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Screening a Mouse Liver Gene Expression Compendium Identifies Modulators of the Aryl hydrocarbon Receptor (AhR)

Keiyu Oshida, Naresh Vasani, Russell S. Thomas, Dawn Applegate, Frank J. Gonzalez, Lauren M. Aleksunes, Curtis D. Klaassen and J. Christopher Corton
Toxicology (2015) DOI: https://doi.org/10.1016/j.tox.2015.07.005 PMID: 26215100

Publication

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), dioxin-like compounds (DLC) as well as some drugs and endogenous tryptophan metabolites. Short-term activation of AhR can lead to hepatocellular steatosis, and chronic activation can lead to liver cancer in mice and rats. Analytical approaches were developed to identify biosets in a genomic database in which AhR activity was altered. A set of 63 genes was identified (the AhR gene expression biomarker) that was dependent on AhR for regulation after exposure to TCDD or benzo[a]pyrene and includes the known AhR targets Cyp1a1 and Cyp1b1. A fold-change rank-based test (Running Fisher's test; p-value ≤ 10(-4)) was used to evaluate the similarity between the AhR biomarker and a test set of 37 and 41 biosets positive or negative, respectively for AhR activation. The test resulted in a balanced accuracy of 95%. The rank-based test was used to identify factors that activate or suppress AhR in an annotated mouse liver/mouse primary hepatocyte gene expression database of ∼ 1850 comparisons. In addition to the expected activation of AhR by TCDD and DLC, AhR was activated by AP20189 and phenformin. AhR was suppressed by phenobarbital and 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) in a constitutive activated receptor (CAR)-dependent manner and pregnenolone-16α-carbonitrile in a pregnane X receptor (PXR)-dependent manner. Inactivation of individual genes in nullizygous models led to AhR activation (Pxr, Ghrhr, Taf10) or suppression (Ahr, Ilst6st, Hnf1a). This study describes a novel screening strategy for identifying factors in mouse liver that perturb AhR in a gene expression compendium.

Toxicogenomics

Microarray Data (PFNA in wild-type and PPARα-null mice)

Gene Expression Omnibus (GEO) Series: GSE55756

Microarray Data (PCN in wild-type and PXR-null mice)

Gene Expression Omnibus (GEO) Series: GSE55746

Microarray Data (the 12 treatment study)

Gene Expression Omnibus (GEO) Series: GSE55084