School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, PR China; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, PR China.
School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, PR China.
J Hazard Mater. 2022 Jun 5;431:128560. doi: 10.1016/j.jhazmat.2022.128560. Epub 2022 Feb 24.
Although the previous research confirmed that triclosan (TCS) induced an estrogen effect by acting on a novel G-protein coupled estrogen-membrane receptor (GPER), the underlying mechanisms by which downstream pathways induce neurotoxicity remain unclear after TCS activation of GPER. By employing a series of techniques (Illumina miRNA-seq, RT-qPCR, and artificial intervention of miRNA expression), we screened out four important miRNAs, whose target genes were directly/indirectly involved in neurodevelopment and neurobehavior. Especially, the miR-144 up-regulation caused vascular malformation and severely affected hair-cell development and lateral-line-neuromast formation, thereby causing abnormal motor behavior. After microinjecting 1-2-cell embryos, the similar phenotypic malformations as those induced by TCS were observed, including aberrant neuromast, cuticular-plate development and motor behavior. By KEGG pathway enrichment analysis, these target genes were demonstrated to be mainly related to the PKC/MAPK signaling pathway. When a PKC inhibitor was used to suppress the PKC/MAPK pathway, a substantial alleviation of TCS-induced neurotoxicity was observed. Therefore, TCS acts on GPER to activate the downstream PKC/MAPK signaling pathway, further up-regulating miR-144 expression and causing abnormal modulation of these nerve-related genes to trigger neurodevelopmental toxicity. These findings unravel the molecular mechanisms of TCS-induced neurodegenerative diseases, and offer theoretical guidance for TCS-pollution early warning and management.
虽然之前的研究证实三氯生（TCS）通过作用于新型 G 蛋白偶联雌激素膜受体（GPER）诱导雌激素效应，但 TCS 激活 GPER 后下游途径诱导神经毒性的潜在机制仍不清楚。通过采用一系列技术（Illumina miRNA-seq、RT-qPCR 和 miRNA 表达的人工干预），我们筛选出了四个重要的 miRNA，其靶基因直接/间接参与神经发育和神经行为。特别是，miR-144 的上调导致血管畸形，并严重影响毛细胞发育和侧线神经嵴形成，从而导致异常的运动行为。在微注射 1-2 细胞胚胎后，观察到与 TCS 诱导的类似表型畸形，包括异常神经嵴、表皮板发育和运动行为。通过 KEGG 途径富集分析，这些靶基因主要与 PKC/MAPK 信号通路相关。当使用 PKC 抑制剂抑制 PKC/MAPK 通路时，TCS 诱导的神经毒性显著减轻。因此，TCS 通过作用于 GPER 激活下游的 PKC/MAPK 信号通路，进一步上调 miR-144 的表达，导致这些与神经相关的基因异常调节，从而引发神经发育毒性。这些发现揭示了 TCS 诱导神经退行性疾病的分子机制，为 TCS 污染预警和管理提供了理论指导。
