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IDENTIFICATION OF COMMON GENES AND PATHWAYS REGULATED BY PPARÁ ACTIVATORS
Citation:
LLOYD, S., B. VALLANAT, M. B. ROSEN, B. D. ABBOTT, K. DAS, R. ZEHR, C. S. LAU, AND C. CORTON. IDENTIFICATION OF COMMON GENES AND PATHWAYS REGULATED BY PPARÁ ACTIVATORS. Presented at Society of Toxicology Annual Meeting 2007, Charlotte, NC, March 25 - 29, 2007.
Description:
Exposure to peroxisome proliferator chemicals (PPC) leads to alterations in the balance between hepatocyte growth and apoptosis, increases in liver to body weights (LW/BW) and liver tumors. There is strong evidence that PPC cause many of their effects related to carcinogenesis through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). The molecular events that occur after PPARα activation and alteration in liver growth are not well characterized. 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 PPAR¿-null mice exposed to a number of PPC using Affymetrix chip data. A number of PPC which all induce liver cancer were compared in this study including WY-14,643 (WY) and di(2-ethylhexyl) phthalate (DEHP) which require PPARα for increases in LW/BW and perfluorooctanoic acid (PFOA) which causes increases in LW/BW in both wild-type and PPARα-null mice. Transcript profiling was performed using either mouse U74Av2 or 430_2 Affymetrix chips. Significantly altered genes were identified using Rosetta Resolver. Under similar exposure conditions (7 consecutive daily gavages) a number of common functional categories of genes were identified including those involved in fatty acid oxidation and transport, peroxisome biogenesis, proteome maintenance, coagulation, complement cascade and oxidative stress as well as those linked to cell growth control. Almost all of these common genes were dependent on PPARα for changes in transcript levels as the changes were not observed in PPARα-null mice. Each chemical also altered a unique set of genes. For WY all of these genes were dependent on PPARα. These results indicate that the model PPC WY, does not alter gene expression in the mouse liver independently of PPARα, and that all PPC examined alter a smaller unique set of genes. Future work will be directed toward characterizing the functional significance of the changes in the cell growth genes commonly regulated by many PPC.