Exploring toxicity and mechanisms of DDTs in Alzheimer's disease through network toxicology and molecular docking insights

BackgroundDichlorodiphenyltrichloroethane (DDT) and its metabolites (DDTs), such as dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), are synthetic organochlorine pesticides with long environmental persistence. Although DDT has been phased out in many countries, DDE and DDD remain prevalent worldwide. Growing evidence links DDTs exposure to Alzheimer's disease (AD), though underlying molecular targets and mechanisms remain unclear.ObjectiveIn this study, we investigated molecular targets and pathways through which DDTs potentially induce AD using network toxicology combined with molecular docking techniques.MethodsAD-related targets associated with DDTs were identified through bioinformatics searches. Key targets were selected via STRING protein-protein interaction analysis and Cytoscape, followed by signaling pathway enrichment analysis. Diagnostic efficacy was evaluated using ROC curve analysis and nomogram modeling based on GEO datasets. Molecular docking validated binding affinity between DDTs and core target proteins predicted by AlphaFold 3.ResultsWe identified 1732 potential molecular targets linking DDTs exposure to AD. Pathway analysis revealed DDTs predominantly affect AD pathogenesis by modulating apoptosis, p53 signaling, TNF signaling, and IL-17 signaling pathways. STRING and Cytoscape analyses identified seven core targets. GEO dataset validation indicated RPL23, RPS6, and RPS8 as pivotal targets, with RPL23 having strongest predictive capacity. Molecular docking confirmed binding interactions between DDTs and RPL23, with binding energies of -7.2 kcal mol^-1 for DDT, -6.5 kcal mol^-1 for DDE, and -7.1 kcal mol^-1 for DDD.ConclusionsThis research provides novel insights into neurotoxic mechanisms of DDT and its persistent metabolites DDE and DDD, and supports enhanced public health strategies for AD prevention.