Hydroxylated Polychlorinated Biphenyl Metabolites Are Anti-estrogenic in a Stably Transfected Human Breast Adenocarcinoma (MCF7) Cell Line

Abstract

Hydroxylated metabolites of polychlorinated biphenyls (OHCBs) have been identified in blood of marine mammals, fish-eating birds, and humans at concentrations in some cases exceeding those of the unmetabolized polychlorinated biphenyls (PCBs). OHCBs have been associated with inhibition of vitamin A and thyroxin transport, estrogenicity in a mouse uterotrophic assay, and feminization of male turtle sexual development. OHCBs, representing both environmentally derived and laboratory exposure-derived metabolites, were tested in anin vitrobioassay utilizing an estrogen-responsive human breast adenocarcinoma cell line (MCF7-LUC) stably transfected with a luciferase reporter gene linked to estrogen responsive elements. OHCB activity was tested at three different media concentrations of 17β-estradiol (E2), comparing the concentration–response curves using charcoal-stripped medium (0.0009 nmE2), and two physiologically relevant E2 concentrations (0.1 and 1.0 nmE2). Eleven of 13 OHCBs tested were anti-estrogenic. Evidence for an estrogen receptor mediated mechanism of action was apparent for only two OHCBs—4-OH-2′,3,3′,4′,5,5′-Cl6-biphenyl and 4,4′-(OH)2-3,3′,5,5′-Cl4-biphenyl. These two have not been identified in environmental samples. The remaining OHCBs exhibited “anti-estrogenicity” that was related to their effect on cell viability and, therefore, cannot be described as exhibiting “hormone disruption” solely by an estrogen receptor mediated mechanism. OHCB anti-estrogenic activity was eliminated in the presence of E2 concentrations normally found in humans, except for 4,4′-(OH)2-3,3′,5,5′-Cl4-biphenyl. 4-OH-2′,3′,4′,5′-Cl4-biphenyl and 4-OH-2′,4′,6′-Cl3-biphenyl were partial estrogen agonists, exhibiting weak estrogenicity in the presence of 0.0009 nmE2 and weak anti-estrogenicity in the presence of 0.1 and 1 nmE2. Human metabolites of PCBs were not estrogenic in MCF7 cells.