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ToxSci Advance Access originally published online on May 5, 2007
Toxicological Sciences 2007 98(2):416-426; doi:10.1093/toxsci/kfm107
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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 Environmental Estrogen, Nonylphenol, Activates the Constitutive Androstane Receptor

Juan P. Hernandez*, Wendong Huang{dagger}, Laura M. Chapman*, Steven Chua{ddagger}, David D. Moore{ddagger} and William S. Baldwin*,1

* Biological Sciences, The University of Texas at El Paso, El Paso, Texas 79968 {dagger} Gene Regulation and Drug Discovery, City of Hope National Medical Center, Duarte, California 91010 {ddagger} Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

1 To whom correspondence should be addressed at University of Texas at El Paso, Biological Sciences, 500 W. University Ave., El Paso, TX 79968. Fax: (915) 747-6888. E-mail: wbaldwin{at}utep.edu.

Received March 8, 2007; accepted April 26, 2007


  Abstract

Nonylphenol (NP) and its parent compounds, the nonylphenol ethoxylates are some of the most prevalent chemicals found in U.S. waterways. NP is also resistant to biodegradation and is a known environmental estrogen, which makes NP a chemical of concern. Our data show that NP also activates the constitutive androstane receptor (CAR), an orphan nuclear receptor important in the induction of detoxification enzymes, including the P450s. Transactivation assays demonstrate that NP increases murine CAR (mCAR) transcriptional activity, and NP treatment can overcome the inhibitory effects of the inverse agonist, androstanol, on mCAR activation. Treatment of wild-type (CAR +/+) mice with NP at 50 or 75 mg/kg/day increases Cyp2b protein expression in a dose-dependent manner as demonstrated by Western blotting, and was confirmed by quantitative reverse transcription–PCR of Cyp2b10 transcript levels. CAR-null (CAR –/–) mice show no increased expression of Cyp2b following NP treatment, indicating that CAR is required for NP-mediated Cyp2b induction. In addition, NP increases the translocation of CAR into the nucleus, which is the key step in the commencement of CAR's transcriptional activity. NP also induced CYP2B6 in primary human hepatocytes, and increased Cyp2b10 messenger RNA and protein expression in humanized CAR mice, indicating that NP is an activator of human CAR as well. In conclusion, NP is a CAR activator, and this was demonstrated in vitro with transactivation assays and in vivo with transgenic CAR mouse models.

Key Words: Nonylphenol; CAR; PXR; Cyp2b10; P450.


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