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ToxSci Advance Access published online on July 26, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn154
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

PCB126 Exposure Disrupts Zebrafish Ventricular and Branchial but Not Early Neural Crest Development

Adrian C. Grimes*,{dagger},¶, Kyle N. Erwin{dagger},¶, Harriett A. Stadt{dagger},¶, Ginger L. Hunter{dagger}, Holly A. Gefroh{ddagger}, Huai-Jen Tsai§ and Margaret L. Kirby{dagger},{square}

* Medical University of South Carolina, Molecular & Cellular Biology & Pathobiology, 173 Ashley Avenue, Charleston SC 29425, USA. Current address: Departamento de Biología del Desarrollo Cardiovascular, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3 E-28029 Madrid {dagger} Duke University Medical Center, Department of Pediatrics, Neonatal-Perinatal Research Institute, Durham, NC 27710, USA {ddagger} Qualyst Inc., 5410 Trinity Road, Suite 108, Raleigh, NC 27606, USA § Institute of Molecular and Cellular Biology, National Taiwan University, Taiwan

{square} Corresponding author. Duke University Medical Center, Department of Pediatrics (Neonatology), Box 3179, Room 157 Bell Research Building, Trent Drive, Durham, NC 27710; Tel (919) 668-1598. Fax: (919) 668-1599. E-mail: mlkirby{at}duke.edu.

Received June 6, 2008; revision received July 7, 2008; accepted July 14, 2008


  Abstract

We have used zebrafish and 3,3',4,4',5-pentachlorobiphenyl (PCB126) to investigate the developmental toxicity of PCBs that exert their effects through the aryl hydrocarbon receptor (AHR). We found that cardiac and neural crest-derived jaw and branchial cartilages are specifically targeted early in development. The suite of malformations include a severely dysmorphic heart with a reduced bulbus arteriosus, abnormal atrioventricular and outflow valve formation, ultimately leading to circulatory failure. Early neural crest migration and patterning of the jaw and branchial cartilages was normal. However, the jaw and branchial cartilages failed to grow to normal size. In the heart, the ventricular myocardium showed a reduction in cell number and size. The heart and jaw/branchial phenotype could be rescued by pifithrin-{alpha}, a blocker of p53. However, the function of pifithrin-{alpha} in this model may act as a competitive inhibitor of PCB at the AHR and is independent of p53. Morpholinos against p53 did not rescue the phenotype, nor were zebrafish with a mutant p53-null allele resistant to PCB126 toxicity. Morpholino knock-down of cardiac troponin T, which blocks the onset of cardiac function, prevented the PCB126-induced cardiac dysmorphogenesis but not the jaw/branchial phenotype. The cardiovascular characteristics appear to be similar to hypoplastic left heart syndrome (HLHS) and introduce the potential of zebrafish as a model to study this environmentally induced cardiovascular malformation. HLHS is a severe congenital cardiovascular malformation that has previously been linked to industrial releases of dioxins and polychlorinated biphenyls (PCBs).

Key Words: zebrafish; ventricular development; valvulogenesis; cardiotoxicity; PCB126; aryl hydrocarbon receptor; proliferation; branchial cartilages.

These authors contributed equally to the experimental work presented.


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