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GENE PROFILING IN WILD TYPE AND PPARÁ NULL MICE EXPOSED TO PFOA
Citation:
ROSEN, M. B., B. D. ABBOTT, J. E. SCHMID, DAN ZEHR, K. DAS, C. J. WOLF, AND C. S. LAU. GENE PROFILING IN WILD TYPE AND PPARÁ NULL MICE EXPOSED TO PFOA. Presented at Current Concepts in Toxicology Workshop, Arlington, VA, February 14 - 16, 2007.
Description:
Perflurooctanoic acid (PFOA) is a perfluoroalkyl acid used in a variety of commercial applications. Concerns have been raised because PFOA is ubiquitous in the environment and can be detected in human tissues. PFOA is a rodent carcinogen and a developmental toxicant in mice. While the mode of action (MOA) of PFOA toxicity is not clear, this compound is a PPARα agonist and a peroxisome proliferator. For this reason, liver tumors in rodents are thought to be related to PPAR¿ signaling. However, PFOA also increases liver weight in the PPARα null mouse. To further study the MOA of PFOA, wild type and PPARα null mice were orally dosed with either PFOA (1 or 3 mg/kg), Wy14,643 (50 mg/kg), or vehicle for 7 days. Wy14,643 was included as a known PPARα agonist. Animals were euthanized, livers weighed, and liver samples collected for preparation of total RNA. Gene profiling analysis was conducted using Applied Biosystems microarrays on 4 animals per group. In wild type mice, Wy14,643 induced many of the predicted PPARα related changes in genes associated with lipid metabolism, sterol biosynthesis, bile acid biosynthesis, retinol metabolism, and inflammation. Wy14,643 had little effect on the PPAR¿ null mouse. On the other hand, while it was clear from the response of the wild type mice that the majority of PFOA related changes were mediated through PPARα, changes in gene expression were nonetheless observed in the knockout animal. These included 177 genes that were similarly altered in both wild type and knockout mice. Among the up-regulated genes were several Cyp2 and Cyp3 genes, Acyl CoA dehydrogenase (long chain), Cyclin D1, Aox1, Dbi, Aldh1a7, and Cyp4a10. Included in the group of down-regulated genes were Complement components 4A and B, Complement factors B and H, Cathepsin C, and Baat. These results indicate that while PFOA influences certain biological processes such as lipid homeostasis, inflammation, and cell cycle progression via a PPARα mediated MOA, there also appears to be a non-PPARα related component to this response. This abstract does not necessarily reflect EPA policy.