Science Inventory

Identification of Gene Markers for Activation of the Nuclear Receptor Pregnane X Receptor

Citation:

Oshida, K., H. Ren, O. Adefuye, S. Hester, L. Aleksunes, R. Dunn, H. Hamadeh, C. D. Klassen, AND C. CORTON. Identification of Gene Markers for Activation of the Nuclear Receptor Pregnane X Receptor. Presented at Society of Toxicology (SOT) Annual meeting, Washington, DC, March 06 - 10, 2011.

Impact/Purpose:

Activation of PXR in the mouse liver can lead to increases in liver weight in part through increased hepatocyte replication similar to a large number of compounds that activate other nuclear receptors and increase liver cancer incidence. Identification of genes that are accurate predictors of PXR activation would be useful in high-throughput screens to assess potential chemical toxicity. We Identified PXR-dependent genes by comparison of differential gene expression in the livers between wild-type and PXR-null mice treated with pregnenolone l6alpha-carb inonitrile (PCN), a chemical that is often used as a model PXR agonist.

Description:

Many environmentally-relevant chemicals and drugs activate the nuclear receptor pregnane X receptor (PXR). Activation of PXR in the mouse liver can lead to increases in liver weight in part through increased hepatocyte replication similar to chemicals that activate other nuclear receptors and increase liver cancer incidence. Identification of genes that are accurate predictors of PXR activation would be useful in high-throughput screens to assess potential chemical toxicity. We identified PXR-dependent genes by comparison of differential gene expression in the livers between wild-type and PXR-null mice treated with pregnenolone 16alphacarbinonitrile (PCN), a chemical that is often used as a model PXR agonist. Using Affymetrix full-genome mouse arrays, 68% of the genes altered by a 4-day exposure to 400 mg/kg of PCN were completely PXR-dependent and included many involved in DNA replication and the cell cycle. Ingenuity-derived pathways common in both strains included Nrf2 and FXR activation, indicating that PCN activates other transcription factors in addition to PXR. Using the same chip type and identical bioinformatic procedures, we identified putative PXR signature genes by comparing the PCN-responsive, PXR-dependent genes with those that were altered in wild-type but not PXR-null mice after 4 or 7 day exposure to the fungicide propiconazole or the experimental drug Compound 013, respectively. A set of 151 genes were identified that exhibited similar fold-change and direction of change and included those involved in cell cycle and progression and glutathione synthesis but surprisingly did not include genes that are often considered as PXR-specific, i.e., Cyp3a family members. We are presently testing the ability of PXR activators to increase hepatocyte proliferation in the mouse liver and in a mouse hepatocyte cell line. These studies identified a PXR-dependent signature set of genes that could be used for predicting PXR involvement in chemical-induced responses. This abstract does not represent EPA policy.

Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Product Published Date: 03/10/2011
Record Last Revised: 12/06/2012
OMB Category: Other
Record ID: 233644

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

INTEGRATED SYSTEMS TOXICOLOGY DIVISION

SYSTEMS BIOLOGY BRANCH