Environmental Agents Function as Endocrine Disruptors Via Nuclear Steroid Receptors

T.R. Brown
Department of Population Dynamics
Division of Reproductive Biology
Johns Hopkins University School of Hygiene and Public Health
Baltimore, MD

The endocrine system serves as a communication system by which hormones coordinate and regulate many of the physiologic responses and functions of the body. In particular, the steroid hormones classified as androgens and estrogens are synthesized and secreted by the testes and ovaries, respectively. These hormones communicate with cells by forming intracellular protein-steroid complexes with nuclear receptors that bind to DNA and regulate the expression of specific genes, and hence influence the function of reproductive target organs. There is increasing evidence that environmental chemicals may also interact with steroid receptors and alter the actions of endogenous hormones leading to increases in hormone-related cancers, alterations in sexual development and impairment of reproductive fertility. These environmental chemicals have been variously referred to as "endocrine disruptors" or "hormone mimics" reflecting their actions as antagonists and agonists of endogenous steroid hormone activity. In vitro assays of androgen and estrogen receptor binding and steroid-dependent activation or repression of receptor-dependent transcriptional activity in the presence or absence of suspected environmental chemicals have been designed to evaluate mechanisms of action and correlations with in vivo observations. For example, the environmental agents, dieldrin, endosulfan, toxaphene and the hydroxylated polychlorinated biphenyls have been regarded as potential xenoestrogens yet they are only weakly estrogenic when assayed for their ability to bind to the estrogen receptor or to elicit transcriptional activation of estrogen responsive genes in a yeast based assay system. Therefore, these results need to be reconciled with epidemiologic data suggesting that environmental xenoestrogen exposure is correlated with problems in wildlife reproduction, decreased male reproductive capacity, and an increased incidence of breast cancer in women. By contrast, vinclozolin, a fungicide, and DDE, the metabolite of the persistent insecticide, DDT, act as antiandrogens by competitively inhibiting binding of androgen to its receptor and inhibiting androgen receptor transcriptional activity in mammalian cells transfected with an androgen receptor expression vector and an androgen-responsive reporter gene. These results do confirm in vivo observations of altered male sexual development in rodents. In summary, concern over the potential endocrine disrupting effects of environmental pollutants is increasing, and therefore, the design and implementation of in vitro assays to elucidate mechanisms of action and to predict in vivo effects of chemical agents may provide significant insights into clinically relevant pathologies.