilling to revoke approval of Diclegis pending adequate testing, it should at a minimum classify Diclegis as a Category C drug for pregnancy owing to probable but yet unmeasured effects on germline. To risk permanent, life-long developmental derangement of even a small subset of grandchildren of Diclegis consumers merely to address a woman’s transient, normal, and harmless NVP is unconscionable. This is a risk-benefit tradeoff no reasonable person would make.<br />
<br />
<br />
<b>The time has come to revise regulation of OTC and prescription drug labeling to expressly include potential for fetal germline perturbation among enumerated pregnancy medication risks</b><br />
<br />
The FDA’s outdated approach to evaluating adverse consequences of pregnancy drug exposures, which ignores the existence and vulnerability of the fetal germline, has misled the medical establishment and American public. The time has come to revise regulation of OTC and prescription drug labeling to expressly include potential for fetal germline perturbation among enumerated pregnancy medication risks.<br />
<br />
Pending appropriate testing of individual drugs, both individually and in combination with other drugs, a blanket pregnancy label warning should be added to medications, as follows: <br />
<br />
““Fetal Risk. A potential risk of taking a medication during pregnancy includes damage to the baby’s vulnerable germ cells (egg or sperm precursors), which may cause disease or developmental disorders in the next generation, your grandchildren. This drug has not yet been tested for fetal germline impact. Because of potential for multigenerational impacts, you are advised to use caution before taking this drug in pregnancy.”<br />
<br />
Pregnant women and their partners have the right to know all, not just some, of the risks involved in ingesting pharmaceutical drugs, particularly to the developmental integrity of their descendants.<br />
<br />
<b>C. Environmental impact</b><br />
<br />
The requested action has no environmental impact, the petitioner claims categorical exclusion.<br />
<b><br />D. Economic impact</b><br />
<br />
The requested action has no economic impact.<br />
<br />
<b>E. Certification</b><br />
<br />
The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.<br />
<br />
I wish to thank the FDA staff for its consideration of this petition.<br />
<br />
Very truly yours,<br />
<br />
Jill G. Escher<br />
<br />
cc: Margaret Hamburg, Commissioner, FDA<br />
Nancy Hayes, Acting Director, Office of Regulatory Policy, Center for Drug Evaluation and Research<br />
Hylton V. Joffe, M.D., M.M.Sc., Director <br />
Audrey Gassman, M.D., Deputy Director<br />
Margaret Kober, Chief, Project Management Staff<br />
Jennifer Mercier, Chief, Project Management StaffUnknownnoreply@blogger.com0tag:blogger.com,1999:blog-471663631306140712.post-33974904631719823392013-04-18T07:12:00.003-07:002013-05-01T19:42:46.485-07:00Autism: A Genetic Epidemic<i>by Jill Escher</i><br />
<br />
People say, "There's no such thing as a genetic epidemic."<br />
<br />
They are wrong. While they are correct that these various disorders we lump together under the banner of "autism" are primarily though not exclusively genetic in nature, these genetic abnormalities are hardly normal or random. They are, for the most part, caused by environmental disruptions that occurred well before these children were conceived.<br />
<br />
We have known for decades that genetic change can occur when environmental insults such as toxic chemicals, radiation, and endocrine disruptors impair the development of our gametes, resulting in <i>de novo</i> genetic or epigenetic abnormalities in the next generation.<br />
<br />
And never in the millions of years of human evolution have we experienced a worse mass toxic event than the largely forgotten <a href="http://prenatalexposures.blogspot.com/p/blog-page.html">Prenatal Pharmaceutical Craze of the 20th century</a>. Synthetic chemicals, marketed as benign little pills, were essentially poured directly into the bodies of tens of millions (probably more than that) of pregnant women around the world. I was exposed to at least three synthetic hormone drugs <i>in utero</i>. And you too may have been exposed to wacky and evolutionarily novel drugs during your embryonic development, the time of greatest vulnerability for our delicate germ cells. <i>The only difference between you and me is that I have my prenatal records, and you don't. I know you don't because so few of these records from the 1950s, 60s and 70s survive. </i><br />
<br />
