Integration of Epidemiology and Network Toxicology Revealed the Arrhythmogenic Potential of Neonicotinoid Insecticides

Arrhythmia is a growing public health concern due to its increasing prevalence and multifactorial etiology. Neonicotinoids (NEOs) are extensively used as neuroactive insecticides, yet their cardiac effects remain unclear. In this study, urinary NEOs and their metabolites were measured in 136 arrhythmia patients and 222 healthy controls to assess exposure-disease associations. Our findings revealed that NEOs were detected in all samples, with higher concentrations in patients than controls (P < 0.05), except for thiamethoxam and clothianidin. Both quantile g-computation and advanced Bayesian kernel machine regression models indicated that coexposure to multiple NEOs increased the risk of arrhythmia and oxidative stress (P < 0.05), with dinotefuran (DIN) contributing most (40.9%). Notably, the oxidative stress biomarker 8-hydroxy-2′-deoxyguanosine mediated 40.0, 28.7, 10.7, and 27.2% of the associations between exposure to mixed NEOs, imidacloprid (IMI), DIN, and Olefin-IMI and arrhythmia risk, respectively. Network toxicology analyses revealed that NEO-related arrhythmia may primarily involve oxidative stress, inflammatory response, and endocrine disruption pathways, with AKT1, EGFR, GAPDH, CASP3, and HSP90AA1 as key target genes. Collectively, this study presents epidemiological evidence linking NEO exposure to arrhythmia risk and identifies potential mechanisms underlying NEO cardiotoxicity.