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IDENTIFICATION OF GENES AND PATHWAYS REGULATED BY PPARα ACTIVATORS: DIFFERENCES BETWEEN WY-14,643 AND PFOA
Citation:
CORTON, C., M. B. ROSEN, H. REN, B. VALLANAT, B. D. ABBOTT, AND C. S. LAU. IDENTIFICATION OF GENES AND PATHWAYS REGULATED BY PPARα ACTIVATORS: DIFFERENCES BETWEEN WY-14,643 AND PFOA. Presented at EUROTOX 2007, Amsterdam, NETHERLANDS, October 07 - 10, 2007.
Impact/Purpose:
research presentation
Description:
Exposure to peroxisome proliferator chemicals (PPC) leads to increases in liver tumor incidence in mice and rats. There is strong evidence that PPC cause effects related to carcinogenesis through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). To help identify common genes and pathways that may be mechanistically linked to PPC-induced carcinogenesis, we have compared the transcript profiles of the livers of wild-type or PPARα-null mice exposed to a number of PPC using Affymetrix chip data. Under similar exposure conditions (7 days of exposure to WY14,643 or perfluorooctanoic acid (PFOA)) a number of common functional categories of genes were identified. Almost all of these common genes were dependent on PPARα. Each chemical also altered a unique set of genes that were regulated independently of PPARα. The PPARα-independent genes that were regulated by PFOA included those controlled by other nuclear receptors. We tested the hypothesis that CAR was involved in the regulation of the PPARα-independent genes by comparing them to those regulated by CAR activators. There was good correlation between these PFOA-regulated genes and those regulated by phenobarbital and TCPOBOP in a CAR-dependent manner. These results indicate that PFOA and WY alter most genes in the mouse liver through PPARα but that a small subset of PFOA-responsive genes are regulated by other nuclear receptors including CAR.