Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China.
Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China.
J Hazard Mater. 2023 Sep 5;457:131831. doi: 10.1016/j.jhazmat.2023.131831. Epub 2023 Jun 12.
Because triclosan (TCS) has been confirmed to cause severe neurotoxicity, it is urgent to disclose the underlying toxicity mechanisms at varying levels. TCS exposure resulted in a series of malformations in larval zebrafish, including reduced neurons, blood-vessel ablation and abnormal neurobehavior. Apoptosis staining and the upregulated expression of proapoptotic genes demonstrated that TCS induced neuronal apoptosis and neurotransmitter disorders. By integrating RT-qPCR analysis with the effects of pathway inhibitors and agonists, we found that TCS triggered abnormal regulation of neuron development-related functional genes, and suppressed the BDNF/TrkB signaling pathway. TCS inhibited total mA-RNA modification level by activating the demethylase ALKBH5, and induced neurodevelopmental toxicity based on the knockdown experiments of alkbh5 and molecular docking. The main novelties of this study lies in: (1) based on specific staining and transgenic lines, the differential neurotoxicity effects of TCS were unravelled at individual, physiological, biochemical and molecular levels in vivo; (2) from a epigenetics viewpoint, the decreasing mA methylation level was confirmed to be mediated by alkbh5 upregulation; and (3) both homology modeling and molecular docking evidenced the targeting action of TCS on ALKBH5 enzyme. These findings open a novel avene for TCS's risk assessment and early intervention of the contaminant-sourcing diseases.
三氯生（TCS）已被证实具有严重的神经毒性，因此迫切需要揭示其在不同层面的毒性机制。TCS 暴露会导致幼鱼出现一系列畸形，包括神经元减少、血管消融和异常神经行为。凋亡染色和促凋亡基因的上调表达表明 TCS 诱导了神经元凋亡和神经递质紊乱。通过将 RT-qPCR 分析与通路抑制剂和激动剂的作用相结合，我们发现 TCS 触发了与神经元发育相关的功能性基因的异常调节，并抑制了 BDNF/TrkB 信号通路。TCS 通过激活去甲基酶 ALKBH5 来抑制总 mA-RNA 修饰水平，并通过 alkbh5 的敲低实验和分子对接证实了其具有神经发育毒性。本研究的主要创新点在于：（1）基于特定染色和转基因系，在体内从个体、生理、生化和分子水平上揭示了 TCS 的差异化神经毒性作用；（2）从表观遗传学角度证实了 mA 去甲基化水平的降低是由 alkbh5 的上调介导的；（3）同源建模和分子对接都证明了 TCS 对 ALKBH5 酶的靶向作用。这些发现为 TCS 的风险评估和污染物来源疾病的早期干预开辟了新途径。
