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Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPARα and CAR
Citation:
ROSEN, M. B., J. S. LEE, H. REN, B. VALLANAT, J. Liu, M. P. Waalkes, B. D. ABBOTT, C. S. LAU, AND C. CORTON. Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPARα and CAR. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 103(1):46-56, (2008).
Impact/Purpose:
What is the study and why was it done?
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 PPARgamma 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).
What is the impact to the field and the Agency?
Our analysis of the transcript profile of PFOA in mouse liver demonstrates that most of the gene expression changes are due to activation of PPARalpha. The remaining changes are likely due to a combination of activation of PPARgamma and another nuclear receptor called constitutive activated receptor or CAR which is activated by phenobarbital and related compounds. This information is important in determining the mode of action of PFOA in causing liver tumors in rodents. PFOA most likely causes liver tumors through PPARalpha because the PPARgamma and CAR-like effects do not also consist of changes linked to key events in liver tumor induction. The overall implication is that the liver tumor induction caused by PFOA would not be relevant to man given that functional PPARalpha is expressed at much lower levels in human liver.
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 linked to liver cancer through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). To determine the role of PPARgamma 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 PPAR-null mice may be partly due to increases in PPARgamma 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 PPARα-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 PPARα, but that a subset of genes are regulated by CAR and possibly PPARgamma in the PPARα-null mouse.
