Effects of Aroclors and individual PCB congeners on activation of the human androgen receptor in vitro.
To investigate possible interactions between the human androgen receptor and PCBs in vitro, we have used a previously characterized human androgen receptor reporter gene assay in which PC-3 LUC(AR+) cells respond to 5alpha-dihydrotestosterone (DHT, 50 pM) with enhanced luciferase activity. The effects of Aroclors, commercial mixtures of PCBs, or polychlorinated terphenyls (PCTs) (0, 0.1, 1.0, and 10.0 microM) on luciferase activity in PC-3 LUC(AR+) cells were determined after exposure for 18 h in the presence and absence of DHT (50 pM). In the absence of DHT, none of the Aroclors induced luciferase activity but, in the presence of DHT (50 pM), Aroclors 1016, 1221, 1232, 1242, 1248, 1254, 1260, 5432, and 5442 acted antagonistically at concentrations that did not affect cell viability. Aroclor 5460 was without effect. Similarly, when PCBs found as human milk contaminants were assessed as individual congeners (each at 1 microM, where no cytotoxic effects were observed), none activated luciferase expression in the absence of DHT but PCBs 49, 66, 74, 105, and 118 completely antagonized the stimulation by DHT (50 pM) and PCBs 138, 153, and 156 were less effective antagonists, reducing the DHT stimulation by about 50%. Thus, 30% (by weight) of the PCBs in human milk are androgen antagonists (PCBs 66, 74, 105, and 118) and a further 25% are partial antagonists (PCBs 138, 153, and 156). A proportionally representative mixture of PCBs that contaminate human milk also caused the DHT-mediated activation of luciferase activity in PC-3 LUC(AR+) cells to be reduced by more than 50%.
Schrader
Timothy J
TJ
Toxicology Research Division, Health Products and Foods Branch, Food Directorate, Health Canada, Sir Frederick G Banting Research Centre, 2202D1 Tunney's Pasture, Ottawa, Ont, Canada K1A 0L2.
Cooke
Gerard M
GM
D000726:Androgen Antagonists / Q000633:toxicity*; D000728:Androgens; D001140:Aroclors / Q000633:toxicity*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008895:Milk, Human / Q000737:chemistry; D011080:Polychloroterphenyl Compounds / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000726:Androgen Antagonists; D000728:Androgens; D001140:Aroclors; D004338:Drug Combinations; D004785:Environmental Pollutants; D011080:Polychloroterphenyl Compounds; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D008156:Luciferases