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Potent Inhibition of Estrogen Sulfotransferase by Hydroxylated Metabolites of Polyhalogenated Aromatic Hydrocarbons Reveals Alternative Mechanism for Estrogenic Activity of Endocrine Disrupters

Departments of Internal Medicine (M.H.A.K., S.B., H.v.T., T.J.V.) and Pediatric Surgery (M.H.A.K., D.T.), Erasmus University Medical Center, 3015 GJ Rotterdam, The Netherlands; Department of Toxicology, German Institute of Human Nutrition (W.M., H.G.), D-14558 Potsdam-Rehbrucke, Germany; Department of Pharmacology and Toxicology, University of Alabama (C.N.F.), Birmingham, Alabama 35294; Department of Molecular and Cellular Pathology, University of Dundee (M.W.H.C.), Dundee DD1 9SY, United Kingdom; Toxicology Group, Department of Agrotechnology and Food Sciences, Wageningen University (A.G.S.), 6700 EA Wageningen, The Netherlands; and Institute for Environmental Studies, Vrije Universiteit (A.B.), 1081 HV Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. Theo J. Visser, Department of Internal Medicine, Erasmus University Medical Center, Room Bd 234, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: . visser{at}inw3.azr.nl

Abstract

Polyhalogenated aromatic hydrocarbons (PHAHs), such as polychlorinated dibenzo-p-dioxins and dibenzofurans, polybrominated diphenylethers, and bisphenol A derivatives are persistent environmental pollutants, which are capable of interfering with reproductive and endocrine function in birds, fish, reptiles, and mammals. PHAHs exert estrogenic effects that may be mediated in part by their hydroxylated metabolites (PHAH-OHs), the mechanisms of which remain to be identified. PHAH-OHs show low affinity for the ER. Alternatively, they may exert their estrogenic effects by inhibiting E2 metabolism. As sulfation of E2 by estrogen sulfotransferase (SULT1E1) is an important pathway for E2 inactivation, inhibition of SULT1E1 may lead to an increased bioavailability of estrogens in tissues expressing this enzyme. Therefore, we studied the possible inhibition of human SULT1E1 by hydroxylated PHAH metabolites and the sulfation of the different compounds by SULT1E1. We found marked inhibition of SULT1E1 by various PHAH-OHs, in particular by compounds with two adjacent halogen substituents around the hydroxyl group that were effective at (sub)nanomolar concentrations. Depending on the structure, the inhibition is primarily competitive or noncompetitive. Most PHAH-OHs are also sulfated by SULT1E1. We also investigated the inhibitory effects of the various PHAH-OHs on E2 sulfation by human liver cytosol and found that the effects were strongly correlated with their inhibitions of recombinant SULT1E1 (r = 0.922). Based on these results, we hypothesize that hydroxylated PHAHs exert their estrogenic effects at least in part by inhibiting SULT1E1-catalyzed E2 sulfation.

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