Gene profiling in the livers of wild-type and PPARalpha-null mice exposed to perfluorooctanoic acid.
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.
Rosen
Mitchell B
MB
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
Abbott
Barbara D
BD
Wolf
Douglas C
DC
Corton
J Christopher
JC
Wood
Carmen R
CR
Schmid
Judith E
JE
Das
Kaberi P
KP
Zehr
Robert D
RD
Blair
Eric T
ET
Lau
Christopher
C
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
D002210:Caprylates; D004785:Environmental Pollutants; D005466:Fluorocarbons; D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; C023036:perfluorooctanoic acid