We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPAR{alpha} and CAR.
- Authors
Mitchell B. Rosen; Janice S. Lee; Hongzu Ren; Beena Vallanat; Jie Liu; Michael P. Waalkes; Barbara D. Abbott; Christopher Lau; J. Christopher Corton
- 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 (PPARα). To determine the role of PPARα in mediating PFOA transcriptional events, we compared the transcript profiles of the livers of wild-type or PPARα-null mice exposed to PFOA or the PPARα 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 PPARα. The PPARα–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 PPARα–dependent manner. The increased expression of these genes in PPARα-null mice may be partly due to increases in PPARγ 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 PPARα–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 PPARα, but that a subset of genes are regulated by CAR and possibly PPARγ in the PPARα-null mouse.
- Publication
Toxicological Sciences, 2008, Vol 103, Issue 1, p46
- ISSN
1096-6080
- Publication type
Academic Journal
- DOI
10.1093/toxsci/kfn025