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The flame retardants, polybrominated diphenyl ethers, are pregnane X receptor activators.
- Source :
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2007 May; Vol. 97 (1), pp. 94-102. Date of Electronic Publication: 2007 Feb 25. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Aryl Hydrocarbon Hydroxylases biosynthesis
Cell Line, Tumor
Cytochrome P-450 CYP3A genetics
Cytochrome P450 Family 2
Dose-Response Relationship, Drug
Enzyme Induction drug effects
Halogenated Diphenyl Ethers
Humans
Hydrocarbons, Brominated toxicity
Liver enzymology
Male
Membrane Proteins genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Pregnane X Receptor
Promoter Regions, Genetic drug effects
RNA, Messenger biosynthesis
Receptors, Steroid deficiency
Receptors, Steroid genetics
Receptors, Steroid metabolism
Steroid Hydroxylases biosynthesis
Transfection
Cytochrome P-450 CYP3A biosynthesis
Flame Retardants toxicity
Gene Expression Regulation, Enzymologic drug effects
Liver drug effects
Membrane Proteins biosynthesis
Phenyl Ethers toxicity
Polybrominated Biphenyls toxicity
Receptors, Steroid agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1096-6080
- Volume :
- 97
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 17324954
- Full Text :
- https://doi.org/10.1093/toxsci/kfm025