ZFIN ID: ZDB-PUB-140720-6
Cardiac Myocyte-Specific AHR Activation Phenocopies TCDD-Induced Toxicity in Zebrafish
Lanham, K.A., Plavicki, J., Peterson, R.E., Heideman, W.
Date: 2014
Source: Toxicological sciences : an official journal of the Society of Toxicology   141(1): 141-54 (Journal)
Registered Authors: Heideman, Warren, Peterson, Richard E.
Keywords: none
MeSH Terms:
  • Animals
  • Cardiotoxicity
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation, Developmental/drug effects
  • Heart Defects, Congenital/chemically induced
  • Heart Defects, Congenital/embryology
  • Heart Defects, Congenital/metabolism
  • Myocytes, Cardiac/drug effects*
  • Myocytes, Cardiac/metabolism
  • Plasmids
  • Promoter Regions, Genetic
  • Receptors, Aryl Hydrocarbon/genetics
  • Receptors, Aryl Hydrocarbon/metabolism*
  • Regional Blood Flow/drug effects
  • Zebrafish*/embryology
  • Zebrafish*/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 25037585 Full text @ Toxicol. Sci.
ABSTRACT
Exposure of zebrafish embryos to 2,3,7,8-tetrachlorordibenzo-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.
ADDITIONAL INFORMATION No data available