The Mother of All FDA Fails

The FDA has never required drug safety assessment for fetal germline impact, even though FDA staff understand that gestational exposures can adversely affect developing germ cells. We must end this catastrophic omission, while also granting all Americans access to their own prenatal medical records.

The Pittsburgh Post-Gazette Tells My Story



http://www.post-gazette.com/stories/news/health/can-autism-be-triggered-in-future-generations-706678/

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.

The accompanying article features a family with multiple kids with ASD.  That mom, like me, had been exposed in utero to "fertility" hormone drugs.  Coincidence?  Oh, I certainly do not think so.

http://www.post-gazette.com/stories/news/health/one-family-four-children-two-forms-of-autism-706693/

And did I mention that the last two autism moms I had coffee with both had similar prenatal exposures in the 1960s?

Surely... just... one... giant... coincidence!
1 comment:

The 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.)

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.

Current areas of interest include:

Epidemiology: Human studies to evaluate epigenetic germline effects of prenatal pharmaceuticals and smoking.

Germline protection: 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.

Symposia and conferences: Sponsorship of and appearances at meetings regarding the connection between environmental epigenetics and abnormal neurodevelopment, including autism.

Medical history: Research on one of the most toxic, but relatively unknown, events in human history: the mass use of novel synthetic prenatal pharmaceuticals, 1950s-70s.

Medical records: Efforts to allow all Americans full access to their prenatal exposure records.

 Laboratory studies: Efforts to evaluate effects of drugs and chemicals on human germ cells.

 Housing and day programs: Facilitating the creation of new housing opportunities and day programs for adults with autism.


In the media and online:

Onslaught of autism: A mom's crusade could help unravel scientific mystery, by Jane Kay, Environmental Health News, July 2013

Mother's Quest Could Help Solve Autism Mystery, San Francisco Chronicle, July 2013

Autism: Germline Disruption in Historical and Personal Context, Presentation at the National Institutes of Health, Interagency Autism Coordinating Committee (15 minute video), July 9, 2013

A Grandmotherly Clue in One Family's Autism Mystery, Autism Speaks Guest Blog, August 27, 2013

Environmental Epigenetics: New Frontiers in Autism Research symposium, sponsored by Autism Speaks, UC Davis MIND Institute, and Escher Fund for Autism, March 22-23, 2013

 Escher Fund for Autism Citizen Petition to the FDA requesting public disclosure of potential risks of prenatal drugs on fetal germ cells.  www.regulations.gov/#!documentDetail;D=FDA-2013-P-0522-0001

“Prenatal Exposures Never Die” Blog


Email: autismhormoneproject@gmail.com.
No comments:

"We must be much better caretakers of our genetic legacy"

From the SF Chronicle yesterday. A shorter version of the story that appeared in Environmental Health News earlier this month.

--Jill Escher

------------------------------------------- 

http://www.sfchronicle.com/health/article/Mother-s-quest-could-help-solve-autism-mystery-4682498.php

Mother's quest could help solve autism mystery

Jane Kay
8:23 AM

Katy Raddatz, Katy Raddatz/Environmental Health
Two of Jill Escher's three children are autistic, despite the low chances.

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.
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.

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.

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.

New studies appear with regularity, suggesting causes but offering no definitive answers for Escher.
"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.

An idea is sparked

 

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.

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.

"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."


Katy Raddatz, Katy Raddatz/Environmental Health
Jill Escher, who has a law degree, educated herself enough about autism to discuss research with experts.

Scientists know that some chemicals can alter developing embryos and fetuses, which can lead to disease later in life.

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.

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.

Pregnancy drug

 

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.
These findings were profound: A single exposure in the womb could induce defects that could be transmitted to the next two generations.

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?

"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.
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.

"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.' "

She was stunned. "Something's happened to my eggs," she thought.

Generational link

 

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?

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.

Many diseases have increased faster than can be explained from normal genetic mechanisms. The epigenetic phenomenon could be a reason.

"If environmental factors influence gene expression, the risk of someone having autism could increase," Amaral said.

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.

"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.

"We think most behavioral disorders are a combination of genetic predisposition, natural differences in reproductive hormones and differences in environmental exposures."

Taking action

 

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.

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.

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.

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.

"We have unwittingly experienced this mass disruption in evolution. It has to stop. We have to be much better caretakers of our genetic legacy."


Jane Kay is a writer for Environmental Health News. For a longer version of this story, go to http://bit.ly/15fjVMq.
4 comments:

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 symposium on the environmental epigenetics of autism, held at the UC Davis MIND Institute.

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.

