Fentin chloride (TPTC) is an organotin compound used extensively in hull construction due to its excellent resistance to corrosion. To explore the biotoxicity of TPTC, In this study, the molecular mechanism of TPTC-induced scoliosis was investigated in the zebrafish model by combining metabolomics and network pharmacology. TPTC exposure causes scoliosis and neurotoxicity in zebrafish, and leads to increasing curvature angles with the increase in concentration. Metabolomic analysis identified 366 significant differential metabolites associated with TPTC-induced scoliosis. Network pharmacology revealed 32 intersecting targets between TPTC and scoliosis, and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that these targets were mainly enriched in pathways, such as, neuroreceptor-ligand interactions, cGMP-PKG signaling, and adrenergic signaling. The combined analysis identified adrenergic receptors as the key targets of TPTC. ELISA revealed increased levels of adrenaline with the increase in TPTC concentrations. RT-qPCR showed that the expression levels of the Urotensin-Related Peptide genes (Urp1, Urp2) and their receptor genes (Utrs2r1), which regulate body axis curvature, are significantly increased downstream of the adrenaline signaling pathway. The use of an adrenaline inhibitor mitigated TPTC-induced scoliosis and the level of Urp1, Urp2 and Utrs2r1 nearly recovered to normal levels. Therefore, TPTC induces scoliosis by acting on adrenergic receptors to interfere with epinephrine and up-regulating the expression of downstream Urotensin-Related Peptide genes.
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