McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Toxicol Sci. 2010 Dec;118(2):554-63. doi: 10.1093/toxsci/kfq305. Epub 2010 Oct 8.
The aryl hydrocarbon receptor (AHR) plays a central role in the toxic responses to halogenated dibenzo-p-dioxins ("dioxins"), in the metabolic adaptation to polycyclic aromatic hydrocarbons, and in the development of the mature vascular system. A number of lines of evidence support the idea that the regulation of adaptive metabolism requires an AHR partnership with the aryl hydrocarbon receptor nuclear translocator (ARNT). Yet, for AHR-dependent vascular development and dioxin toxicity, the role of ARNT is less certain. In fact, numerous models have been proposed over the years to suggest that the AHR signals in important ways via ARNT-independent events. In an effort to clarify the role of ARNT in AHR-mediated dioxin hepatotoxicity, we generated a conditional Arnt mouse model. Such a model was essential because global inactivation of Arnt results in embryonic lethality presumably due to this protein's role as a heterodimeric partner for the hypoxia-inducible factors (HIFs). Using a hepatocyte-specific Arnt deletion, we were able to demonstrate that hepatocyte ARNT is required for major aspects of AHR-mediated dioxin toxicity in the liver. Results from this conditional Arnt allele are also consistent with a model where hepatocyte ARNT is unrelated to AHR-mediated hepatovascular development. In sum, these data suggest that AHR-ARNT dimers within the hepatocyte direct the toxic and adaptive and developmental functions associated with the AHR and that developmental vascular events arise due to signaling in a distinct cell type expressing this dimeric pair.
芳香烃受体 (AHR) 在卤代二苯并-对-二恶英（“二恶英”）的毒性反应、多环芳烃的代谢适应以及成熟血管系统的发育中发挥着核心作用。有许多证据表明，适应性代谢的调节需要 AHR 与芳香烃受体核转位蛋白（ARNT）形成伙伴关系，从而支持这一观点。然而，对于 AHR 依赖性血管发育和二恶英毒性，ARNT 的作用则不太确定。事实上，多年来提出了许多模型来表明 AHR 通过 ARNT 独立事件以重要方式发出信号。为了阐明 ARNT 在 AHR 介导的二恶英肝毒性中的作用，我们生成了条件性 Arnt 小鼠模型。这种模型是必不可少的，因为 ARNT 的全局失活会导致胚胎致死，这可能是由于该蛋白作为缺氧诱导因子 (HIF) 的异二聚体伴侣的作用。使用肝细胞特异性 Arnt 缺失，我们能够证明肝细胞 ARNT 是 AHR 介导的二恶英在肝脏中引起毒性和适应性以及发育毒性的主要方面所必需的。来自该条件性 Arnt 等位基因的结果也与肝细胞 ARNT 与 AHR 介导的肝血管发育无关的模型一致。总之，这些数据表明，肝细胞内的 AHR-ARNT 二聚体指导与 AHR 相关的毒性、适应性和发育功能，并且发育中的血管事件是由于表达该二聚体对的特定细胞类型中的信号传导引起的。
