title: Cardiac myocyte-specific AHR activation phenocopies TCDD-induced toxicity in zebrafish.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705-2222.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Lanham
authors.affiliation: Department of Pharmaceutical Sciences, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705-2222.
authors.forename: Jessica
authors.initials: J
authors.lastname: Plavicki
authors.affiliation: Department of Pharmaceutical Sciences, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705-2222.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Peterson
authors.affiliation: Department of Pharmaceutical Sciences, 777 Highland Avenue, University of Wisconsin, Madison, Wisconsin 53705-2222 wheidema@wisc.edu.
authors.forename: Warren
authors.initials: W
authors.lastname: Heideman
mesh_terms: D000818:Animals; D066126:Cardiotoxicity; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000196:embryology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010957:Plasmids; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C474372:AHR2 protein, zebrafish; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D029961:Zebrafish Proteins