Exoestrogens: Mechanisms of action and strategies for identification and assessment

Public attention has recently been focused on the increased incidence of hormone-dependent cancers. However, less than one half of these increases can be attributed to improved detection methods and/or recently identified genetic factors. Consequently, it has been suggested that certain exogenous compounds are able to modulate the endocrine system by augmenting the sex steroid burden. This hypothesis is supported by a number of studies demonstrating physiologic and morphologic changes in wildlife exposed to high concentrations of environmental contaminants that are capable of eliciting responses typically induced by sex steroids. Due to associated steroidlike activities, these chemicals have been termed endocrine disrupters. The most well-characterized endocrine disrupters are exoestrogens, whose effects are similar to those produced by endogenous estrogens such as 17 beta-estradiol, although they are structurally unrelated. This broad structural diversity suggests that exoestrogens may elicit effects through a number of divergent pathways including direct binding and activation of the estrogen receptor (ER); binding to other nuclear receptors, which then interact with an estrogen responsive element. and through other receptor and/or signal transduction pathways. One such pathway involves the aryl hydrocarbon receptor (AhR), which binds a number of environmental contaminants such as polychlorinated biphenyls, dioxins, and furans. Several mechanisms have been elucidated that partially explain the AhR-mediated antiestrogenic activities of dioxins and related compounds. These include increased estrogen metabolism, down-regulation of estrogen receptor protein levels and binding activity, and decreased ER-mediated gene expression. A number of assays, both in vitro and in vivo, have been developed to identify and assess the endocrine disrupting potential of a compound. However, due to the broad structural diversity and number of potential mechanisms of action, a battery of complementary in vitro and in vivo assays is required to comprehensively assess the endocrine disrupting capability of exoestrogens.