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IDENTIFICATION OF EARLY MOLECULAR EVENTS AFTER PEROXISOME PROLIFERATOR EXPOSURE IN THE RODENT LIVER
Citation:
REN, H., B. VALLANAT, AND C. CORTON. IDENTIFICATION OF EARLY MOLECULAR EVENTS AFTER PEROXISOME PROLIFERATOR EXPOSURE IN THE RODENT LIVER. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
Development of peroxisome proliferators 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. Microarray data sets collected from various experiments involving mouse liver treated with PP were used in Gene Set Enrichment Analysis to elucidate the mechanisms of early responses.
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 α(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. Microarray data sets collected from various experiments involving mouse liver treated with PP were used in Gene Set Enrichment Analysis (Broad Institute, MIT, Boston MA) to elucidate the mechanisms of early responses. We identified enriched gene sets from GSEA analysis and compared these results with differentially expressed genes identified from Affymetrix expression array analysis of the livers of mice and rats exposed to three different peroxisome proliferators for 12 to 24 hrs. A number of common sets of genes were identified including those that were up regulated (cell cycle, DNA replication, Myc, fetal liver vs adult liver, statin pathway) and down regulated (pyruvate metabolism, TNF alpha, Brca1, etc.). These common sets of genes will be examined in a number of pathway tools (e.g., Ingenuity Pathway Analysis) to help to understand the relationships of different molecular and cellular functions after PP exposure and to determine the pathways affected that lead to increases in cell proliferation and decreases in apoptosis.