Mechanistic exploration on neurodevelopmental toxicity induced by upregulation of alkbh5 targeted by triclosan exposure to larval zebrafish

  • J Hazard Mater. 2023 Sep 5:457:131831. doi: 10.1016/j.jhazmat.2023.131831.
Weiwei Wang  1 ,  Xin Li  2 ,  Qiuhui Qian  3 ,  Jin Yan  3 ,  Haishan Huang  2 ,  Xuedong Wang  4 ,  Huili Wang  5
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China.
  • 4. School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou 215009, China. Electronic address: [email protected].
  • 5. 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. Electronic address: [email protected].
PMID: 37320907 DOI: 10.1016/j.jhazmat.2023.131831
Abstract

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 m6A-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 m6A 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.

Keywords
M(6)A RNA methylation; Triclosan; TrkB receptor; Zebrafish larvae; alkbh5.
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