Triclosan (TCS) is ubiquitous in a wide range of personal care and consumer products, and it is acute/chronic exposure may result in several nervous system disorders. Previous studies demonstrated TCS-induced abnormal expression of miRNAs, but no investigations focused on upstream changes of miRNAs and associated molecular mechanisms. Herein, phenotype observation and behavioral analysis confirmed that TCS exposure (0, 62.5, 125, 250 μg/L) led to developmental neurotoxicity in zebrafish larvae, especially for oligodendrocyte precursor cells (OPCs). High-throughput sequencing demonstrated the critical role of miR-219 in the differentiation of OPCs. Larvae with miR-219 depletion showed the same phenotype caused by TCS. Functional tests with miR-219 knock-down and over-expression showed that miR-219 promoted differentiation of OPCs by acting on myelination inhibitors. The miR-219 also protected against TCS-induced inhibition of cell differentiation. Several epigenetic features were identified to reveal potential upstream regulatory mechanisms of miR-219. In particular, five CpG islands hyper-methylated with increasing TCS concentrations in the promoter region of miR-219. TCS inhibited OPC differentiation by influencing epigenetic effects on miR-219-related pathways, contributing to severe neurotoxicity. These findings enhance our understanding of epigenetic mechanisms affecting demyelination diseases due to TCS exposure, and also provide theoretical guidance for early intervention and gene therapy of environmentally induced diseases.

中文翻译：

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三氯生通过靶向中枢神经系统少突胶质细胞分化的miR-219的异常表达诱导斑马鱼的神经毒性。

三氯生（TCS）在各种个人护理和消费产品中无处不在，急性/长期接触可能导致几种神经系统疾病。先前的研究证明了TCS诱导的miRNA异常表达，但没有研究集中在miRNA的上游变化和相关的分子机制上。在这里，表型观察和行为分析证实，TCS暴露（0、62.5、125、250μg/ L）导致斑马鱼幼虫，特别是少突胶质前体细胞（OPC）的发育神经毒性。高通量测序证明了miR-219在OPC分化中的关键作用。miR-219耗竭的幼虫表现出由TCS引起的相同表型。使用miR-219敲低和过表达的功能测试表明，miR-219通过作用于髓鞘形成抑制剂而促进了OPC的分化。miR-219还可以防止TCS诱导的细胞分化抑制。确定了几种表观遗传学特征，以揭示miR-219的潜在上游调控机制。特别是，在miR-219的启动子区域中，随着TCS浓度的增加，五个CpG岛发生了超甲基化。TCS通过影响miR-219相关途径的表观遗传效应来抑制OPC分化，从而导致严重的神经毒性。这些发现增强了我们对由于TCS暴露而影响脱髓鞘疾病的表观遗传机制的理解，也为环境干预性疾病的早期干预和基因治疗提供了理论指导。miR-219还可以防止TCS诱导的细胞分化抑制。确定了几种表观遗传学特征，以揭示miR-219的潜在上游调控机制。特别是，在miR-219的启动子区域中，随着TCS浓度的增加，五个CpG岛发生了超甲基化。TCS通过影响miR-219相关途径的表观遗传效应来抑制OPC分化，从而导致严重的神经毒性。这些发现增强了我们对由于TCS暴露而影响脱髓鞘疾病的表观遗传机制的理解，也为环境干预性疾病的早期干预和基因治疗提供了理论指导。miR-219还可以防止TCS诱导的细胞分化抑制。确定了几种表观遗传学特征，以揭示miR-219的潜在上游调控机制。特别是，在miR-219的启动子区域中，随着TCS浓度的增加，五个CpG岛发生了超甲基化。TCS通过影响miR-219相关途径的表观遗传效应来抑制OPC分化，从而导致严重的神经毒性。这些发现增强了我们对由于TCS暴露而影响脱髓鞘疾病的表观遗传机制的理解，也为环境干预性疾病的早期干预和基因治疗提供了理论指导。特别是，在miR-219的启动子区域中，随着TCS浓度的增加，五个CpG岛发生了超甲基化。TCS通过影响miR-219相关途径的表观遗传效应来抑制OPC分化，从而导致严重的神经毒性。这些发现增强了我们对由于TCS暴露而影响脱髓鞘疾病的表观遗传机制的理解，也为环境干预性疾病的早期干预和基因治疗提供了理论指导。特别是，在miR-219的启动子区域中，随着TCS浓度的增加，五个CpG岛发生了超甲基化。TCS通过影响miR-219相关途径的表观遗传效应来抑制OPC分化，从而导致严重的神经毒性。这些发现增强了我们对由于TCS暴露而影响脱髓鞘疾病的表观遗传机制的理解，也为环境干预性疾病的早期干预和基因治疗提供了理论指导。