Carney Sara A, Chen Jing, Burns C Geoffrey, Xiong Kong M, Peterson Richard E, Heideman Warren
Molecular and Environmental Toxicology Program, University of Wisconsin, Madison, Wisconsin 53705, USA.
Mol Pharmacol. 2006 Aug;70(2):549-61. doi: 10.1124/mol.106.025304. Epub 2006 May 19.
Proper regulation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is required for normal vertebrate cardiovascular development. AHR hyperactivation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during zebrafish (Danio rerio) development results in altered heart morphology and function, culminating in death. To identify genes that may cause cardiac toxicity, we analyzed the transcriptional response to TCDD in zebrafish hearts. Zebrafish larvae were exposed to TCDD for 1 h at 72 h after fertilization (hpf), and the hearts were extracted for microarray analysis at 1, 2, 4, and 12 h after exposure (73, 74, 76, and 84 h postfertilization). The remaining body tissue was also collected at each time for comparison. TCDD rapidly induced expression in 42 genes within 1 to2hof exposure. These genes function in xenobiotic metabolism, proliferation, heart contractility, and pathways that regulate heart development. Furthermore, these expression changes preceded signs of cardiovascular toxicity, characterized by decreased stroke volume, peripheral blood flow, and a halt in heart growth. This identifies strong candidates for important AHR target genes. It is noteworthy that the TCDD-induced transcriptional response in the hearts of zebrafish larvae was substantially different from that induced in the rest of the body tissues. One of the biggest differences included a cluster of genes that were down-regulated 12 h after exposure in heart tissue, but not in the body samples. More than 70% of the transcripts in this heart-specific cluster promote cellular growth and proliferation. Thus, the developing heart stands out as being responsive to TCDD at both the level of toxicity and gene expression.
芳烃受体（AHR）是一种配体激活的转录因子，正常脊椎动物心血管发育需要对其进行适当调节。斑马鱼（Danio rerio）发育过程中，2,3,7,8 - 四氯二苯并 - 对 - 二恶英（TCDD）导致AHR过度激活，会使心脏形态和功能发生改变，最终导致死亡。为了鉴定可能导致心脏毒性的基因，我们分析了斑马鱼心脏对TCDD的转录反应。在受精后72小时（hpf），将斑马鱼幼虫暴露于TCDD 1小时，在暴露后1、2、4和12小时（受精后73、74、76和84小时）提取心脏进行微阵列分析。每次也收集剩余的身体组织用于比较。TCDD在暴露后1至2小时内迅速诱导42个基因表达。这些基因在异源物质代谢、增殖、心脏收缩力以及调节心脏发育的途径中发挥作用。此外，这些表达变化先于心血管毒性迹象出现，心血管毒性的特征是心输出量减少、外周血流减少以及心脏生长停止。这确定了重要的AHR靶基因的有力候选者。值得注意的是，斑马鱼幼虫心脏中TCDD诱导的转录反应与身体其他组织中诱导的反应有很大不同。最大的差异之一包括一组基因，这些基因在心脏组织中暴露12小时后下调，但在身体样本中未下调。这个心脏特异性簇中超过70%的转录本促进细胞生长和增殖。因此，发育中的心脏在毒性和基因表达水平上对TCDD都有明显反应。
