Disruption of autophagic balance and oxidative defense in TOCP-induced sciatic nerve toxicity: Integrating computational toxicology and experimental validation

Tri-ortho-cresyl phosphate (TOCP) is a widely used organophosphate ester with established multiple organ toxicity, yet its neurotoxic mechanisms remain incompletely elucidated. This study integrated network toxicology, molecular docking, and animal experiments to investigate the molecular mechanisms underlying TOCP-induced sciatic nerve toxicity. A total of 173 potential targets were identified through public databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these targets are significantly involved in autophagy, apoptosis, glycerolipid metabolism, and multiple neurodegenerative pathways. Focusing on four core targets (BECN1, SQSTM1/p62, SLC7A11, GLUL), molecular docking demonstrated strong binding affinities between TOCP and these proteins (binding energies < −5 kcal/mol). In a hen model, TOCP exposure (750 mg/kg, single oral gavage) induced marked sciatic nerve damage, characterized by myelin disruption and axonal degeneration. Western blot analysis further validated protein expression changes: compared with the control group, TOCP exposure upregulated Beclin-1, SQSTM1/p62, LC3II/Ⅰ, NCOA4, ACSL4, and Fe 2+ levels by 1.919-, 2.443-, 1.497-, 1.506-, 1.243-, and 1.669-fold, respectively ( P  < 0.05), while downregulating SLC7A11, GLUL, FTH1, and GPX4 expression to 0.458-, 0.893-, 0.813-, and 0.573-fold of the control levels ( P  < 0.05). Collectively, these findings demonstrate that TOCP exerts neurotoxicity primarily by disrupting autophagic balance and impairing the oxidative defense system. This study provides novel insights into the molecular mechanisms of TOCP-induced sciatic neurotoxicity and offers a theoretical foundation for its prevention and treatment.