And prenatal pharmaceuticals are just the start. Agent Orange, to which millions of Americans and Vietnamese were exposed, alters germline epigenetics. And pesticides, fungicides, flame retardants, PCBs, cigarette smoking, smog, radiation, and more and more mutagens and epimutagens that poured into our drugs, our food, our water, our air.<i> Because these things screwed with the human germline, sometimes subtly but all too often acutely, we have epidemic of this bizarrely abnormal neurodevelopment in our kids.</i><br />
<br />
Below are my slides from a March 2013 presentation about this at <a href="http://www.autismepigenetics.org/">an autism science symposium</a>. I think they speak for themselves, but a video of my talk will also be posted soon to the UC Davis MIND Institute website for a bit more color commentary. Lots of stuff percolating out there about germline exposures and autism, thank God (and many awesome researchers of course) for shining a light on this issue and the insanity of it all.<br />
<br />
<i>That said, it's incredible to me that IMFAR 2013, the world's largest autism conference, taking place next month, has almost no discussion of gamete-environment impairment in the etiology of autism spectrum disorders. It's like having a conference on babies born with flaps instead of arms and not bringing up thalidomide.</i><br />
<br />
By the way, I certainly do not contend germline exposure is the <i>only</i> <a href="http://prenatalexposures.blogspot.com/p/what-else-causes-impaired.html">cause of the autism epidemic</a>, but it's likely to be one of the biggies. Any thoughts or feedback can be emailed to <a href="mailto:autismhormoneproject@gmail.com">autismhormoneproject@gmail.com</a>. <br />
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We should worry now, like yesterday. "It is estimated that between 1958-1965 half of
all new mothers (US) took two to four pharmaceutical products while
pregnant." (<span class="il">Annie</span> <span class="il">Murphy</span> <span class="il">Paul</span>, "Origins," pp 79-80.) Unknownnoreply@blogger.com9tag:blogger.com,1999:blog-471663631306140712.post-61357455538828366722013-04-10T17:58:00.000-07:002013-04-11T07:36:50.447-07:00Suspension of Approval Urged for New Morning Sickness Drug, Diclegis, Pending Assessment of Fetal Germline Impacts<div class="separator" style="clear: both; text-align: center;">
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<br />
Hylton V. Joffe, M.D., M.M.Sc., Director Audrey Gassman, M.D., Deputry Director<br />
Margaret Kober, Chief, Project Management Staff<br />
Jennifer Mercier, Chief, Project Management Staff<br />
Food and Drug Administration Center for Drug Evaluation and Research <br />
Division of Reproductive and Urologic Products 5901-B Ammendale Road <br />
Beltsville, MD 20705-1266<br />
Phone: (301) 796-2130<br />
Fax: (301) 796-9897<br />
<br />
Via Fax, U.S. Mail and email to hylton.joffe@fda.hhs.gov<br />
<br />
April 11. 2013<br />
<b><br />Re: Request to suspend approval for Diclegis pending fetal germline impact assessment, and to issue additional warnings for Diclegis and all other prenatal drugs regarding potential for fetal germ cell perturbation</b><br />
<br />
Dear Dr. Joffe, Dr. Gassman, Ms. Kober and Ms. Mercier:<br />
<br />
I am writing to urgently request that the FDA take immediate steps to suspend approval for the prenatal drug Diclegis pending appropriate safety testing for impacts to fetal germ cells, the precursor cells to the baby’s egg or sperm. In addition, I urge the FDA to take immediate steps to issue warnings regarding potential germline impact of all prenatally administered drugs.<br />
<br />
While testing of Diclegis revealed no increase in obvious somatic birth defects caused by fetal exposure to the drug, neither the FDA nor the drugmaker has made any attempts to ascertain whether fetal exposure to the compound may perturb the epigenetic programming of the vulnerable fetal germ cells, the tissues which are most vulnerable during early embryonic development, and are of course the most important in the child’s body, assuming that child desires to reproduce upon reaching maturity. <br />
<br />
Any molecular disturbance of the germ cells would constitute a severe, yet hidden, birth defect of the exposed child, as it would likely result in subtle or severe developmental abnormalities in the <u>grandchildren</u> of the women taking the drug.<br />
<br />
