title: The flame retardants, polybrominated diphenyl ethers, are pregnane X receptor activators.
abstract: Polybrominated diphenyl ethers (PBDEs) are used as flame retardants and are universally present in the environment. An exponential increase in PBDE concentrations in the U.S. population have been reported over the last 3 decades. PBDEs 47 (tetraBDE) and 99 (pentaBDE) are the most commonly detected PBDE congeners in the environment and in human samples. PBDE209 (decaBDE) is the only remaining PBDE flame retardant commercially manufactured in the United States. Several PBDEs are known to induce cyp3a in rats, but the mechanism of induction remains unclear. The goal of this study was to clarify the mechanism by which PBDE congeners induce cyp3a. Treatment of C57BL6 mice with PBDEs 47, 99, and 209 induced gene expressions of cyp3a11 and 2b10, but not cyp1a1/2. Because the first two genes are known target genes of pregnane X receptor (PXR), a ligand-activated transcription factor in the nuclear hormone receptor superfamily, we hypothesized that PBDE congeners are PXR activators. Using reporter gene luciferase assays, the present data show that PBDEs 47, 99, and 209 activated PXR and its human counterpart, steroid X receptor, but not aryl hydrocarbon receptor. Furthermore, induction of cyp3a11 and 2b10 by PBDEs 47, 99, and 209 was markedly suppressed in PXR-knockout mice, indicating that PBDE congeners activate PXR in vivo. In summary, our study provides the first evidence that PBDEs are activators for xenobiotic nuclear receptor.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Erik K
authors.initials: EK
authors.lastname: Pacyniak
authors.forename: Xingguo
authors.initials: X
authors.lastname: Cheng
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Kevin
authors.initials: K
authors.lastname: Crofton
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005411:Flame Retardants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D055768:Halogenated Diphenyl Ethers; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010647:Phenyl Ethers / Q000633:toxicity*; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D014162:Transfection
chemical_list: D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D006842:Hydrocarbons, Brominated; D008565:Membrane Proteins; D010647:Phenyl Ethers; D011075:Polybrominated Biphenyls; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; C511295:2,2',4,4'-tetrabromodiphenyl ether; C086401:pentabromodiphenyl ether; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; C010902:decabromobiphenyl ether