title: Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295R adrenocortical carcinoma cells.
abstract: The present study investigated the effects of the known xenoestrogen bisphenol A (BPA) relative to eight BPA-related diphenylalkanes on estrogen receptor (ER)-mediated vitellogenin (vtg) production in hepatocytes from male carp (Cyprinus carpio), and on aromatase (CYP19) activity in the human adrenocortical H295R carcinoma cell line. Of the eight diphenylalkanes, only 4,4'-(hexafluoropropylidene)diphenol (BHF) and 2,2'-bis(4-hydroxy-3-methylphenyl)propane (BPRO) induced vtg, i.e., to a maximum of 3% to 4% (at 100 microM) compared with 8% for BPA relative to the maximum induction by 17beta-estradiol (E2, 1 microM). Bisphenol A diglycidyl ether (BADGE) was a potent antagonist of vtg production with an IC50 of 5.5 microM, virtually 100% inhibition of vtg at 20 microM, and an inhibitive (IC50) potency about one-tenth that of the known ER antagonist tamoxifen (IC50, 0.6 microM). 2,2'-Diallyl bisphenol A, 4,4'-(1,4-phenylene-diisopropylidene)bisphenol, BPRO, and BHF were much less inhibitory with IC50 concentrations of 20-70 microM, and relative potencies of 0.03 and 0.009 with tamoxifen. Bisphenol ethoxylate showed no anti-estrogenicity (up to 100 microM), and 4,4'-isopropylidene-diphenol diacetate was only antagonistic at 100 microM. When comparing the (anti)estrogenic potencies of these bisphenol A analogues/diphenylalkanes, anti-estrogenicity occurred at lower concentrations than estrogenicity. 4,4'-Isopropylidenebis(2,6-dimethylphenol) (IC50, 2.0 microM) reduced E2-induced (EC50, 100 nM) vtg production due to concentration-dependent cytotoxicity as indicated by a parallel decrease in MTT activity and vtg, whereas the remaining diphenylalkanes did not cause any cytotoxicity relative to controls. None of the diphenylalkanes (up to 100 microM) induced EROD activity indicating that concentration-dependent, CYP1A enzyme-mediated metabolism of E2, or any Ah-receptor-mediated interaction with the ER, was not a likely explanation for the observed anti-estrogenic effects. At concentrations as great as 100 microM, none of the diphenylalkanes directly inhibited aromatase (CYP19) activity in H295R cells. Environmental exposure of fish to BPA and related diphenylalkanes, depending on the structure, may pose anti-estrogenic, and to a lesser extent estrogenic, risks to development and reproduction.
authors.affiliation: National Wildlife Research Centre, Canadian Wildlife Service, Environment Canada, Ottawa, Ontario, Canada K1A 0H3. robert.letcher@ec.gc.ca
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Letcher
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Sanderson
authors.forename: Abraham
authors.initials: A
authors.lastname: Bokkers
authors.forename: John P
authors.initials: JP
authors.lastname: Giesy
authors.forename: Martin
authors.initials: M
authors.lastname: van den Berg
mesh_terms: D018268:Adrenocortical Carcinoma / Q000201:enzymology; D000473:Alkanes / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000633:toxicity; D002347:Carps / Q000378:metabolism*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology / Q000633:toxicity; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D010636:Phenols / Q000494:pharmacology* / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014819:Vitellogenins / Q000096:biosynthesis* / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D000473:Alkanes; D001141:Aromatase; D047072:Aromatase Inhibitors; D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds; D019363:Cytochrome P-450 CYP1A1; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D004968:Estrogens, Non-Steroidal; D010636:Phenols; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D013629:Tamoxifen; D014819:Vitellogenins; C006780:bisphenol A; D000098826:Bisphenol A Compounds