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INTERSPECIES EXTRAPOLATION AND IN VITRO SCREENING BASED UPON RECOMBINANT AR AND ER PROTEINS
Citation:
WILSON, V. S., P. C. HARTIG, C. V. RIDER, M. C. CARDON, C. R. LAMBRIGHT, K. L. BOBSEINE, AND L. E. GRAY. INTERSPECIES EXTRAPOLATION AND IN VITRO SCREENING BASED UPON RECOMBINANT AR AND ER PROTEINS. Presented at CENR-EDC Workshop, Reston, VA, February 20, 2007.
Description:
While EDCs have the potential to act via several mechanisms of action, one of the most widely accepted is the ability of environmental chemicals to interact directly with either the estrogen (ER) or androgen receptor (AR). Although we know that the steroid receptors of the lower vertebrates are not identical in sequence to the mammalian receptors (which are typically used for hazard ID) a great deal of uncertainty exists about species differences in receptor binding. For example, some studies report that the triazines bind reptilian ER, but not mammalian ER. In addition, major differences in binding of some compounds for rainbow trout ER, alligator ER and human ER have been reported by some investigators, while others have not found similar differences in binding affinities. For AR binding, several studies also have reported that toxicants and steroids which bind human AR do not bind AR of lower vertebrates (i.e. fathead minnow AR and goldfish AR have been reported to have affinities for some chemicals that differ greatly from human AR). Such observations need to be reexamined with purer receptor preparations.
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 isolating receptors and developing AR and ER binding assays from representative species from several classes of vertebrates and invertebrates. AR and ER from multiple species are being examined in order to be able to draw significant conclusions as to the ability to extrapolate data across species. Studies comparing binding of a set of about 20 compounds to fathead minnow, rainbow trout, and human AR indicate good concordance in binding across all three species. Preliminary comparisons of a set of compounds to the fathead and human ER, however, indicate that this same concordance may not be true for the estrogen receptor. A comprehensive comparison across species is critical to determine 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, these studies will increase confidence in risk assessment decisions that involve extrapolation across species.