ENDOCRINE DISRUPTION: A CRITICAL REVIEW OF ENVIRONMENTAL ESTROGENS FROM A MECHANISTIC PERSPECTIVE

With the aid of such systems as the E-screen assay (MCF-7 human breast cancer cells) and/or estrogen receptor (ER) binding assays, estrogenic activity has been identiŽed in a wide variety of nonsteroidal substances, such as polychlorobiphenyls, alkylphenols, bisphenols, pesticides (e.g., DDT derivatives, methoxychlor, kepone), pharmaceutical agents (e.g., diethylstilbestrol [DES], tamoxifen, raloxifene), and phytoestrogens. With few exceptions (notably DES), most xenoestrogens show weak estrogenic and ER binding activity (e.g., 1/1000 to 1/1,000,000 that of the endogenous hormone, estradiol). A series of observations and episodes, some controversial, have led to the perception that endocrine disruption via hormonally active environmental substances is a hazard to wildlife and humans. As a result of Congressional legislation, the U.S. Environmental Protection Agency (EPA) formed the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to develop and implement a multitiered program for the screening and testing of potentially 87,000 chemicals and mixtures for hormonal (primarily estrogenic) activity and endocrine disruptive effects. This review explores the issue of xenoestrogens from a mechanistic perspective. Many nonsteroidal substances can interact with the ligand binding domain of the ER, albeit weakly, because they share characteristics common to both estradiol and DES, these being a ring structure (preferably unencumbered phenolic) along with a hydrophobic center. However, ER binding does not explain the nature of the biological response. As exempliŽed by a diversity of estrogenic and antiestrogenic effects exhibited by estradiol, tamoxifen, and raloxifene and by the antiestrogenic effect of DDT in the tiger salamander, different ER ligands evoke distinct response proŽles that appear to be inuenced by the target tissue and species. These distinct proŽles are determined by the ligand itself and the diversity of ER isoforms (® or ̄), response elements, and individual coregulatory proteins that associate with ER. Endocrine disruption may also be inuenced by the role of plasma binding on the delivery of xenoestrogens to cells, chirality of xenoestrogens, cross-talk between ER signaling and other signaling systems (e.g., aryl hydrocarbon receptor), and alternate mechanisms (e.g., antiandrogen effects). In view of the complexities pertaining to mechanisms of action of xenoestrogens and knowledge yet to be obtained in this area, it would appear that the screening and testing approach undertaken by EDSTAC is premature at this time.