Unveiling the Link between Neonicotinoid Exposure and Cognitive Impairment in the Elderly: A Multiscale Framework Integrating Epidemiological Evidence with Network Toxicology and Molecular Docking

High Resolution Image Download MS PowerPoint Slide Neonicotinoids (NEOs) are the most widely used insecticides worldwide and have been detected in various biological samples. While NEO neurotoxicity has been demonstrated in animal studies, epidemiological evidence in humans remains limited, and the underlying mechanisms are not fully elucidated. In this study, urinary concentrations of six parent NEOs and four metabolites were quantified in 1150 older adults from Shenzhen, China. Quantile-based g-computation, weighted quantile sum regression, and Bayesian kernel machine regression were employed to assess the joint effects of NEO mixture on cognitive impairment. Co-exposure to NEOs was positively associated with the risk of cognitive impairment (OR = 1.65, 95% CI: 1.05–2.60, P = 0.03). Imidacloprid (IMI), dinotefuran (DIN), and thiacloprid (THD) were recognized as the major contributors to the overall effect. Moreover, integrative network toxicology and molecular docking analyses identified eight core targets as potential mediators in NEO-induced neurotoxicity (HSP90AA1, TP53, JUN, EGFR, JAK2, STAT3, MET, and PIK3R1), suggesting coordinated disruptions in neuroactive ligand–receptor interactions, kinase-regulated signaling pathways, inflammatory responses, apoptosis processes, and synaptic function. Although mitochondrial DNA copy number (mtDNA-CN) has been implicated in cognitive aging, no significant mediating effect was observed in the exposure-outcome relationship. These findings warrant validation in large-scale cohorts and experimental studies.