Lanham Kevin A, Plavicki Jessica, Peterson Richard E, Heideman Warren
Department of Pharmaceutical Sciences, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705-2222.
Department of Pharmaceutical Sciences, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705-2222
Toxicol Sci. 2014 Sep;141(1):141-54. doi: 10.1093/toxsci/kfu111. Epub 2014 Jul 18.
Exposure of zebrafish embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the zebrafish aryl hydrocarbon receptor 2 (AHR) to produce developmental and cardiovascular toxicity. AHR is found in the heart; however, AHR activation by TCDD is not confined to the heart and occurs throughout the organism. In order to understand the cause of cardiotoxicity, we constructed a constitutively active AHR (caAHR) based on the zebrafish AHR2 and expressed it specifically in cardiomyocytes. We show that AHR activation within the cardiomyocytes can account for the heart failure induced by TCDD. Expression of the caAHR within the heart produced cardiac malformations, loss of circulation, and pericardial edema. The heart-specific activation of AHR reproduced several other well-characterized endpoints of TCDD toxicity outside of the cardiovascular system, including defects in swim bladder and craniofacial development. This work identifies a single cellular site of TCDD action, the myocardial cell, that can account for the severe cardiovascular collapse observed following early life stage exposure to TCDD, and contributes to other forms of toxicity.
将斑马鱼胚胎暴露于2,3,7,8-四氯二苯并对二恶英（TCDD）会激活斑马鱼芳烃受体2（AHR），从而产生发育毒性和心血管毒性。心脏中存在AHR；然而，TCDD对AHR的激活并不局限于心脏，而是在整个机体中发生。为了了解心脏毒性的原因，我们基于斑马鱼AHR2构建了一种组成型活性AHR（caAHR），并使其在心肌细胞中特异性表达。我们发现心肌细胞内的AHR激活可导致TCDD诱导的心力衰竭。心脏内caAHR的表达会导致心脏畸形、循环丧失和心包水肿。AHR在心脏中的特异性激活重现了TCDD在心血管系统之外的其他一些特征明确的毒性终点，包括鳔和颅面发育缺陷。这项研究确定了TCDD作用的单个细胞位点，即心肌细胞，它可以解释在生命早期阶段暴露于TCDD后观察到的严重心血管衰竭，并导致其他形式的毒性。