Watch it here: https://www.youtube.com/watch?v=8_0iMnxsKSo


No comments:

Onslaught of autism: A mom's crusade could help unravel scientific mystery

http://www.environmentalhealthnews.org/ehs/news/2013/autism-epigenetics

 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. 

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.

 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.

Onslaught of autism: A mom's crusade could help unravel scientific mystery

Jill Escher’s dogged quest to unravel why two of her children are autistic 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.
ShareThis
Lance Neilson/flickr   
One in every 88 kids in the United States is diagnosed with autism, a neurological disease with unknown causes.

Jane Kay
Environmental Health News
July 16, 2013
SAN JOSE, Calif. – 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.
Upstairs, her 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.
Katy Raddatz
Jill Escher meets with Brad Boardman, executive director of the Morgan Autism Center, to discuss a grant from Escher's foundation.
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 one in every 88 U.S. children. The Escher children's intellectual development is stalled at an early pre-school level, and they need constant care and protection.
For years, Escher and her husband, Christopher, 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? Their food? The couple tried to hunt down any health problems in their lineage but found none. A glass of wine while pregnant? Paint fumes? Pollution from freeways?
New studies appear with regularity, suggesting causes but offering no definitive answers.
“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.
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.
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.
“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.”
From generation to generation
Scientists know that some chemicals can alter developing embryos and fetuses, which can lead to disease later in life.
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 possibly even subsequent generations.
National Institutes of Health
Autism affects normal development of communication and social skills.
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. Also, the disrupted programming in how genes are turned on and off – the very genes that instruct cell growth and function – may be passed on to more descendants.
“The autism explosion has been with us for more than two decades, and we have little to show about what's causing it. We have many hundreds of thousands of functionally disabled people who didn't exist before, and we have our heads in the sand.” –Jill Escher  The power of pharmaceuticals to do just that came to light with a synthetic estrogen that harmed at least two generations of offspring of women who took it. DES, or diethylstilbestrol, was prescribed to up to 10 million pregnant women in the United States and the United Kingdom 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 a rare form of cancer of the vagina and cervix and other reproductive disorders, and the sons have increased risk for some reproductive problems. Startling scientists, DES granddaughters turned up with an increased incidence of urinary and genital malformations, irregular menstrual cycles and other abnormalities.
These findings were profound: A single exposure of a pregnant woman seemed to induce defects in her fetus's eggs, triggering health effects in the next generation.
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?
A personal quest
When Escher’s first child, Evan, was born in 1997, he met his developmental markers. Two years later came Jonathan. “He was really colicky, and always seemed to be in some pain that we couldn't soothe. He would sit in the backyard and pick up rocks and dirt,” she said.
She saw the ominous signs: no eye contact, no babbling as a baby. The Eschers took him for an assessment. As soon as the doctor walked into the waiting room, he suspected autism.
Jill Escher saw the ominous signs in her son Jonny: no eye contact, no babbling as a baby. As soon as a doctor walked into the waiting room, he suspected autism. Then when Sophie was born seven years later, she showed similar signs.“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 and remains so today,” Escher said.
Then when Sophie was born seven years after Jonathan, she showed similar signs. She didn't play or make eye contact. Her diagnosis came soon after. Genetic testing revealed no known abnormalities in either child, and no clinician could think of any reason for two children with such severe disabilities.
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.
In 2000 and 2002, one in every 150 U.S. children was diagnosed with autism spectrum disorders, which affect the brain’s normal development of social and communication skills. But the rate climbed to one in 88 in 2008, according to the CDC. Many experts believe the rise is due to a combination of a real increase in prevalence plus improved diagnoses.
“We don't know why the numbers are increasing, and we don't know which portions of the brain are affected when a person has autism,” said neuroscientist David Amaral, research director at the University of California, Davis, MIND Institute.
Source: Centers for Disease Control and Prevention
“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,” he said.
With no scientific training, Escher, 47, has educated herself enough to discuss new research with Amaral and other autism experts. She has a law degree from the University of California, Berkeley, and five years' experience as a clerk in the U.S. District Court in San Jose. Five years ago, Escher and her husband founded a small family fund that first financed school recreational activities for autistic children, then research into its causes.
To her horror, she learned that researchers had discovered an autism cluster in West Los Angeles, where she grew up. In her search for answers, Escher came across a Tel Aviv University study linking in vitro fertilization with increased risk of autism.
“That's when it hit me that I might have been a fertility kid,” she said. She remembered a scrap of information tucked away. At 13, the cover of Time magazine featured a test tube to illustrate creating a baby with the aid of science. Someone – she thinks it was her dad – said to her, “You were just like that baby. You were a miracle child. You were wanted very badly.” She wasn’t a test tube baby, but she wondered if her mother had taken fertility drugs.
Escher called her mother, and asked. “They gave me a whole bunch of stuff. I don't know what it was,” her mother said.
At Escher's request, her mother called her former obstetrician. Four pages of records, stored on microfilm, were sent to Escher. Scrawled over the pages was a list of synthetic hormone drugs that her mother took. Over and over, she saw steroid hormones: Deluteval (a progestin with estradiol) and prednisolone. Escher learned that her mother had gone to a West Los Angeles fertility clinic run by Dr. Edward Tyler, who had prescribed Pergonol and Clomid to induce ovulation to help her conceive. And it was Tyler who had prescribed a continuing regimen of hormones and steroids, including weekly injections, as a way to prevent miscarriage during the pregnancy.
Escher asked some autism researchers about the fertility drugs, but got no encouragement, so she set the records aside.
But when the sister of a friend who had been exposed to DES in the womb died of breast cancer, she realized that the effects of some drugs could last for generations. “DES was a real eye opener in terms of transgenerational effects of prenatal exposure to drugs,” she said.
Washington State University
Michael Skinner is a pioneer in environmental epigenetics.
“I was listening to a podcast, 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.'”
She was stunned. “Something's happened to my eggs,” she thought.
Searching the epigenome for answers

