Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity.
Polychlorinated biphenyls (PCBs) are ubiquitous environmental persistent contaminants giving rise to potential health hazard. Some PCBs exert dioxin-like activities mediated through the aryl hydrocarbon receptor. Although reports on interaction with other nuclear receptors are sparce, some congeners are hypothesized to possess endocrine disruptive potential. Here we present evidence that the three PCBs most abundant in biological extracts, 2,2',3'4,4',5-hexachlorobiphenyl (PCB#138), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB#153), and 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB#180) have pleiotropic effects on the estrogen- and androgen-receptor. In MCF-7 cells a slightly increased cell proliferation was observed at low concentrations (1-10 nM) in cells co-treated with 0.01 nM 17beta-Estradiol, whereas the compounds inhibited cell growth significantly at 1 and 10 microM. In reporter gene (ERE-tk-CAT) analysis the three congeners exhibited a significantly estrogen receptor-ligand mediated decrease of the chloramphenicol transferase activity in both control and 10 nM 17beta-estradiol induced MCF-7 cells. In addition, PCB#138 elicited a dose-dependent antagonistic effect on androgen receptor activity in transiently co-transfected Chinese Hamster Ovary cells with an IC(50), of 6.2 microM. In summary, this study indicate that the di-ortho, multiple-chloro substituted biphenyls, PCB#138, PCB#153 and PCB#180, can compete with the binding of the natural ligand to two nuclear receptors and thus possess the ability to interfere with sexual hormone regulated processes.
Bonefeld-Jørgensen
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Unit of Environmental Biotechnology, Department of Environmental and Occupational Medicine, University of Aarhus, Building 260, Vennelyst Boulevard 6, DK-8000, Aarhus, Denmark. ebj@mil.au.dk
Andersen
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Rasmussen
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Vinggaard
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D059002:Androgen Receptor Antagonists; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000032:analysis; D011078:Polychlorinated Biphenyls / Q000493:pharmacokinetics* / Q000633:toxicity*; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D059002:Androgen Receptor Antagonists; D004785:Environmental Pollutants; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D004958:Estradiol; D011078:Polychlorinated Biphenyls; D008156:Luciferases