当前位置： SCI文献检索 > TOXICOLOGY期刊下所有文献 > Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR).

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

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.

journal_name

Toxicology

journal_title

Toxicology

authors

Oshida K,Vasani N,Thomas RS,Applegate D,Gonzalez FJ,Aleksunes LM,Klaassen CD,Corton JC

doi

10.1016/j.tox.2015.07.005

subject

Has Abstract

pub_date

2015-10-02 00:00:00

pages

99-112

eissn

0300-483X

issn

1879-3185

pii

S0300-483X(15)30010-X

journal_volume

336

pub_type

杂志文章

在线工具

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