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A Global Genomic and Genetic Strategy to Predict Pathway Activation of Xenobiotic Responsive Transcription Factors in the Mouse Liver
Citation:
Oshida, K., N. Vasani, M. B. ROSEN, B. D. ABBOTT, C. LAU, B. N. CHORLEY, S. Hester, W. O. Ward, G. Guo, R. Thomas, D. Applegate, T. Kensler, AND C. CORTON. A Global Genomic and Genetic Strategy to Predict Pathway Activation of Xenobiotic Responsive Transcription Factors in the Mouse Liver. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
A Global Genomic and Genetic Strategy to Predict Pathway Activation of XenobioticResponsive Transcription Factors in the Mouse Liver
Description:
Many drugs and environmentally-relevant chemicals activate xenobiotic-responsive transcription factors(TF). Identification of target genes of these factors would be useful in predicting pathway activation in in vitro chemical screening. Starting with a large compendium of Affymetrix files (>2000), we identified gene signatures by comparing the transcription profiles after exposure to TF activators in wild-type and TF-null mice. The signatures included those regulated by PPARalpha, CAR, PXR, AhR, Nrf2, FXR, and glucocorticoid receptor (GR). In addition, we identified sets of genes associated with phenomenon that are linked to liver toxicity/cancer including inflammation and cytotoxicity. Validation was carried out by characterization of the signature gene expression under independent conditions of chemical exposure or perturbation known to alter the TF. By using the sets of signature genes to query the compendium, a number of novel observations were made. 1) PPARalpha is activated in a number of nullizygous mouse models that also lead to liver toxicity and may be linked to steatosis. 2) Nrf2 is activated by a large number of conditions including environmentally-relevant chemicals, gene mutations, and bacterial infections. 3) GR is activated by a number of conditions including caloric restriction and systemic damage outside the liver. 4) Feminization of male-specific signature genes occurred after castration, in GH-defective dwarf mice, during bacterial infections and chemical exposure. Our approach allows for creation of new gene signatures associated with other pathways or phenomenon in the mouse liver that can be tested using the compendium. We are presently using the signature sets to predict pathway activation after chemical exposure in mouse primary hepatocytes. (This abstract does not represent EPA policy.)