Single-cell and metabolomic profiling reveals multi-lineage hepatic perturbations and metabolic reprogramming in pregnant mice exposed to dimethomorph

Dimethomorph (DMM), a widely used morpholine fungicide, poses emerging concerns for reproductive health due to its environmental persistence and anti-androgenic activity. However, pregnancy-specific hepatotoxicity mechanisms remain uncharacterized. Here, we present the first single-cell resolution map of DMM-induced hepatic disruptions in pregnant mice, integrating scRNA-seq with untargeted metabolomics. DMM exposure (180 mg/kg/day, GD7–birth) caused synchronized downregulation of oxidative phosphorylation and DNA repair genes across hepatocytes, endothelial cells, fibroblasts, and hematopoietic lineages. Cell type-specific reprogramming included attenuated placental development signals in endothelium, accelerated terminal differentiation in fibroblasts and hematopoietic stem/progenitor cells, and a metabolic shift in hepatocytes from lipid oxidation to protein synthesis. Metabolomic analysis confirmed a systemic transition from carbohydrate to lipid metabolism, with elevated steroids, bile acids, and fatty acids, and suppressed purine and riboflavin metabolism—resembling metabolic syndrome signatures. These multi-lineage alterations reveal a unified mechanism of mitochondrial-genotoxic stress and highlight potential secondary risks to placental and fetal health. Our findings provide a critical mechanistic foundation for human pregnancy risk assessment of DMM.