Jurgelewicz Amanda, Dornbos Peter, Warren Melanie, Nault Rance, Arkatkar Anooj, Lin Hui, Threadgill David W, Zacharewski Tim, LaPres John J
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Toxicol Sci. 2021 May 27;181(2):285-294. doi: 10.1093/toxsci/kfab032.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor in the Per-Arnt-Sim superfamily of environmental sensors that is linked to several metabolic diseases, including nonalcoholic fatty liver disease. Much remains unknown regarding the impact of genetic variation in AHR-driven disease, as past studies have focused on a small number of inbred strains. Recently, the presence of a wide range of interindividual variability amongst humans was reported in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototypical ligand of the AHR. In this study, a panel of 14 diverse mouse strains was exposed to TCDD for 10 days to characterize the AHR-mediated response across genetic backgrounds. Responses to TCDD are heavily dependent on genetic background. Although mice carry 1 of 4 Ahr alleles known to impact the affinity to AHR-ligands, we observed significant intra-allelic variability suggesting the presence of novel genetic modifiers of AHR signaling. A regression-based approach was used to scan for genes regulated by the AHR and/or associated with TCDD-induced phenotypes. The approach identified 7 genes, 2 of which are novel, that are likely regulated by the AHR based on association with hepatic TCDD burden (p ≤ .05). Finally, we identified 1 gene, Dio1, which was associated with change in percent body fat across the diverse set of strains (p ≤ .05). Overall, the results in this study exemplify the power of genetics-based approaches in identifying novel genes that are putatively regulated by the AHR.
芳烃受体（AHR）是环境传感器Per-Arnt-Sim超家族中的一种配体激活转录因子，与多种代谢疾病相关，包括非酒精性脂肪性肝病。关于AHR驱动疾病中基因变异的影响，仍有许多未知之处，因为过去的研究集中在少数近交系上。最近，有报道称人类对AHR的典型配体2,3,7,8-四氯二苯并对二恶英（TCDD）存在广泛的个体间差异。在本研究中，一组14种不同的小鼠品系暴露于TCDD 10天，以表征不同遗传背景下AHR介导的反应。对TCDD的反应在很大程度上依赖于遗传背景。尽管小鼠携带已知影响与AHR配体亲和力的4种Ahr等位基因中的1种，但我们观察到显著的等位基因内变异，表明存在AHR信号传导的新型遗传修饰因子。使用基于回归的方法扫描由AHR调控和/或与TCDD诱导表型相关的基因。该方法鉴定出7个基因，其中2个是新基因，基于与肝脏TCDD负荷的关联，它们可能受AHR调控（p≤0.05）。最后，我们鉴定出1个基因Dio1，它与不同品系组中体脂百分比的变化相关（p≤0.05）。总体而言，本研究结果例证了基于遗传学方法在鉴定可能受AHR调控的新基因方面的作用。
