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Environmental estrogens and endocrine disruption: importance of comparative endocrinology.

Recognition in the late 1980s that environmental contaminants possess hormone-like activity was a major advance (1) that has since captured the attention of scientists, industry, government regulators, policy specialists, and nongovernment organizations around the globe. Governments have responded with research programs designed to address the endocrine disruption hypothesis with the result that significant research resources have been directed toward this issue. Not surprisingly, the endocrine disruption literature continues to expand along with increasing calls from nongovernment organizations for government regulation and bans on the manufacture of suspect chemicals. However, the potential for adverse health effects in the human population, together with the socioeconomic implications and the cost to industry, make it vital that governments and industry undertake the necessary research to ensure that regulatory decisions are evidence based and delivered in a timely manner. Adverse health effects in the human population thought to be linked to exposure to environmental contaminants with hormone-like activity include but are not limited to: increased prevalence of cryptorchidism and hypospadias (2); testicular (3), breast (4), and prostate cancer (5); endometriosis (6); polycystic ovarian syndrome (7); and declines in semen quality (8, 9). Of these health outcomes, the strength of the association is best for developmental abnormalities of the male reproductive tract, leading to the proposal of the testicular dysgenesis syndrome (10); however, this hypothesis needs to be tested. Nevertheless, there is an ever-expanding list of chemicals that have been found to bind with steroid receptors (estrogen and androgen) acting as either agonist or antagonist that activate the receptor and modify the expression of estrogenand androgenregulated genes in vitro and in vivo (11, 12). Tissue culture studies demonstrate that environmental contaminants can both increase the expression of steroidogenic enzymes such as steroid acute regulatory protein and aromatase (13, 14), as well as increase the expression of enzymes involved in the metabolism of gonadal steroids (15, 16). Furthermore, animal studies have demonstrated that exposure to chemicals with hormone-like activity change functional characteristics of steroid-dependent target tissues. Moreover, there is a growing body of evidence that shows that the developing organism is more sensitive to the potential adverse health effects resulting from exposure to endocrine toxicants (17). Of growing interest is the realization that hormone-like chemicals can program cells and thus affect endocrine function through epigenetic mechanisms (5, 18–21), effects that may persist across more than one generation. Finally, it is generally accepted that there are limitations in the translation of results from animal studies to humans. Overall, the weight of evidence for human health effects are thought to be weak to moderate (22), owing in part to inconsistencies in the epidemiological literature, lack of evidence documenting exposure, paucity of experimental data concerning mechanism of action, lack of suitable animal models for the outcome of interest such as testicular or prostate cancer, and limited evidence for the biological plausibility of the proposed hypothesis. Consequently, adverse health effects associated with exposure to hormonally active chemicals remain controversial and hotly debated. In contrast to the human population, effects such as feminization of fish are generally accepted examples of the effects of hormone-like chemicals (23–26). However, it is important to appreciate that the chemicals responsible remain to be determined and, equally important, the mechanisms involved in the uptake and bioaccumulation of chemical contaminants in fish have not been elucidated. Of note, a prior study has demonstrated that steroids are taken up by fish in relation to the steroids affinity for sex hormone binding globulin (SHBG) (27), a protein that that has been detected in the gills of fish. Recent studies have also demonstrated that sex steroids are present in waste water effluent (28), and thus fish may be exposed to both hormonally active environmental contaminants as well as naturally occurring sex steroids. Therefore, it is important to determine whether SHBG in fish gills can function as a portal for the entry of hormonally active chemicals into fish. This question is addressed in this issue of Endocrinology by Miguel-Queralt and Hammond (29) who investigated the expression of SHBG in the gills of zebra fish and measured the uptake from water of radiolabeled steroids. Results of this study reveal that SHBG is expressed (mRNA and protein) in gills of zebra fish although mRNA levels are profoundly lower than expression levels in the liver. SHBG immunoreactivity was demonstrated in the fish gill by immunohistochemistry and confirmed by Western blot, although the authors note that contribution from blood contamination cannot be ignored. The authors further demonstrated that zebra fish rapidly take up radiolabeled testosterone and ethinylestradiol but are prevented from doing so by hypothermic anesthesia or exposure to excess unlabeled zfSHBG ligands, thus providing support for the hypothesis that SHBG provides a portal for the entry of steroids into fish. The release rate of radiolabeled steroids back into the water was also demonstrated to be slow suggesting that this mechanism can provide a means for concentration of xenoestrogens in fish tissue. The authors further demonstrate that the relative binding affinity (RBA) of SHBG for natural steroids was high, whereas the RBA for the xenobiotics Bisphenol A, benzanthracene, and dichlorodiphenyldichloroethylene was very low. Taken together, these data demonstrate that the SHBG is abundantly expressed in the gills where it efficiently sequesters steroids from the Abbreviations: RBA, Relative binding affinity; SHBG, sex hormonebinding globulin.