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

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. [Display omitted] • Developmental malformations induced by TCS include reduced neurons, ablation of blood vessels and neuron apoptosis. • TCS regulates the abnormal expression of olig 2, gfap, mbp, bdnf , ngn1 and nestin related to neurodevelopment. • TCS-induced neurotoxicity results from the suppressed gene expression of ntrk2a and creb in the BDNF/TrkB signaling pathway. • The reduced total m6A-RNA methylation level is modulated by activating alkbh5 expression. • Both siRNA and molecular docking confirm that TCS triggers neurotoxicity by targeting alkbh5 up-regulation. [ABSTRACT FROM AUTHOR]