ToxSci Advance Access originally published online on February 14, 2008
Toxicological Sciences 2008 103(1):46-56; 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
and CAR
,1
* NHEERL/ORD, U.S. EPA, Research Triangle Park, North Carolina 27711
NHEERL Toxicogenomics Core, U.S. EPA, Research Triangle Park, North Carolina 27711
National Cancer Institute, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at Environmental Carcinogenesis Division, National Health and Environmental Effects Research Lab, U.S. Environmental Protection Agency, 109 T.W. Alexander Dr., MD-B143-06, Research Triangle Park, NC 27711. Fax: (919) 541-0694. E-mail: corton.chris{at}epa.gov.
Received December 19, 2007; accepted February 4, 2008
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Abstract |
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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
). To determine the role of PPAR in mediating PFOA transcriptional events, we compared the transcript profiles of the livers of wild-type or PPAR-null mice exposed to PFOA or the PPAR 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. The PPAR–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–dependent manner. The increased expression of these genes in PPAR-null mice may be partly due to increases in PPAR
expression upon PFOA exposure. Many of the identified xenobiotic metabolism genes are known to be under control of the nuclear receptor CAR (constitutive activated/androstane receptor) and the transcription factor Nrf2 (nuclear factor erythroid 2–related factor 2). There was excellent correlation between the transcript profile of PPAR–independent PFOA genes and those of activators of CAR including phenobarbital and 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (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, but that a subset of genes are regulated by CAR and possibly PPAR in the PPAR-null mouse.
Key Words: peroxisome proliferator; perfluorinated alkyl acid; perfluorooctanoic acid; liver cancer.
The information in this document has been funded by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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