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?
So far, no one has looked, although one ambitious study is about to be launched in Europe.
“Right now research looks at environment and it looks at genetics. But it doesn't look at the environmental effects on the germ line. These are critical questions. So far we're silent on them,” Escher said.
Science is very compartmentalized, she said.
“We already have all the pieces. We just need to put them in order. But you don't have one person stringing it all together,” she said.
Escher is trying to be the one to do that.
One of the first scientists she contacted was Michael Skinner, a professor in the School of Molecular Biosciences at Washington State University.
“The majority of brain disease has been shown not to be genetically based, and autism is likely environmentally induced during some period of development.” –Michael Skinner, Washington State UniversitySkinner laid out the shift in thinking that is setting off waves of disagreement among geneticists. For more than a century, scientists believed that only alterations in the DNA sequence could be passed on to subsequent generations. Now they are considering a change in that thinking: The way in which normal genes are expressed, or turned on and off, may be passed on, too. An abnormal exposure to a pregnant woman – a toxicant or smoking, for instance – might change the genetic switching that controls the development of a fetus. These alterations then may be passed on to multiple generations.
This is called epigenetic inheritance.
Continue reading on Page 2

Onslaught of autism. Page 2

(Continued from Page 1)
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.
Skinner explained it to Escher this way: “Think of the genome as the computer, and the epigenome as the software.”
Epigenome NoE
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.
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 "transgenerational."
“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 symposium on epigenetics and autism at UC Davis in March, partly supported by a grant from the Escher Fund for Autism.
In lab animals, Skinner and other scientists have linked a dozen chemicals – including bisphenol A, which is an ingredient of polhycarbonate plastics, phthalates used as plasticizers, the insecticide DEET and a fungicide – to transgenerational epigenetic changes that have led to tumors, prostate disease, reproductive problems and other problems in at least three generations of offspring.
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.
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.
"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 Emilie Rissman, professor of biochemistry and molecular genetics at the University of Virginia School of Medicine.
Many diseases have increased faster than can be explained from normal genetic mechanisms. The epigenetic phenomenon could be a reason.
“If environmental factors influence gene expression, the risk of someone having autism could increase,” said Amaral of the University of California, Davis.
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.
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. The study didn't look at epigenetic effects, however.

University of Utah
A pregnant woman's exposures may harm not just her fetus but the fetus's developing reproductive cells.
“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.
“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.”
University of California, Davis, autism researcher Janine M. LaSalle 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.
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.
“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.
“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.”
Antidepressants under the microscope
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.
“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.
Centers for Disease Control and Prevention
 About 1 in 9 people 12 years and older in the United States takes antidepressants.
Prenatal use of SSRIs, or selective serotonin reuptake inhibitors such as Prozac and Zoloft, have surged since their introduction in the late 1980s.
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.
“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.
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.
“I'm concerned that the warning voices aren't being heard, and the evidence of harm is being drowned out.” –Dr. Adam Urato, Tufts University  Studies in animals 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.
For example, researchers in Sweden reported a link between antidepressants and autism. Pregnant women taking SSRIs showed a more-than-triple increase in risk of offspring with autism spectrum disorder.
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 increased risk of autism associated with SSRIs with the strongest effect found in the first trimester.
One research group concluded that “fetal and infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.“
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.”
Today, prenatal use of SSRIs, or selective serotonin reuptake inhibitors such as Prozac and Zoloft, have surged since their introduction in the late 1980s.There have been no studies on the epigenetic or germ line effects of SSRIs.
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.
Escher is impatient with the FDA, saying it is missing an opportunity to explore a hypothesis that autism researchers call viable.
“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.
“It makes sense on paper. But nobody's asking the question,” she said.
FDA petitioned, NIH involved
Two months ago, Escher petitioned the FDA. 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.
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.
“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.
Wikipedia
Her cause is supported by some scientists, including Tel Aviv University theoretical biologist Eva Jablonka, who has been studying transgenerational epigenetic effects for years.
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.”
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.
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 no concerns for an increased risk for malformations from first trimester exposure to these ingredients,” Fischer said.
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.
Earlier this month, Escher, along with Alycia Halladay of the national nonprofit Autism Speaks, 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.
The National Institutes of Health has begun funding some epigenetics studies related to autism and prescription drugs.
"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, FDAA 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.
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.
Scientists, Escher said, have access to a treasure trove: the parents and grandparents of autistic children.
“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.
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.
"We have unwittingly experienced this mass disruption in evolution. It has to stop. We have to be much better caretakers of our genetic legacy.”
1 comment:

