How the DES tragedy illuminated several crucial concepts embedded in the endocrine disruption hypothesis

Neuroendocrine Disruption: Historical Roots, Current Progress, Questions for the Future

2011 Paper Abstract

Defining and Testing the Endocrine Disrupting Hypothesis – A Role for Neuroendocrinologists

The best evidence for both the importance of animal models for predicting human outcomes and causality between early life exposure and adult disease has been definitively provided by the unfortunate case of the estrogenic pharmaceutical, diethylstilbestrol (DES). Prescribed to pregnant women to avert miscarriage (a practice subsequently discovered to be ineffective), it exposed their fetuses to high levels of a powerful synthetic estrogen. While the children appeared anatomically normal at birth, the daughters grew up to have a high incidence of reproductive tract structural abnormalities, and an increased prevalence of very rare clear cell vaginal and cervical carcinomas. It is now recognized that DES sons experience higher rates of reproductive disorders and cancers as well. This tragic event was critically informative because it illuminated several crucial concepts embedded in the endocrine disruption hypothesis. First, it provided a direct cause-and-effect relationship between prenatal exposure to an estrogenic compound, and the later development of an endocrine cancer. Second, it also emphasized that the human fetus is not fully protected from exogenous hormones, as once believed, and that human health is just as vulnerable to endocrine disruption as wildlife and laboratory species. Finally, it demonstrated that animal models can in fact be good predictors of human health outcomes, as comparisons of results of perinatal DES exposures between mice and humans reveal very similar results. Of particular relevance to neuroendocrinologists, actions of DES on the hypothalamus and pituitary have been known for over sixty years, a predictable finding based on the abundance of estrogen receptors in these regions. The DES model, as currently studied in the DES daughters, sons, and now grandchildren, together with laboratory animal models of DES exposure, has provided translational links to the developmental origins of adult disease. Current research on EDCs has been informed by DES, including recent work by some of the original investigators who first described DES’s effects. Still, an understanding of the impacts of EDCs on neuroendocrinology is still in its infancy, and it is imperative that this data gap be filled by future research.

Human Health Trends

… Concomitant with this decline in reproductive health is a similarly paced increase in the incidence of childhood psychological and behavioral disorders such as attention deficit disorder and autism spectrum disorders (ASD). A recent survey of over 78,000 families conducted by the National Survey of Children’s Health revealed that as many as 1.1% of all children born in the US are now diagnosed with ASD, with rates in boys nearly four times that of girls. In their ground-breaking 2010 report, the President’s Cancer Panel highlighted that rates of cancer in children continue to increase, and argued for a greater research focus on the relationship between exposure to toxicants and cancer. In all cases, the underlying cause of such alarming human health trends is likely multi-faceted, and although lifestyle factors such as delayed childbearing, diet, stress, and body composition likely play a role, the rapidity of the increase in reproductive and behavioral disorders, and cancer, suggests an environmental component.

It is now widely hypothesized that exposure to EDCs, both synthetic and naturally occurring, are at least partially responsible. We believe this a plausible hypothesis but robustly testing it is not straightforward. For example, did the decline in male fecundity result from exposure in the womb, when the gonads were forming; during puberty, when the reproductive system was maturing; in adulthood, when conception is desired; or all of the above? Obviously, obtaining absolute proof of endocrine disruption in humans by a chemical (or a mixture of chemicals) with weak hormonal activity is likely impossible because it would be unethical to conduct a double-blind study where one group is exposed to a suspected toxicant and the other is not. So how can data obtained from animal models be used to inform human risk assessment? Can health effects that result from environmental factors be improved or corrected once diagnosed? Could effects be transmitted to subsequent generations by epigenetic or other mechanisms?  …

  • Read and download the full study (free access) Neuroendocrine Disruption: Historical Roots, Current Progress, Questions for the Future, on the NCBI, PubMed, PMC2964387, 2011 Oct 1.

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