As FDA staff are no doubt aware, the delicate process of fetal germline reprogramming occurs during weeks 6-18 of human gestation, precisely the time period of morning sickness experienced by most pregnant women. During this period the germ cells are specified and migrate along the genital ridge to the rapidly developing fetal gonads. During this time, the germ cells are demethylated and remethylated in a manner controlled in large part by the exogenous molecular signaling environment present in the womb. <br />
<br />
Indeed, it is likely that morning sickness — wherein a pregnant woman becomes exceedingly sensitive to her environment — evolved as a mechanism to protect the exposed and sensitive germline from potentially harmful exposures. Yet, administration of Diclegis is expressly targeted at this known window of epigenetic susceptibility, and may wreak unknown and unmitigatable havoc on the germ cell programming. <br />
<br />
Animal models have repeatedly demonstrated fetal germline vulnerabilities and adulteration caused by both acute and low-level exposures to exogenous compounds, resulting in multigenerational impairments. These perturbations may have any number of pathological outcomes, including abnormal neurodevelopment and behavior of the grandchild offspring. See, for example, Crews, Epigenetic transgenerational inheritance of altered stress responses, Proc Natl Acad Sci USA. 2012 doi: 10.1073/pnas.1118514109; Hunt, Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey, PNAS (2012); Rissman, Gestational Exposure to Bisphenol A Produces Transgenerational Changes in Behaviors and Gene Expression, Endocrinology 1195 (2012); Skinner, Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior, PLoS ONE 3(11): e3745 (2008); Gore, Transgenerational neuroendocrine disruption of reproduction, Nature Reviews Endocrinology 7, 197-207 (2011). Indeed, in the past several years, this susceptibility of early mammalian germ cells to chemical manipulation and damage has become textbook knowledge. It is reckless in the extreme for the FDA to continue to ignore this well accepted dimension of profound risk.<br />
<br />
The role of germline epimutation in today’s epidemics of autism and other mysterious neurodevelopmental abnormality is seen as urgent among leading scientists, see, eg, DeMarini, Declaring the Existence of Human Germ-Cell Mutagens, Environmental and Molecular Mutagenesis 53:166^172 (2012), Michael Demartini, Yauk et al 2013, Harnessing genomics to identify environmental determinants of heritable disease, Mutat Res. 2013 January; 752(1): 6–9, and Autism Epigenetics Summary Statement, http://autismepigenetics.org/wp/wp-content/uploads/2012/11/SummaryThemesPDF13.pdf, and must also ring the alarm bells within the walls of the FDA. By controlling drug approval and prenatal drug risk information, the FDA serves as the sole gatekeeper for protecting the fetus and its germline from dangerous drug exposures, yet to date has never taken a single step to review the probable germ cell impacts of any of the many drugs prescribed to and taken by pregnant women.<br />
<br />
Antihistamine CNS depressants such as Diclegis can reasonably expected to interfere with the fine-tuned molecular programming of the germ cells owing to the disruption of normal receptor activity. Per the dosing instructions, 10mg of the antihistamine may be taken up to 4 times daily, for 40 mg daily, for likely 90 days, for a total of 3600 mg of foreseeable antihistamine drug exposure, not including the B6 component, and not including synergistic, cumulative effects of other drugs taken by the patient, which may include fertility treatment hormones, antidepressant drugs, antihypertensives, diabetes drugs, PPIs and others. What is the effect of this massive quantity of evolutionarily novel xenobiotic chemicals on human germ cell development? <i>Given what evolutionary biology now teaches us about the epigenetic susceptibilities of the early germline, it is shocking that the FDA has never even asked the question.</i><br />
<br />
<b>The FDA must demand that this germline and multigenerational testing for epigenetic and other impacts occurs before even a single prescription is written in the United States. The public can no longer sit idly while the FDA ignores what could easily be a massive, if unintended, assault on future generations. The blind spot regarding fetal germline vulnerability must end; pregnant women and their partners have the right to know all, not just some, of the risks involved in ingesting pharmaceutical drugs, particularly to the developmental integrity of their descendants. </b><br />
<br />
With gratitude for your kind and prompt consideration,<br />
<br />
Jill Escher<br />
