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Screening a mouse liver gene expression Compendium Identifies Effectors of the Aryl Hydrocarbon receptor (AhR)
Citation:
Oshida, K., N. Vasani, W. Ward, R. Thomas, D. Applegate, F. Gonzalez, L. Aleksunes, C. Klaassen, AND C. Corton. Screening a mouse liver gene expression Compendium Identifies Effectors of the Aryl Hydrocarbon receptor (AhR). TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 336:99-112, (2015).
Impact/Purpose:
TO BE SUBMITTED TO TOX SCI
Description:
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; chronic activation can lead to liver cancer in mice and rats. Analytical approaches were developed to identify b[osets in a genomic database in which AhR activity was altered. A set of 63 genes was identified (the AhR gene expression signature) that was dependent on AhR for regulation after exposure to TCDD or benzo[a]pyrene and includes the known AhR targets Cypl al and Cypl bl . A fold-change rank-based test (Running Fisher's test; p-value :S 10-4) was used to evaluate the similarity between the AhR signature and a test set of 3 7 and 41 biosets positive or negative, respectively for AhR activation; the test resulted in a balanced accuracy of 89%. The rank-based test was used to identify factors that activate or suppress AhR in an annotated mouse liver/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-16a-carbonitrile in a pregnane X receptor (PXR)-dependent manner. Inactivation of individual genes in nullizygous models led to AhR activation (Pxr, Ghrhr, Tajl 0) or suppression (Ahr, Ilst6st, Hnfl a). This study describes a novel screening strategy for identifying factors that perturb AhR in a gene expression compendium. (249 words)