Prenatal Exposures: Should You Be Worried?

by Jill Escher (@Autism_Exposed)

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!


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, panicked, questions from a number of corners. 

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.

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?

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.

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.

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 corticosteroids are known to have epigenetic effects on DNA, yet early embryos are routinely exposed to these very genotoxic drugs.

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.

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 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.

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.

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?

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 in utero, 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.

So the question is, can the in utero 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 strongly urge precaution and recommend against any use of antidepressant drugs during (or several months before) pregnancy.

As an alternative to drugs to elevate mood, women should consider natural alternatives, including a mood-boosting Paleo-type diet 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.

Exercise and talk therapy have also shown to be helpful. But food makes mood, and women should strive to adopt a highly nutritious mood-boosting diet, free of low-fat and processed crap, well before becoming pregnant.

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.

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 in utero drug exposures.

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?

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, it has never 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. 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 Citizen's Petition to the FDA.

2 comments:

Videos from Environmental Epigenetics: New Frontiers in Autism Research

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.

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, autismepigenetics.org.

Presenter: Jill Escher
Affiliation: Escher Fund for Autism
Date: March 22, 2013
Length: 13:04
Summary: 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.
Presenter: Tracey Woodruff, Ph.D., MPH
Affiliation: Program on Reproductive Health and the Environment, UCSF
Date: March 22, 2013
Length: 22:47
Summary: 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.
Presenter: Dana Dolinoy, Ph.D.
Affiliation: University of Michigan School of Public Health
Date: March 22, 2013
Length: 30:00
Summary: 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.
Presenter: David Crews, Ph.D.
Affiliation: Section of Integrative Biology, University of Texas at Austin
Date: March 22, 2013
Length: 27:45
Summary: 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.
Presenter: Michael Skinner, Ph.D.
Affiliation: Washington State University
Date: March 22, 2013
Length: 40:32
Summary: 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.
Presenter: Amander Clark, Ph.D.
Affiliation: UCLA
Date: March 22, 2013
Length: 19:12
Summary: 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.
Presenter: M. Danielle Fallin, Ph.D.
Affiliation: Johns Hopkins Bloomberg School of Public Health
Date: March 22, 2013
Length: 26:24
Summary: 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.
   Epigenetic inheritance of complex behaviors and their alteration by traumatic stress in mammals
Presenter: Prof. Isabelle Mansuy
Affiliation: Brain Research Institute, University of Zurich
Date: March 22, 2013
Length: 30:34
Summary: 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.
Presenter: Andrea Gore, Ph.D.
Affiliation: University of Texas at Austin
Date: March 22, 2013
Length: 43:34
Summary: 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.
Presenter: June Reinisch, Ph.D. and Erik L. Mortensen, CanD
Affiliation: University of Copenhagen Prenatal Development Project
Date: March 22, 2013
Length: 31:39
Summary: 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.
Presenter: Rosanna Weksberg, M.D., Ph.D.
Affiliation: University of Toronto
Date: March 22, 2013
Length: 23:58
Summary: 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.
Presenter: Emilie Rissman, Ph.D.
Affiliation: University of Virginia
Date: March 22, 2013
Length: 23:58
Summary: 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.
Presenter: Janine LaSalle, Ph.D.
Affiliation: Medical Microbiology and Immunology, UC Davis School of Medicine
Date: March 22, 2013
Length: 30:21
Summary: 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.
Presenter: Adam Urato, M.D.
Affiliation: Chairman, Dept. of OB/GYN, MetroWest Medical Center, Assistant Professor, Tufts Medical Center
Date: March 23, 2013
Length: 29:23
Summary: 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.
No comments:
Subscribe to: Posts (Atom)