DES metabolic disruption

Endocrine disruptors: from endocrine to metabolic disruption

2011 Study Abstract

Metabolic disruption mediated by inappropriate activation of the estrogen receptor

ERα and ERβ are the main mediators of the biological effects of estrogens. Upon estrogen binding, they form homodimers that bind to the promoters of estrogen-responsive genes. These molecules share a similar structure and bind to the same response element but have varying relative binding affinities for some steroid hormones. In addition to their well-established roles in reproduction, ERα and ERβ are involved in brain development and function of many other organs, such as skin, bone, and liver. Several lines of evidence link ERs to metabolism. For example, in postmenopausal women and ovarectomized rodents in which estrogen is low, one observes an increase in white adipose tissue; estrogen replacement therapy reverses these effects. ERα but not ERβ appears to mediate these effects, as inferred from studies using mice in which ERα is knocked out: Both male and female mutant mice show increased insulin resistance and impaired glucose tolerance. Although the underlying mechanisms remain unclear for these observed results, it seems likely that ERα activation modulates neural networks controlling food intake as well as acts directly in adipose tissue. At a cellular level, preadipocytes also express ERα and ERβ, and during development, estrogens contribute to an increase in adipocyte number, with subsequent effects on adipocyte function. At the molecular level, ERs and estrogens regulate many aspects of metabolism, including glucose transport, glycolysis, mitochondrial structure and activity, and fatty acid oxidation.

There are two important aspects to consider with respect to estrogen-like activity and metabolic changes.

  1. The first aspect concerns nongenomic responses to estrogen mediated by the nonclassical transmembrane receptor GPR30. GPR30 deletion in mice revealed its major role in many facets of estrogen metabolic activity, with phenotypes including impaired glucose tolerance and reduction of bone growth. This membrane receptor can also be activated by BPA and nonylphenol, as assessed in an in vitro cell culture model. Further studies are thus needed to evaluate the in vivo relevance of this activation.
  2. The second major question concerns exposure to estrogenic EDCs during the critical period of development. Indeed, embryos and fetuses are likely to be much more sensitive to perturbation by endocrine-like activities. Protective mechanisms available in adult animals, such as DNA repair mechanisms or liver detoxification and metabolism, are not fully functional in the fetus or neonate. Thus, exposure to EDCs during this period can cause adverse effects, some of which are not apparent until much later in life. This point is best illustrated by prenatal exposure to the estrogen derivative diethylstilbestrol (DES), which was widely used until the 1970s as an antimiscarriage medication; this early exposure impaired reproduction later in life. Mice exposed to low DES doses during pregnancy produced normal-sized offspring but later showed an age-dependent increased body weight gain and altered obesity-related gene expression. Prenatal exposure to DES also led to elevated serum levels of leptin, adiponectin, interleukin (IL)-6, and triglycerides in mice prior to their becoming overweight and obese.

Exposure During Critical Periods of Development

The dramatic effect of DES exposure on female babies illustrates the critical issue of exposure during development. Consistent with the well-known functions of classic hormones in developing reproductive organs, the effects are easily understood when these hormones are disrupted or mimicked. Even disregarding transgenerational effects, the metabolic consequences of prenatal exposure that manifest in adulthood are difficult to assess and to understand. As discussed above, controversy surrounds many of these consequences, and only systematic animal studies may lead to a fair risk evaluation. Future efforts should be aimed at elucidating whether and how epigenetic imprinting is involved in these pathologies.

Sources

  • Endocrine Disruptors: From Endocrine to Metabolic Disruption, Annual Review of Physiology Volume 73, Casals-Casas, pp 135-162, 2011.
  • Featured image alan King.
DES DIETHYLSTILBESTROL RESOURCES

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