The vulnerable fetal sperm and egg

The ovary and eggs of the female fetus are susceptible to damage by abnormal exposures. In both genders, gamete development begins in the mid first trimester.  A female baby is born with all of her eggs.

When a pregnant woman takes a drug, three generations are exposed simultaneously: the mother, the fetus, and, due to the fetal germline exposure, the future grandchildren. Far from being inert marbles of imperturbable DNA, fetal egg and sperm are sensitive and responsive to the uterine environment.  This is largely due to a molecular phenomenon called "epigenetics," which refers to the complex landscape of countless millions of tiny chemical switches that control gene expression.  

It is well established that drug and other chemical exposures can impair germ cell development (see Research page for some of the studies), particularly during certain sensitive periods of development when the DNA is relatively exposed.  For example, prenatal exposure to the synthetic estrogen drug DES is known to affect the Third Generation's risk for cancer. Prenatal exposure to the synthetic endocrine disruptor BPA has been shown to disrupt both male and female germ cells in animal studies.  And prenatal exposure to synthetic endocrine disrupting herbicides such as vinclozolin and dioxin (Agent Orange) are shown to have germline effects.

How do germ cells develop? Why are they vulnerable?

During the process of sexual differentiation of the embryo, at about 6 weeks gestation, primordial germ cells migrate to the embryonic genital ridge and then undergo a process called germline reprogramming over roughly weeks 6-18 of gestation.  During this period, the DNA is stripped of most of the parental epigenetic markers and reprogrammed to achieve what is called totipotency.  Totipotency basically refers to the ability of this single cell, in combination with another gamete encountered at fertilization, to differentiate into a complex organism of trillions of functionally different cells.

The arrows show primordial germ cells migrating to the genital ridge in the mouse embryo. During early gestation in mammals the cells are stripped of the parental marks and reprogrammed for totipotency.  Abnormal chemical or pharmaceutical exposures during this and other sensitive periods can impair proper molecular development of the germline. (From Petra Hajkova: Epigenetic reprogramming in mouse germ cells)

Healthy germline programming is driven by molecular-level expectations resulting from hundreds of millions of years of evolution on a planet that was free of synthetic chemicals.  When novel substances such as synthetic pharmaceuticals or their metabolites enter the womb, these bizarre molecules can throw the normal course of germline development into disarray in a number of ways.  For example, an endocrine disruptor (artificial hormone-like substance) can block or bind abnormally to hormone receptors populating the surface of the germ cells, disturbing the chemical tagging of the DNA packing called histones, resulting in faulty genetic coding. Germline reprogramming occurs again shortly following fertilization but not all marks are erased.

Germline development differs between males and females.  In males, spermatogenesis begins in early gestation, but continues throughout the male's lifetime.  In females, the eggs largely develop by about five months of gestation--a baby girl is born with all her eggs.  Beginning in puberty, the eggs begin to undergo an additional process of division and ripening.

Comparison of oogenesis and spermatogenesis. (From Petra Hajkova: Epigenetic reprogramming in mouse germ cells)

Does it matter whether the father or mother was exposed?

Based on a survey of autism parents, we have found severity of neurodevelopmental symptoms to generally be more severe when the mother was exposed than if the father was exposed.  That may be due to the fact that maternal germ cell development remains relatively arrested as compared to the male germ line after birth.

Although germ cells are the most important group of cells in the fetus, as they will give rise to the next and all succeeding generations, and even though their vulnerabilities are by now well documented, the FDA has never examined or required testing of germline impacts of pharmaceutical drugs. This is colloquially known as "The Oversight of the Century" or perhaps "The Mother of All Recklessness."