Project 3: PCBs and Hydroxysteroid (Alcohol_ Sulfotransferases

University Of Iowa, Iowa City IA

Investigators

Linked publications & trials

Abstract

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