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.

中文翻译：

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筛选小鼠肝脏基因表达纲要可鉴定芳烃受体（AhR）的调节剂。

芳基烃受体（AhR）是一种配体激活的转录因子，介导2,3,7,8-四氯二苯并-p-二恶英（TCDD），二恶英样化合物（DLC）以及某些生物的毒性作用药物和内源性色氨酸代谢产物。AhR的短期激活可导致肝细胞脂肪变性，而慢性激活可在小鼠和大鼠中导致肝癌。开发了分析方法来鉴定基因组数据库中的生物集，在该数据库中，AhR活性发生了变化。确定了一组63个基因（AhR基因表达生物标记），这些基因在暴露于TCDD或苯并[a] re后依赖于AhR进行调节，其中包括已知的AhR靶标Cyp1a1和Cyp1b1。基于倍数变化等级的测试（Running Fisher检验；p值≤10（-4））用于评估AhR生物标志物与37个和41个生物组分别对AhR激活呈阳性或阴性的测试集之间的相似性。测试得出95％的平衡精度。基于等级的检验用于在〜1850个比较的带注释的小鼠肝脏/小鼠原代肝细胞基因表达数据库中识别激活或抑制AhR的因子。除了预期通过TCDD和DLC激活AhR之外，还通过AP20189和苯乙双胍激活了AhR。AhR被苯巴比妥和1,4-Bis [2-（3,5-二氯吡啶氧基）]苯（TCPOBOP）依赖于本构激活受体（CAR）抑制，而孕烯醇酮-16α-腈被孕烷X受体（PXR）抑制）依赖方式。无效合子模型中单个基因的失活导致AhR激活（Pxr，Ghrhr，Taf10）或抑制（Ahr，Ilst6st，Hnf1a）。这项研究描述了一种新颖的筛选策略，用于识别干扰基因表达纲集中的AhR的小鼠肝脏中的因子。