Journal Article

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

Robert J. Letcher, Josephine G. Lemmen, Bart van der Burg, Abraham Brouwer, Åke Bergman, John P. Giesy and Martin van den Berg

in Toxicological Sciences

Volume 69, issue 2, pages 362-372
Published in print October 2002 | ISSN: 1096-6080
Published online October 2002 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/69.2.362
In Vitro Antiestrogenic Effects of Aryl Methyl Sulfone Metabolites of Polychlorinated Biphenyls and 2,2-Bis(4-chlorophenyl)-1,1-dichloroethene on 17β-Estradiol-Induced Gene Expression in Several Bioassay Systems

More Like This

Show all results sharing these subjects:

  • Medical Toxicology
  • Toxicology (Non-medical)

GO

Show Summary Details

Preview

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.

Keywords: polychlorinated biphenyls; methylsulfone metabolites; estrogen-responsive cells; in vitro bioassays; antiestrogenicity; gene expression

Journal Article.  8940 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.