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Gene Profiling in the Livers of Wild-type and PPAR-Null Mice Exposed to Perfluorooctanoic Acid

¹ U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, Research Triangle Park, North Carolina, USA
² U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Environmental Carcinogenesis Division, Research Triangle Park, North Carolina, USA
³ Applied Biosystems, 850 Lincoln Centre Dr, Foster City, California, USA

Correspondence: Mitchell B. Rosen, U.S. Environmental Protection Agency, MD 72, Research Triangle Park, NC 27711, USA; e-mail:rosen.mitch{at}epa.gov.

Health concerns have been raised because perfluorooctanoic acid (PFOA) is commonly found in the environment and can be detected in humans. In rodents, PFOA is a carcinogen and a developmental toxicant. PFOA is a peroxisome proliferator-activated receptor (PPAR) activator; however, PFOA is capable of inducing heptomegaly in the PPAR-null mouse. To study the mechanism associated with PFOA toxicity, wild-type and PPAR-null mice were orally dosed for 7 days with PFOA (1 or 3 mg/kg) or the PPAR agonist Wy14,643 (50 mg/kg). Gene expression was evaluated using commercial microarrays. In wild-type mice, PFOA and Wy14,643 induced changes consistent with activation of PPAR. PFOA-treated wild-type mice deviated from Wy14,643-exposed mice with respect to genes involved in xenobiotic metabolism. In PFOA-treated null mice, changes were observed in transcripts related to fatty acid metabolism, inflammation, xenobiotic metabolism, and cell cycle regulation. Hence, a component of the PFOA response was found to be independent of PPAR. Although the signaling pathways responsible for these effects are not readily apparent, overlapping gene regulation by additional PPAR isoforms could account for changes related to fatty acid metabolism and inflammation, whereas regulation of xenobiotic metabolizing genes is suggestive of constitutive androstane receptor activation.

Key Words: PFOA • PPAR • PPAR-null • gene expression • microarray • liver

Abbreviations: PFOA, perfluoroctanoic acid • PFAA, perfluoroalkyl acid • PPAR, peroxisome proliferator-activated receptor • CAR, constitutive androstane receptor • FXR, farnesoid X receptor • AhR, aryl hydrocarbon receptor • PXR, pregnane X receptor • SXR, steroid and xenobiotic receptor • RIN, RNA integrity number • RT-PCR, reverse transcription polymerase chain reaction

This version was published on June 1, 2008

Toxicologic Pathology, Vol. 36, No. 4, 592-607 (2008)
DOI: 10.1177/0192623308318208


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