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Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for Involvement of the Nuclear Receptors PPARα and CAR
Citation:
ROSEN, M. B., H. REN, B. VALLANAT, J. Liu, M. Waalkes, B. D. ABBOTT, C. S. LAU, AND C. CORTON. Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for Involvement of the Nuclear Receptors PPARα and CAR. Presented at European Centre for Ecotoxicology and Toxicology of Chemicals workshop on omics in (eco)toxicology: case studies and risk assessment, Malage, SPAIN, December 06 - 07, 2007.
Impact/Purpose:
The objective of the study was to determine the involvelment of the nuclear receptor PPARα in mediating the effects of the chemical PFOA and to use transcript porfiling to determine the mode of action of liver tumor induction
Description:
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 related to liver carcinogenesis through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). For PFOA the molecular events that occur after PPARα activation and alteration in liver growth are not well characterized. To help identify genes and pathways that may be mechanistically linked to PFOA-induced liver cancer, 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). Under similar exposure conditions (7 days of exposure), 85% or 99.7% of the genes altered by PFOA or WY exposure were dependent on PPARα. The PPARα-independent genes did not overlap. The PPARα-independent genes regulated by PFOA fell into a number of categories including those involved in lipid homeostasis that were also regulated by WY in a PPARα-independent manner. Given that PPAR subtypes regulate gene expression through the same response element, these lipid homeostasis genes may be regulated by PPARβ or PPARγ in the absence of PPARα. The largest set of PPARα-independent genes included those involved in xenobiotic metabolism under control of the nuclear receptor CAR and to a lesser extent the transcription factor Nrf2 regulated by oxidants and anti-oxidants. In a direct comparison there was an excellent correlation between the PPARα-independent PFOA genes and those regulated by activators of CAR including phenobarbital and TCPOBOP in a CAR-dependent manner but not those regulated by Nrf2. These results indicate that WY and PFOA alter most genes in the mouse liver through PPARα but that a subset of genes responsive to PFOA may be regulated by CAR and other PPAR subtypes in the PPARα-null mouse.