Combined Analysis of Network Toxicology and Multiomics Revealed the Potential Mechanism of Mancozeb-Induced Hepatotoxicity in Mice Offspring

Mancozeb (MCZ), a broad-spectrum dithiocarbamate fungicide, raises significant concerns regarding its potential hepatotoxicity. Despite their extensive agricultural application, the mechanisms underlying MCZ-induced intergenerational liver injury remain poorly understood. Here, we integrated network toxicology, transcriptomics, metabolomics, and animal experiments to elucidate MCZ-induced hepatotoxicity in F1 male offspring. Based on the predictions from ADMETlab 3.0 and protein-protein interaction network analysis, AKT1, TP53, MAPK1/3, and ESR1 were identified as core targets. Molecular docking and molecular dynamics simulations further validated the binding affinity of MCZ for these key proteins. Multiomics integration revealed steroid hormone biosynthesis as the central pathway mediating MCZ-induced liver damage. Subsequent animal experiments confirmed this mechanistic framework, highlighting the critical role of disrupted steroid hormone biosynthesis in MCZ-induced liver injury. This study establishes the mechanistic basis of MCZ-induced developmental exposure-associated hepatotoxicity in F1 male offspring, offering valuable insights for future toxicological investigations and environmental risk assessments of dithiocarbamate fungicides.