ToxSci Advance Access published online on February 25, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm025
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The Flame Retardants, Polybrominated Diphenyl Ethers (PBDE), are Pregnane X Receptor (PXR) Activators
1 University of Kansas Medical Center, Kansas City, KS 2 National Institute of Environmental Health Sciences, Research Triangle Park, NC 3 Environment Protection Agency, Research Triangle Park, NC
Corresponding author: Grace L. Guo, PhD, Assistant Professor, Dept. of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, (Tel) 913-588-0481, (Fax) 913-588-7501, (E-mail) lguo{at}kumc.edu
Received December 11, 2006; revision received February 15, 2007; accepted February 16, 2007
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Abstract |
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Polybrominated diphenyl ethers (PBDEs) are used as flame retardants and are universally present in the environment. An exponential increase in PBDE concentrations in the US population have been reported over the last three 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 USA. 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 (SXR), but not Aryl hydrocarbon receptor (AhR). Furthermore, induction of cyp3a11 and cyp2b10 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.
Key Words: Polybrominated diphenyl ether; PBDE; nuclear receptor; PXR; induction; cyp3a; cyp2b.
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