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Species comparisons in molecular and functional attributes of the androgen and estrogen receptor
Citation:
WILSON, V. S. Species comparisons in molecular and functional attributes of the androgen and estrogen receptor. Presented at Society for the Study of Reproduction, San Antonio, TX, July 21 - 25, 2007.
Impact/Purpose:
Presentation
Description:
While endocrine disrupting compounds (EDCs) have the potential to act via several mechanisms of action, one of the most widely studied is the ability of environmental chemicals to interact directly with either the estrogen (ER) or androgen receptor (AR). In vitro screening assays designed to identify hormone mimics or antagonists typically use mammalian (rat, human) androgen receptors (AR). Although the amino acid sequences of receptors from nonmammalian vertebrates are not identical to the mammalian receptors, it is uncertain whether these differences affect interactions of potential endocrine disrupting chemicals (EDC) with the receptors. It is known that specific mutations in the human AR result in abnormal male sexual phenotypes as the structural changes in AR protein decrease the affinity of the receptor for endogenous androgens. This suggests that individuals or species with minor variations in the AR sequence may be more or less susceptible to some toxicants and that even subtle differences within species might affect the organism’s response to EDCs. Some studies indicate that steroid hormone receptors from non-mammalian vertebrates not only differ from mammalian receptors structurally but also in their binding affinities for some steroids and environmental chemicals. With these issues in mind, and to test the hypothesis that EDC’s bind steroid receptors from mammalian and non-mammalian vertebrates and invertebrates with similar affinity, we are developing AR and ER binding assays from representative species from several classes of vertebrates and invertebrates. Recombinant receptors from multiple species are being examined in order to be able to draw significant conclusions as to the ability to extrapolate data across species. Current studies compare the affinity of both endogenous steroids and EDCs to recombinant fish (fathead minnow and rainbow trout) and human AR and ER. These types of studies are critical for determining the necessity of including receptors from other species in in vitro assessments and will impact the number and scope of assays needed to perform a thorough assessment. Ultimately, they will increase confidence in risk assessment decisions which involve extrapolation across species.