PCB126 exposure disrupts zebrafish ventricular and branchial but not early neural crest development
PCB126 exposure disrupts zebrafish ventricular and branchial but not early neural crest development
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DOI：
10.1093/toxsci/kfn154
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发表时间：
2008-11-01
影响因子：
3.8
通讯作者：
Kirby, Margaret L.
中科院分区：
文献类型：
--
作者：
Grimes, Adrian C.;Erwin, Kyle N.;Kirby, Margaret L.
以斑马鱼和3，3 '，4，4'，5-五氯联苯（PCB 126）为实验材料，研究了多氯联苯（PCBs）通过芳香烃受体（AHR）发挥作用的发育毒性。我们发现，心脏和神经嵴（NC）衍生的颌骨和鳃软骨是专门针对早期的发展。最终导致循环衰竭的一系列畸形包括严重畸形的心脏，动脉球减少，房室和流出道瓣膜形成异常。早期NC迁移和图案的颌骨和鳃软骨是正常的。然而，颌骨和鳃软骨未能生长到正常大小。在心脏中，心室肌显示细胞数量和大小减少。心脏和颌/鳃表型可以通过pifithrin-alpha（一种p53阻滞剂）来挽救。然而，pifithrin-alpha在该模型中的功能可能在AHR中作为PCB的竞争性抑制剂，并且可能不依赖于p53。针对p53的吗啉并没有拯救的表型，也不是斑马鱼与突变p53无效等位基因耐PCB 126毒性。Morpholino敲低心肌肌钙蛋白T，这阻止了心脏功能的发作，防止了PCB 126诱导的心脏畸形，但不是下巴/鳃表型。心血管特征似乎类似于发育不良性左心综合征（HLHS），并引入斑马鱼作为研究这种环境诱导的心血管畸形的模型的潜力。HLHS是一种严重的先天性心血管畸形，以前曾被认为与二恶英和多氯联苯的工业排放有关。
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-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 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.