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A Global Genomic Screening Strategy Reveals Genetic and Chemical Activators ofPeroxisome Proliferator-Activated Receptor alpha (PPARalpha)
Citation:
Corton, C., N. Vasani, Mitch Rosen, B. Abbott, C. Lau, W. Ward, R. Thomas, D. Applegate, AND K. Oshida. A Global Genomic Screening Strategy Reveals Genetic and Chemical Activators ofPeroxisome Proliferator-Activated Receptor alpha (PPARalpha). Presented at Society of Toxicology Annual Meeting, March 10 - 14, 2013.
Impact/Purpose:
This abstract will be presented at the Society of Toxicology meeting March 10-14, 2012, San Antonio, TX
Description:
A comprehensive survey of chemical, diet and genetic perturbations that activate PPARalpha in the mouse liver has not been carried out but would be useful to identify the factors that may contribute to PPARalpha-dependent liver tumors. A gene signature dependent on PPARalpha activation was identified by comparing the transcript profiles after exposure to three PPARalpha activators (Wy-14,643, fenofibrate, perfluorooctanoic acid) in wild-type and PPARalpha-null mice. In independent experiments using transcript profiles from the livers of chemically exposed male or female mice, the signature correctly predicted activation by 2 known PPARalpha activators but not 10 activators of other pathways. Individual genes in the signature (i.e., Cyp4a10, Pdk4) were used in RT-PCR experiments to show the specificity of the response to PPARalpha compared to chemical-induced activation of other xenobiotic-activated transcription factors. The signature was used with standard classification methods to identify perturbations in which PPARalpha was activated in an Affymetrix compendium of 750 mouse liver transcript comparisons encompassing a broad range of chemical, dietary and genetic perturbations. We found that PPARalpha is activated by a number of novel chemicals, dietary regimens and genetic mutations. Specific findings include activation by 1) chemicals that cause steatosis (e.g., TCDD, BaP), 2) dietary regimens of triglycerides, "fast food" and "cafeteria" diets, and fish oil, and 3) nullizygous mutations in a number of genes (Mfp2, Ercc1, Por, Hnfla, Fah/p21, Udf2, Hifla, Hif2a) that could be secondary to steatosis. The findings increase our understanding of the factors that impact PPARalpha activation and that could contribute to increases in PPARalpha-dependent liver tumors. (This abstract does not represent EPA policy.)