Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR). (2nd October 2015)

• Record Type: Journal Article
• Authors: Oshida, Keiyu; Vasani, Naresh; Thomas, Russell S.; Applegate, Dawn; Gonzalez, Frank J.; Aleksunes, Lauren M.; Klaassen, Curtis D.; Corton, J. Christopher
• Is Part Of: Toxicology. Volume 336(2015)
• Page Start: 99
• Page End: 112
• Publication Date: 2015-10-02
• Subjects: Aryl hydrocarbon receptor -- Peroxisome proliferator-activated receptor -- Transcript profiling -- Liver cancer -- Constitutive activated receptor -- Keap1 -- Nrf2 -- Pregnane X receptor; AhR aryl hydrocarbon receptor -- AOP adverse outcome pathway -- B[a]P benzo[a]pyrene -- CAR constitutive activated receptor -- DLC dioxin-like compound -- DMBA 7, 12-dimethylbenzanthracene -- DRE dioxin responsive element -- ERα estrogen receptor α -- FXR farnesoid X receptor -- GR glucocorticoid receptor -- MIE molecular initiating event -- Nrf2 nuclear factor (erythroid-derived 2)-like 2 -- PB phenobarbital -- PCN pregnenolone-16-α-carbonitrile -- PCR polymerase chain reaction -- PFOA perfluorooctanoic acid -- PPAR peroxisome proliferator-activated receptor -- PXR pregnane X receptor -- STAT5b signal transducer and activator of transcription 5B -- TCDD 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin -- TCPOBOP 1, 4-bis[2-(3, 5-dichloropyridyloxy)] benzene -- WY WY-14, 643; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2015.07.005
• Languages: English
• ISSNs: 0300-483X

Abstract

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.