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.

The influence of heart developmental anatomy on cardiotoxicity-based adverse outcome pathways in fish

“…If this occurs prior to kidney morphogenesis, it may result in a failure to form the pronephros. More broadly for zebrafish, secondary effects on jaw development due to edema (or loss of circulation) are a well-recognized adverse outcome pathway for cardiotoxicity caused by exposure to PAHs and dioxins (Incardona, et al, 2004;Lanham, et al, 2014).…”

“…While these compounds disrupt cardiac function through a variety of mechanisms (Clark et al, 2010;Incardona et al, 2005;Incardona et al, 2006;Incardona et al, 2011;Lanham et al, 2014;Prasch et al, 2003;Van Tiem and Di Giulio, 2011), they all cause embryonic heart failure at sufficiently high exposure concentrations.…”

Histological and Transcriptomic Changes in Male Zebrafish Testes Due to Early Life Exposure to Low Level 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

“…TCDD has a long half-life in tissues, and could thus cause prolonged AhR activation, which has been associated with toxic endpoints. 55 Nonetheless, it is remarkable that these AhR-responsive genes are significantly upregulated 10 months after a brief, low level TCDD exposure. In fact, the long-term histological and transcriptomic changes in these TCDD-treated zebrafish testes highlight the developmental basis for adult-onset disease.…”

A high throughput passive dosing format for the Fish Embryo Acute Toxicity test

“…Villeneuve et al (2014) used the adverse outcome pathway (AOP) framework to hypothesize possible mechanisms underlying impaired swim bladder inflation. Recent research has shown that compounds from a wide variety of chemical classes and modes of action impair swim bladder inflation (Hagenaars et al, 2014;Lanham et al, 2014;Wang et al, 2014), probably through a variety of underlying mechanisms (e.g., Bagci et al, 2015). However, the current description of AOPs related to swim bladder inflation do not provide information to understand the role of narcosis, and AOPs related to narcosis do not specifically focus on swim bladder inflation effects.…”