title: Biotransformation of brominated flame retardants into potentially endocrine-disrupting metabolites, with special attention to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47).
abstract: In this study, the endocrine-disrupting (ED) potency of metabolites from brominated flame retardants (BFRs) was determined. Metabolites were obtained by incubating single-parent compound BFRs with phenobarbital-induced rat liver microsomes. Incubation extracts were tested in seven in vitro bioassays for their potency to compete with thyroxine for binding to transthyretin (TTR), to inhibit estradiol-sulfotransferase (E2SULT), to interact with thyroid hormone-mediated cell proliferation, and to (in-)activate the androgen, progesterone, estrogen, or aryl hydrocarbon receptor. For most BFRs, TTR-binding potencies, and to a lesser extent E2SULT-inhibiting potencies, significantly increased after biotransformation. Microsomal incubation had less pronounced effects on other ED modes of action, due to low biotransformation efficiency and background activities determined in control incubations without BFRs. Moreover, cell-based bioassays suffered from cytotoxicity from metabolites of lower-brominated polybrominated diphenyl ethers. For the environmentally relevant 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), six hydroxylated metabolites were identified. Individual metabolites had TTR-binding and E2SULT-inhibiting potencies 160-1600 and 2.2-220 times higher than BDE-47 itself, whereas their combined potencies in a realistic mixture were well predicted via concentration addition. In combination with other environmentally relevant hydroxylated organohalogens acting on TTR-binding and E2SULT inhibition, internal exposure to BFR metabolites may significantly contribute to the overall risk of endocrine disruption.
authors.affiliation: Institute for Environmental Studies (IVM), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. timo.hamers@ivm.vu.nl
authors.forename: Timo
authors.initials: T
authors.lastname: Hamers
authors.forename: Jorke H
authors.initials: JH
authors.lastname: Kamstra
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.forename: Albertinka J
authors.initials: AJ
authors.lastname: Murk
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Martin J M
authors.initials: MJ
authors.lastname: Van Velzen
authors.forename: Abraham
authors.initials: A
authors.lastname: Brouwer
authors.forename: Ake
authors.initials: A
authors.lastname: Bergman
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D052244:Endocrine Disruptors / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D005411:Flame Retardants / Q000378:metabolism* / Q000494:pharmacology; D055768:Halogenated Diphenyl Ethers; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011075:Polybrominated Biphenyls / Q000378:metabolism* / Q000494:pharmacology; D011228:Prealbumin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015238:Sulfotransferases / Q000037:antagonists & inhibitors; D013974:Thyroxine / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D004791:Enzyme Inhibitors; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls; D011228:Prealbumin; C511295:2,2',4,4'-tetrabromodiphenyl ether; D004958:Estradiol; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D015238:Sulfotransferases; D013974:Thyroxine; D010634:Phenobarbital