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.
Methylsulfonyl (MeSO(2)) 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'-MeSO(2)-2,2',4,5,5'-pentachlorobiphenyl (CB101) and -2,2',4,5'-tetrachlorobiphenyl (CB49), which are among the most environmentally persistent MeSO(2)-PCBs, and 3-MeSO(2)-4,4'-DDE on estrogen receptor (ER)-dependent gene expression in four cell-based bioassay systems. Congener- and concentration-dependent antagonism of 17beta-estradiol (E2)-induced gene expression, rather than induction of ER-dependent gene expression, was observed for the MeSO(2)-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'-MeSO(2)-CB101 and -CB49 had the highest antagonistic potency (i.e., maximum inhibition of about 70%, LOECs of 1.0 microM and 2.5 microM), whereas 3'-MeSO(2)-CB101 and -CB49 were less antagonistic; the precursor CB101 and MeSO(2)-PCB analog MeSO(2)-2,5-dichlorobenzene had no effect. Relative to the 4-MeSO(2)-PCBs, tamoxifen (IC(50), 0.06 microM and 0.7 microM) 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-MeSO(2)-4,4'-DDE was neither estrogenic nor antiestrogenic in either of the bioassays. Inhibitory trends for the MeSO(2)-PCBs in a bioassay based on stably transfected human embryonic kidney cell (HEK293-ERalpha-ERE) were similar to the ER-CALUX and CARP-HEP/vtg bioassays, whereas the antagonism was weaker in a related HEK293-ERbeta-ERE bioassay. Our findings suggest that the 4'-MeSO(2)-PCBs are antiestrogenic in vitro via a reversible or surmountable interaction with fish or human ER, and that the interaction with human ERalpha is apparently favored over ERbeta. MeSO(2)-PCB metabolites are persistent and bioaccumulative contaminants, and therefore, could be potentially active as environmental antiestrogens in wildlife and humans.
Letcher
Robert J
RJ
Institute for Risk Assessment Sciences (IRAS), Utrecht University, NL-3508 TD Utrecht, The Netherlands. letcher@uwindsor.ca
Lemmen
Josephine G
JG
van der Burg
Bart
B
Brouwer
Abraham
A
Bergman
Ake
A
Giesy
John P
JP
van den Berg
Martin
M
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000633:toxicity*; D001943:Breast Neoplasms / Q000378:metabolism; D002347:Carps / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000633:toxicity*; D005260:Female; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D011078:Polychlorinated Biphenyls / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology; D014819:Vitellogenins / Q000096:biosynthesis
C472353:4'-MeSO(2)-2,2',4,5'-tetrachlorobiphenyl; C472352:4'-MeSO(2)-2,2',4,5,5'-pentachlorobiphenyl; D001713:Biphenyl Compounds; D004965:Estrogen Antagonists; D014819:Vitellogenins; D013629:Tamoxifen; D000077267:Fulvestrant; D003633:Dichlorodiphenyl Dichloroethylene; D004958:Estradiol; D011078:Polychlorinated Biphenyls; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1