In Vitro Antiestrogenic Effects of Aryl Methyl Sulfone Metabolites of Polychlorinated Biphenyls and 2,2-Bis(4-chlorophenyl)-1,1-dichloroethene on 17beta-Estradiol-Induced Gene Expression in Several Bioassay Systems

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Abstract
Methylsulfonyl (MeSO2) metabolites of polychlorinated biphenyls (PCBs) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethene (4,4‘-DDE), itself a metabolite of the insecticide 4,4‘-DDT, are emerging as a major class of contaminants in the tissues of wildlife and humans. We investigated the antiestrogenic capacity and potencies of 3‘- and 4‘-MeSO2-2,2‘,4,5,5‘-pentachlorobiphenyl (CB101) and -2,2‘,4,5‘-tetrachlorobiphenyl (CB49), which are among the most environmentally persistent MeSO2-PCBs, and 3-MeSO2-4,4‘-DDE on estrogen receptor (ER)-dependent gene expression in four cell-based bioassay systems. Congener- and concentration-dependent antagonism of 17β-estradiol (E2)-induced gene expression, rather than induction of ER-dependent gene expression, was observed for the MeSO2-PCBs on lucifierase activity in stably transfected human breast adenocarcinoma T47D cells (ER-CALUX) and vitellogenin (vtg) production in primary hepatocytes from male carp fish (Cyprinus carpio) (CARP-HEP/vtg). 4‘-MeSO2-CB101 and -CB49 had the highest antagonistic potency (i.e., maximum inhibition of about 70%, LOECs of 1.0 μM and 2.5 μM), whereas 3‘-MeSO2-CB101 and -CB49 were less antagonistic; the precursor CB101 and MeSO2-PCB analog MeSO2-2,5-dichlorobenzene had no effect. Relative to the 4-MeSO2-PCBs, tamoxifen (IC50, 0.06 μM and 0.7 μM) was about 40 and 7 times more potent in the ER-CALUX and CARP-HEP/vtg assays, respectively. Congener- and concentration-dependent effects on aryl hydrocarbon receptor-mediated induction of EROD activity (carp hepatocytes), luciferase expression (H4IIE rat hepatoma [H4IIE.luc] cell line), or cell viability were not observed. 3-MeSO2-4,4‘-DDE was neither estrogenic nor antiestrogenic in either of the bioassays. Inhibitory trends for the MeSO2-PCBs in a bioassay based on stably transfected human embryonic kidney cell (HEK293-ERα-ERE) were similar to the ER-CALUX and CARP-HEP/vtg bioassays, whereas the antagonism was weaker in a related HEK293-ERβ-ERE bioassay. Our findings suggest that the 4‘-MeSO2-PCBs are antiestrogenic in vitro via a reversible or surmountable interaction with fish or human ER, and that the interaction with human ERα is apparently favored over ERβ. MeSO2-PCB metabolites are persistent and bioaccumulative contaminants, and therefore, could be potentially active as environmental antiestrogens in wildlife and humans.