Project 3: PCBs and Hydroxysteroid (Alcohol_ Sulfotransferases

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Polychlorinated biphenyls (PCBs) are metabolized in humans and other mammals to hydroxylated derivatives (OHPCBs), and these metabolites play significant roles in chemical carcinogenesis, endocrine hormone disruption, and other toxic responses. OHPCBs inhibit phenol sulfotransferases that are involved in the metabolism of thyroid hormone and estrogens, but little is known about the interactions of PCBs and OHPCBs with another major family of sulfotransferases, the hydroxysteroid (alcohol) sulfotransferases, which are involved both in hormone metabolism and chemical carcinogenesis. The long term goal of this research is to better understand the effects of PCBs and OHPCBs on the catalytic function and regulation of sulfotransferases and to elucidate the relationships between these effects and the roles that PCBs and OHPCBs have in adverse health effects. The primary objective of the work proposed for the present project is to address the gap in our knowledge related to the effects of PCBs and OHPCBs on the hydroxysteroid sulfotransferases. The central hypothesis for this project is that certain PCBs and hydroxylated metabolites of PCBs can regulate catalytic function and/or expression of hydroxysteroid sulfotransferases. This hypothesis will be tested by pursuing three specific aims: 1) to study 30-quantitative structure-activity relationships for OHPCBs as inhibitors and substrates of two model hydroxysteroid sulfotransferases: rat STa and human SULT2A1; 2) to explore the effects of changes in the ratio of oxidized to reduced glutathione (one result of the generation of reactive oxygen species from PCB-metabolism as studied in Project 1 and Project 2) on the catalytic function of rat STa and human SULT2A1 with OHPCBs as substrates and inhibitors; and 3) to study changes in the levels of expression of rat STa mediated by PCBs and OHPCBs. This research will yield significant new insight into the effects that semi-volatile PCBs and OHPCBs have in regulating hydroxysteroid sulfotransferases that are important in steroid hormone homeostasis as well as in the metabolic activation of carcinogenic hydroxyalkyl polycyclic aromatic hydrocarbons.