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Triclosan induces zebrafish neurotoxicity by abnormal expression of miR-219 targeting oligodendrocyte differentiation of central nervous system

Abstract

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.

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Acknowledgements

This work was jointly supported by the National Natural Science Foundation of China (31770552), Natural Science Foundation of Zhejiang and Jiangsu Province (LY20C03005 and BK20191455), Xinmiao Talent Project of Zhejiang Province (2019R413085), and Entrepreneurship and Innovation Program of Jiangsu Province (2017-2018).

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Correspondence to Xuedong Wang or Huili Wang.

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Ling, Y., Sun, L., Wang, D. et al. Triclosan induces zebrafish neurotoxicity by abnormal expression of miR-219 targeting oligodendrocyte differentiation of central nervous system. Arch Toxicol (2020). https://doi.org/10.1007/s00204-020-02661-1

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Keywords

  • Triclosan
  • Zebrafish
  • miR-219
  • DNA methylation
  • Oligodendrocytes
  • Myelin