Escher Fund for AutismUnknownnoreply@blogger.com28tag:blogger.com,1999:blog-471663631306140712.post-4673320565130975692012-02-23T13:59:00.004-08:002013-04-08T16:41:03.759-07:00Oops, we forgot the germline<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjDVCNQ-NZ_Mx6rhBpgPKQvfgHg1BC8V0SkHHXapcwIUBwrX_MdmTv0sN3cwQNVtLM97-9JWnVYeY9YP5Uh6BqIuGevQ1LgFw3XrOI8B6X-2A646kYTSjx1FO_YIKgyPEFG7zN1882Ch1UF/s1600/Miltown+preg+ad+1950s+(Wallace).png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjDVCNQ-NZ_Mx6rhBpgPKQvfgHg1BC8V0SkHHXapcwIUBwrX_MdmTv0sN3cwQNVtLM97-9JWnVYeY9YP5Uh6BqIuGevQ1LgFw3XrOI8B6X-2A646kYTSjx1FO_YIKgyPEFG7zN1882Ch1UF/s320/Miltown+preg+ad+1950s+(Wallace).png" width="226" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>For decades, conventional medical practice had no qualms about heavily medicating pregnant women, even for anxiety caused by the price of a new crib. </b></td></tr>
</tbody></table>
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The decades of the 1950s, 60s, and 70s were the heyday of prenatal pharmaceutical use. Countless millions of us were exposed <i>in utero</i> to synthetic hormones, tranquilizers, amphetamines, morning sickness medications, and/or other drugs prescribed almost indiscriminately in a haze of unbridled<i> </i>enthusiasm for the promise of the new pharmacopeia. Until the 1970s, little thought was given to these potent chemicals' impacts on
the fetus, as doctors falsely considered the placenta a fairly impenetrable barrier to the mother's medication. As we grew up, we were seldom told of our exposures, little follow-up research was done, maternal memories faded, and old medical records were thrown away.<br />
<br />
Though many of the drugs appear to have been fairly benign, others, depending on biochemistry, timing and dosage, were teratogenic, meaning they damaged the fetus, sometimes
dramatically, as is the case with thalidomide and DES, and sometimes subtly, as in the case of other sedatives and progestins.<br />
<br />
But the damage did not stop at the fetus. <u>Gestational exposure affects not only the
fetus itself, but<b><i> </i></b>also, likely to a more significant extent, its exquisitely vulnerable
developing germline, those cells which develop into the child's
eventual egg or sperm, and therefore, the grandchild generation</u>.<br />
<br />
While it's unlikely that the pharmaceutical exposures would induce classic mutations in the germline's genetic sequence, research suggests that many synthetic compounds can adulterate the more environmentally sensitive "<u>epigenetic</u>" programming, that is, the countless millions of tiny chemical switches that control genetic expression. Epigenetic mayhem can result in disruptions of normal development in the resulting offspring, much like early programming bugs in software can cause later computer malfunctioning.<b> </b><br />
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<b>A generation-skipping effect</b><br />
<b><br /></b>
Germline damage is a tiny latent birth defect of the fetus, and results in a generation-skipping effect.<b> </b>While the fetus itself may appear to have escaped noticeable damage because of the relative resilience of its somatic cells, pharmaceutically-induced germline DNA instability will manifest only in the next generation. Consider for a moment that you started life as two cells no larger than the dot on this letter "i." Research shows these cells to be epigenetically vulnerable to abnormal exogenous exposures during sensitive periods of development, including when the cells are developing within the fetal gonads <i>in utero</i>.<br />
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<b>Germline errors can result in abnormal brain development and behavior</b><br />
<b></b><br />
Genes related to autism and brain development appear to be more susceptible than others to novel genetic alterations occurring within the germ cells themselves, and not inherited directly from the parents. (<a href="http://www.cell.com/abstract/S0092-8674%2812%2901404-3">Michaelson et al.</a> 2012). These "de novo" mutations and epimutations can be random, or can be precipitated by destabilizing exogenous factors such as the abnormal chemical/pharmaceutical exposures discussed here. (See <a href="http://prenatalexposures.blogspot.com/p/research-on-germline-exposure.html">Research</a> page for some relevant studies). In addition, a large percentage of the genome is devoted to genes coding for proteins relating to neurological development; therefore if one was to throw darts at the genome, brain development genes would almost certainly be among those hit. Another factor to consider is that research has shown that the unfathomably complex process of human neurodevelopment is highly regulated by epigenetic factors; so when we tamper with epigenetic marks, abnormal wiring and functioning may reasonably be expected to result.<br />
