Blocking expression of AHR2 and ARNT1 in zebrafish larvae protects against cardiac toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin
Blocking expression of AHR2 and ARNT1 in zebrafish larvae protects against cardiac toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin
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DOI：
10.1093/toxsci/kfl093
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发表时间：
2006-11-01
影响因子：
3.8
通讯作者：
Heideman, Warren
中科院分区：
文献类型：
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作者：
Antkiewicz, Dagmara S.;Peterson, Richard E.;Heideman, Warren
斑马鱼(Danio Rerio)已经成为研究发育过程的一个有吸引力的脊椎动物模型，并正在成为研究外来化合物扰乱正常发育机制的模型系统。受精后不久用2，3，7，8-四氯二苯并-对二恶英(TCDD)处理的胚胎表现出一系列对心脏的不利影响：早期心肌细胞数量减少，随后心脏环状结构和形态发生变化，明显的心室压缩和心脏整体尺寸缩小。这些变化伴随着心功能受损，包括心输出量的减少和最终不可逆转的室性停顿。TCDD对心脏的中介作用机制尚不清楚。然而，人们普遍认为芳烃受体(AHR)的激活介导了脊椎动物TCDD毒性的终点。在斑马鱼中，存在多种形式的AHR和AHR核转运蛋白(ARNT)，这就提出了TCDD毒性的不同终点是否由AHR/ARNT途径的不同成分介导的问题。为了解决这个问题，我们使用吗啉寡核苷酸技术特异性地阻断了zfAHR2、zfARNT1、zfARNT2和zfCYP1A的表达，并评估了先前描述的TCDD对发育中的变异体的心脏形态、大小和功能的影响。我们报道，阻断zfAHR2和zfARNT1的表达可以对抗TCDD引起的斑马鱼幼虫心脏形态的改变、心肌细胞数量的减少、心输出量的减少和心脏停顿，而zfarnt2和zfcyp1a Morolinos不能阻止TCDD诱导的心脏毒性。
The zebrafish (Danio rerio) has become an attractive vertebrate model for studying developmental processes, and is emerging as a model system for studying the mechanisms by which xenobiotic compounds perturb normal development. Embryos treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) shortly after fertilization exhibit a range of adverse effects on the heart: an early reduction in cardiac myocyte number, followed by a change in heart looping and morphology, with an apparent compaction of the ventricle and overall decrease in heart size. These changes are accompanied by impaired cardiac function including a decrease in cardiac output and eventually irreversible ventricular standstill. The mechanisms involved in mediating effects of TCDD on the heart remain unknown. However, it is widely accepted that aryl hydrocarbon receptor (AHR) activation mediates endpoints of TCDD toxicity in vertebrates. In zebrafish, there are multiple forms of AHR and AHR nuclear translocator protein (ARNT) raising the question about whether different endpoints of TCDD toxicity are mediated by different components of the AHR/ARNT pathway. To address this question we used morpholino oligonucleotide technology to specifically block the expression of zfAHR2, zfARNT1, zfARNT2, and zfCYP1A, and assessed the previously described effects of TCDD on heart morphology, size, and function in the developing morphants. We report that blocking zfAHR2 and zfARNT1 expression provided protection against the TCDD-mediated alteration in heart morphology, reduced cardiac myocyte number, decreased cardiac output and ventricular standstill in zebrafish larvae, while the zfarnt2 and zfcyp1a morpholinos did not block the TCDD-induced cardiac toxicity.