EPA Science Inventory

Prediction of Pathway Activation by Xenobiotic-Responsive Transcription Factors in the Mouse Liver

Citation:

Oshida, K., N. Vasani, M. Rosen, B. Abbott, C. Lau, B. N. CHORLEY, S. Hester, G. Guo, T. Kensler, C. Klaassen, AND C. CORTON. Prediction of Pathway Activation by Xenobiotic-Responsive Transcription Factors in the Mouse Liver. Presented at Genetics and Environmental Mutagenesis Society (GEMS) Fall Meeting, , Chapel Hill, NC, November 08, 2011.

Description:

Many drugs and environmentally-relevant chemicals activate xenobioticresponsive 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 sets of signature genes that are dependent on specific TF including PPARaipha, CAR, PXR, AhR, Nrf2, FXR, and glucocorticoid receptor (GR). Target genes were identified by comparing the profiles after exposure to TF activators in wild-type and TF-null mice. In addition. we identified sets of genes associated with phenotypes that are linked to liver toxicity/cancer including inflammation and cytotoxicity, By using the sets of signature genes to query the compendium. a number of novel observations were made . 1) PPARaipha 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 phenotypes 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)

Purpose/Objective:

Our approach allows for creation of new gene signatures associated with other pathways or phenotypes 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.

URLs/Downloads:

Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Start Date: 11/08/2011
Completion Date: 11/08/2011
Record Last Revised: 12/13/2012
Record Created: 11/28/2011
Record Released: 11/28/2011
OMB Category: Other
Record ID: 239726

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

INTEGRATED SYSTEMS TOXICOLOGY DIVISION

SYSTEMS BIOLOGY BRANCH