ToxSci Advance Access originally published online on July 26, 2008
Toxicological Sciences 2008 106(1):193-205; doi:10.1093/toxsci/kfn154
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PCB126 Exposure Disrupts ZebraFish Ventricular and Branchial but Not Early Neural Crest Development
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* Department of Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, South Carolina 29425
Duke University Medical Center, Department of Pediatrics, Neonatal-Perinatal Research Institute, Durham, North Carolina 27710
Qualyst, Inc., Raleigh, North Carolina 27606
Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan 106
3 To whom correspondence should be addressed at Duke University Medical Center, Department of Pediatrics (Neonatology), Box 3179, Room 157 Bell Research Building, Trent Drive, Durham, NC 27710. Fax: (919) 668-1599. E-mail: mlkirby{at}duke.edu.
Received June 6, 2008; accepted July 14, 2008
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Abstract |
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We have used zebrafish and 3,3',4,4',5-pentachlorobiphenyl (PCB126) to investigate the developmental toxicity of polychlorinated biphenyls (PCBs) that exert their effects through the aryl hydrocarbon receptor (AHR). We found that cardiac and neural crest (NC)–derived jaw and branchial cartilages are specifically targeted early in development. The suite of malformations, which ultimately leads to circulatory failure, includes a severely dysmorphic heart with a reduced bulbus arteriosus and abnormal atrioventricular and outflow valve formation. Early NC 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-
, a blocker of p53. However, the function of pifithrin- in this model may act as a competitive inhibitor of PCB at the AHR and is likely 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 knockdown 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 PCBs.
Key Words: zebrafish; ventricular development; valvulogenesis; cardiotoxicity; PCB126; aryl hydrocarbon receptor; proliferation; branchial cartilages.
1 Present address: Departamento de Biología del Desarrollo Cardiovascular, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3 E-28029 Madrid, Spain.
2 These authors contributed equally to the experimental work presented.