title: Gene profiling in the livers of wild-type and PPARalpha-null mice exposed to perfluorooctanoic acid.
abstract: 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 alpha (PPARalpha) activator; however, PFOA is capable of inducing heptomegaly in the PPARalpha-null mouse. To study the mechanism associated with PFOA toxicity, wild-type and PPARalpha-null mice were orally dosed for 7 days with PFOA (1 or 3 mg/kg) or the PPARalpha 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 PPARalpha. 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 PPARalpha. 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.
authors.affiliation: Office of Research and Development, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. rosen.mitch@epa.gov
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Rosen
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Abbott
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wolf
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Corton
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Wood
authors.forename: Judith E
authors.initials: JE
authors.lastname: Schmid
authors.forename: Kaberi P
authors.initials: KP
authors.lastname: Das
authors.forename: Robert D
authors.initials: RD
authors.lastname: Zehr
authors.forename: Eric T
authors.initials: ET
authors.lastname: Blair
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
mesh_terms: D000818:Animals; D002210:Caprylates / Q000493:pharmacokinetics / Q000633:toxicity*; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D005466:Fluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000633:toxicity; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002210:Caprylates; D004785:Environmental Pollutants; D005466:Fluorocarbons; D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; C023036:perfluorooctanoic acid