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ToxSci Advance Access originally published online on February 25, 2007
Toxicological Sciences 2007 97(1):94-102; doi:10.1093/toxsci/kfm025
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Flame Retardants, Polybrominated Diphenyl Ethers, Are Pregnane X Receptor Activators

Erik K. Pacyniak*, Xingguo Cheng*, Michael L. Cunningham{dagger}, Kevin Crofton{ddagger}, Curtis D. Klaassen* and Grace L. Guo*,1

* Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 {dagger} National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 {ddagger} Environment Protection Agency, Research Triangle Park, North Carolina 27709

1 To whom correspondence should be addressed at the Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. Fax: 913-588-7501. E-mail: lguo{at}kumc.edu.

Received December 11, 2006; accepted February 16, 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.

Key Words: PBDE; nuclear receptor; PXR, induction; cyp3a; cyp2b.


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