<br />
Research shows that perturbations of epigenetic instructions may result in various irregularities during the process of neurodevelopment, including the the failure of neurons to migrate or proliferate, impairment of communication at the neural synapses, and the failure of neurons to develop
robust dendritic complexity. Depending on the nature and extent of the damage, irregularities may manifest in a
variety of ways we see and diagnose as abnormal behavior, including:<br />
<br />
• Autism spectrum disorders, Aspergers, pervasive development disorder<br />
• Learning disabilities<br />
• ADHD, ADD<br />
• Emotional disturbance <br />
• OCD<br />
• Sensory processing disorders<br />
• Anxiety, mood disorders and depression<br />
• Mental illness <br />
• Tourette's syndrome, tics<br />
<br />
Incidence
of these conditions, many of which were exceedingly rare before the
late 1980s, has skyrocketed. For example, autism, once numbering a
handful per 10,000, now affects 1 in 88 children according to the
Centers for Disease Control.<br />
<br />
<b>Real exposure histories in real autism families</b><br />
<br />
In preliminary surveys, we have found that a considerable percentage of parents of neurodevelopmentally challenged children had themselves suffered significant early <i>in-utero</i> exposures to pharmaceuticals (read a few of their stories on the <a href="http://prenatalexposures.blogspot.com/p/blog-page_4.html">Family Stories</a> page), particularly synthetic hormones, mood altering medications, and anti-nausea medications. In contrast, their unexposed siblings, serving as a makeshift control group, tended to have typically developing children, lending credence to our causation hypothesis. In addition, the affected children had no genetic disorders, and no other risk factors, and the families had no histories of neurodevelopmental disorder.<br />
<br />
<b>What else can harm human germ cells?</b><br />
<br />
Though we focus our attention here on pharmaceuticals, those chemicals are hardly the only exposures that, administered during susceptible periods of development, can wreak havoc on the human germline. Other culprits include:<br />
<br />
• Environmental endocrine disruptors such as Agent Orange (dioxin), pesticides, herbicides, fungicides, and flame retardants<br />
• Maternal smoking and recreational drugs<br />
• Various plasticizers and industrial chemicals<br />
• Radiation<br />
• Heavy metals <br />
<b><br /></b>
<b>Is germline impairment the sole cause of the autism epidemic? </b><br />
<br />
Though we believe the germline exposure syndrome is likely a significant contributor to skyrocketing autism rates, the markedly abnormal neurodevelopment we call autism has many other known and suspected triggers, including:<br />
<br />
• Prenatal (proximal, first-generation) drug exposures, including antidepressants, anticonvulsants, and terbutaline<br />
• Epigenetic consequences (including imprinting disorders) stemming from fertility treatments such as IVF and ICSI<br />
• Prematurity, multiple births and perinatal complications (sometimes also relating to assisted fertility)<br />
• Prenatal infections, autoimmunity and inflammation<br />
• Classic random <i>de novo</i> genetic mutations<br />
• Familial genetic syndromes such as Fragile X<br />
• Fetal hypothyroidism <br />
• Post-natal events such as encephalitis and acute inflammation<br />
<br />
<b>How you can learn more</b><br />
<br />
1. Check out the website for the March 2013 Autism Speaks - UC Davis symposium, <a href="http://autismepigenetics.org/">Environmental Epigenetics: New Frontiers in Autism Research</a>. That website will archive videotaped presentations and other material from the event.<br />
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2. Listen to this February 25, 2013 Super Human Radio <a href="http://www.superhumanradio.com/shr-1145-big-pharma-the-fda-and-epigenetics-autism-and-spectrum-disorders-hidden-history.html">podcast</a> with host Carl Lanore.<br />
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3. List to this April 4, 2013 Underground Wellness <a href="http://www.blogtalkradio.com/undergroundwellness/2013/04/05/autism-the-plausible-cause-no-one-is-talking-about">podcast</a> with host Sean Croxton <br />
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4. Read our Pages, listed at the upper right.Unknownnoreply@blogger.com2