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ToxSci Advance Access published online on February 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn025
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Published by Oxford University Press 2008.

Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPAR{alpha} and CAR

Mitchell B. Rosen1, Janice S. Lee1, Hongzu Ren1,2, Beena Vallanat1,2, Jie Liu3, Michael P. Waalkes3, Barbara D. Abbott1, Christopher Lau1 and J. Christopher Corton1,2,4

1 NHEERL/ORD, US EPA, Research Triangle Park, NC 27711 2 NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711 3 National Cancer Institute, Research Triangle Park, NC 27711

4 Corresponding author to whom correspondence should be sent: Chris Corton, Environmental Carcinogenesis Division, National Health and Environmental Effects Research Lab, US Environmental Protection Agency, 109 T.W. Alexander Dr., MD-B143-06, Research Triangle Park, NC 27711, corton.chris{at}epa.gov, 919-541-0092 (office), 919-541-4201 (fax), 919-801-0887 (cell)

Received December 19, 2007; revision received January 28, 2008; accepted February 4, 2008


  Abstract

A number of perfluorinated alkyl acids including perfluorooctanoic acid (PFOA) elicit effects similar to peroxisome proliferator chemicals (PPC) in mouse and rat liver. There is strong evidence that PPC cause many of their effects linked to liver cancer through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR{alpha}). To determine the role of PPAR{alpha} in mediating PFOA transcriptional events, we compared the transcript profiles of the livers of wild-type or PPAR{alpha}-null mice exposed to PFOA or the PPAR{alpha} agonist WY-14,643 (WY). After 7 days of exposure, 85% or 99.7% of the genes altered by PFOA or WY exposure, respectively were dependent on PPAR{alpha}. The PPAR{alpha}-independent genes regulated by PFOA included those involved in lipid homeostasis and xenobiotic metabolism. Many of the lipid homeostasis genes including acyl-CoA oxidase (Acox1) were also regulated by WY in a PPAR{alpha}-dependent manner. The increased expression of these genes in PPAR{alpha}-null mice may be partly due to increases in PPAR{gamma} expression upon PFOA exposure. Many of the identified xenobiotic metabolism genes are known to be under control of the nuclear receptor CAR and the transcription factor Nrf2. There was excellent correlation between the transcript profile of PPAR{alpha}-independent PFOA genes and those of activators of CAR including phenobarbital and TCPOBOP but not those regulated by the Nrf2 activator, dithiol-3-thione. These results indicate that PFOA alters most genes in wild-type mouse liver through PPAR{alpha}, but that a subset of genes are regulated by CAR and possibly PPAR{gamma} in the PPAR{alpha}-null mouse

Key Words: Peroxisome proliferators; perfluorinated alkyl acids; perfluorooctanoic acid; liver cancer.


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