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PPARÁ-DEPENDENT GENE EXPRESSION CHANGES IN THE MOUSE LIVER AFTER EXPOSURE TO PEROXISOME PROLIFERATORS
Citation:
REN, H., B. VALLANAT, S. ANDERSON, W. BAO, R. WOLFINGER, AND C. CORTON. PPARÁ-DEPENDENT GENE EXPRESSION CHANGES IN THE MOUSE LIVER AFTER EXPOSURE TO PEROXISOME PROLIFERATORS. Presented at Society of Toxicology Annual Meeting 2007, Charlotte, NC, March 25 - 29, 2007.
Description:
Peroxisome proliferators (PP) are a large class of structurally diverse chemicals that mediate their effects in the liver mainly through the PP-activated receptor ¿ (PPARα). Development of PP induced hepatocarcinogenesis in mouse liver is known to be dependent on PPARα but downstream events related to the alteration in cell proliferation and apoptosis are not well defined and are needed for mode of action analysis. Using BrdU labeling of replicating hepatocytes, we first characterized cell proliferation effects in wild-type and PPAR¿-null mice at 12, 24, 48, and 96 hrs after initial exposure. Cell proliferation peaked at 48 hrs in wild-type mice. PPARα-null mice did not exhibit changes at any of the time points measured. Gene expression changes after the 12 hr treatment were assessed using Affymetrix U74Av2 gene chips. Significance Analysis of Microarray data showed that ~500 genes were significantly different between the treated and untreated groups at a 0.05 False Discovery Rate and almost all of the genes were dependent on PPARα for regulation. To further understand the biological significance of these alterations, we compared the gene expression profiles to those from historical experiments assembled in a PP Compendium containing Affymetrix gene chip data from rats and mice exposed to different PP. Sets of genes commonly regulated by PP were identified at different time points and after exposure to different PP. These genes fell into a number of categories known to be regulated by PPARα strengthening the argument that many PP cause effects in the liver through PPARα.