Normal adult zebrafish can completely regenerate lost myocardium following partial amputation of the ventricle apex. We report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly impairs this regeneration. Adult male zebrafish were injected with vehicle (control) or TCDD (70ng/g, ip) 1 day prior to partial amputation of the ventricle apex. Gross observation and histological analysis of the amputated heart at 21 days postamputation revealed that TCDD-exposed fish had not progressed beyond the initial clot formation stage, whereas the vehicle control fish showed substantial recovery and almost complete resolution of the formed clot. In contrast, hearts that were not surgically wounded showed no signs of TCDD toxicity. Striking features in the TCDD-exposed hearts were the absence of the normal sheath of new tissue enveloping the wound and the absence of intense cell proliferation at the site of the wound. In addition, the patterns of collagen deposition at the wound site were different between the TCDD and vehicle groups. Because the receptor for TCDD is the aryl hydrocarbon receptor ligand-activated transcriptional regulator, we examined the effects of TCDD exposure on gene expression in the ventricle using DNA microarrays. Samples were collected just prior to amputation and at 6h and 7 days postamputation. TCDD-pretreated hearts had dysregulated expression of genes involved in heart function, tissue regeneration, cell growth, and extracellular matrix. Because embryonic, but not adult, hearts are major targets for TCDD-induced cardiotoxicity, we speculate that the need for embryonic-like cells in regeneration is connected with the effects of TCDD in inhibiting the response to wounding.

译文

正常成年斑马鱼可以在部分截肢心室尖后完全再生丢失的心肌。我们报告2,3,7,8-四氯二苯并-对-二恶英 (TCDD) 显著损害这种再生。成年雄性斑马鱼在脑室尖部分截肢前1天注射赋形剂 (对照) 或TCDD (70ng/g,ip)。截肢后21天对截肢心脏的总体观察和组织学分析表明,暴露于TCDD的鱼没有进展超过最初的凝块形成阶段,而媒介物对照鱼则显示出实质性的恢复和形成的凝块的几乎完全消退。相反,未手术受伤的心脏没有TCDD毒性的迹象。暴露于TCDD的心脏的显着特征是没有包裹伤口的新组织的正常鞘,并且在伤口部位没有强烈的细胞增殖。此外,TCDD组和媒介物组在伤口部位的胶原沉积模式也不同。由于TCDD的受体是芳基烃受体配体激活的转录调节因子,因此我们使用DNA微阵列检查了TCDD暴露对心室中基因表达的影响。在截肢前以及截肢后6小时和7天收集样本。TCDD预处理的心脏与心脏功能,组织再生,细胞生长和细胞外基质有关的基因表达异常。由于胚胎而不是成年心脏是TCDD诱导的心脏毒性的主要靶标,因此我们推测再生中对胚胎样细胞的需求与TCDD抑制对创伤的反应有关。

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