Triclosan targets miR-144 abnormal expression to induce neurodevelopmental toxicity mediated by activating PKC/MAPK signaling pathway

Abstract

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.