An in Silico Analysis of Dicofol-Induced Neurotoxicity Mechanisms in Humans

Abstract

Dicofol (DCF) is an organochlorine pesticide that has recently been recognized as a persistent organic pollutant. This study begins by investigating the neurotoxicity of DCF and its metabolites through in silico tools. It subsequently explores the molecular mechanisms and key targets associated with DCF-induced neurotoxicity in humans by employing network toxicology, multi-level bioinformatics approaches, and molecular docking analyses. The prediction results indicate that both DCF and its metabolites can traverse the blood-brain barrier, penetrating the central nervous system, and inducing neurotoxicity. A thorough analysis has identified 56 potential targets linked to DCF-induced neurotoxicity. Gene Ontology enrichment analysis revealed significant associations with pathways related to sodium ion transmembrane transport, sodium/potassium-exchanging ATPase complexes, and P-type calcium transporter activity. Pathway enrichment analysis suggests that DCFinduced neurotoxicity arises from disruptions in ion transport via P-type ATPases. Further examination of gene-gene and protein-protein interactions, along with centrality analysis, identified 11 hub targets, including ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1, ATP1B2, and MAPK1, as key players. Notably, six of these targets are subunits of the Na+/K+-ATPase, a P-type ATPase. Molecular docking results demonstrated that DCF binds more effectively to the ATP1A3-ATP1B1 protein complex than to its natural ligand, ATP. These findings suggest that DCF may inhibit Na+/K+-ATPase through ATP1A3, resulting in an imbalance of sodium and potassium gradients and ultimately leading to neurotoxicity.