Perturbed nuclear receptor signaling by DES linked to obesity

DES effects on body weight may depend both on the time of exposure and on the dose–response


The modern world is plagued with expanding epidemics of diseases related to metabolic dysfunction. The factors that are driving obesity, diabetes, cardiovascular disease, hypertension, and dyslipidemias (collectively termed metabolic syndrome) are usually ascribed to a mismatch between the body’s homeostatic nutrient requirements and dietary excess, coupled with insufficient exercise.

The environmental obesogen hypothesis proposes that exposure to a toxic chemical burden is superimposed on these conditions to initiate or exacerbate the development of obesity and its associated health consequences. Recent studies have proposed a first set of candidate obesogens (diethylstilbestrol, bisphenol A, phthalates and organotins among others) that target nuclear hormone receptor signaling pathways (sex steroid, RXR-PPARgamma and GR) with relevance to adipocyte biology and the developmental origins of health and disease (DOHaD).

Perturbed nuclear receptor signaling can alter adipocyte proliferation, differentiation or modulate systemic homeostatic controls, leading to long-term consequences that may be magnified if disruption occurs during sensitive periods during fetal or early childhood development.

Diethylstilbestrol (DES)

Between the 1940–1980s, the synthetic estrogen diethylstilbestrol was prescribed to women for estrogen deficient states as hormone replacement therapy and to an estimated 2–8 million pregnant women at risk of miscarriage. Subsequent studies established the long-term endocrine disrupting consequences of DES exposure for multiple generations.

DES exposed mothers have an increased risk of developing breast cancer, whereas DES daughters display a high incidence of reproductive tract abnormalities, cervical and vaginal neoplasias, infertility and autoimmune disorders; DES sons also exhibit increased health risks.

A prenatal mouse exposure model recapitulates many of these alterations. Consistent with its estrogenic activity, DES doses between 10–100 μg kg−1 day−1 result in a depressed birth weight that is subsequently maintained. Surprisingly though, a dose of 1 μg kg−1 day−1 did not alter birth weight. Rather it was associated with a significant rise in adult body weight.

New data from Newbold et al. now demonstrate that high doses of DES (1 mg kg−1 day−1) administered between postnatal day 1–5 (during the period of adipocyte differentiation), cause an initial body weight reduction, followed by a period of “catch-up” growth around puberty and a sustained increase in adult body weight. This increase was associated with a higher percent body fat and preceded by elevated serum levels of adipokines and triglycerides.

Hence, it appears that the pro- or anti-adipogenic effects of this estrogenic insult may depend both on the time of exposure and on non-monotonic aspects of the dose–response curve.



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