Characterizing the effect of bisphenol-A on the metabolism of maternally derived

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DESCRIPTION (provided by applicant): All vertebrate embryos develop in the presence of maternally derived steroids and accumulating evidence suggests that these steroids are subject to prolific embryonic metabolism. This metabolism is frequently thought of as a "buffer" that regulates embryonic exposure to maternal steroids. The recent demonstration that maternally derived estradiol is converted to estrone sulfate early in development and that the endocrine disrupting chemical bisphenol-A inhibits this conversion has prompted further investigation to understand how bisphenol-A disrupts steroid metabolism and the long-term consequences of this disruption. The proposed research utilizes a wild turtle model that provides an excellent system for evaluating the interaction between maternal steroids, endocrine disruption, and metabolism because: (1) steroids and steroidogenic enzymes are conserved across vertebrates, (2) turtle embryos are very amenable to experimental manipulation, and (3) sex determination in turtles is sensitive to steroids and endocrine disrupting chemicals which provides a diagnostic tool for assessing endocrine disruption. The first aim of the proposal will determine if bisphenol-A is a ubiquitous inhibitor of steroid sulfonation. This aim will characterie the metabolic fate of progesterone, testosterone, and corticosterone during early development and test the hypothesis that BPA is broadly capable of inhibiting embryonic metabolism of steroids. To accomplish this aim, exogenous steroid and bisphenol-A manipulations will be used to determine metabolite formation during early development. The second aim of the proposal will determine the inhibiting effects of bisphenol-A on the in ovo metabolism of maternally derived estradiol. This aim will test the hypothesis that inhibition of normal embryonic steroid metabolism has phenotypic consequences for the resulting hatchling. To accomplish this aim, exogenous manipulations will also be employed to assess the effects of these manipulations on offspring sex. The results from this work will provide important new information on endocrine disruption that may extend beyond the effects of bisphenol-A, and shed light on an underlying mechanism for non-receptor mediated pathways for endocrine disruptor activity.