Fenitrothion induces sex-specific glucose metabolism dysregulation in rats by targeting PK/glycolysis in males and IDH3/TCA cycle in females

Fenitrothion (FNT) is a widely used organophosphorus insecticide, and its potential health hazards have raised increasing public concern. However, the mechanisms underlying FNT-induced glucose metabolic dysregulation remain poorly understood. Here, Sprague-Dawley rats were exposed to FNT (0.37, 3.7 or 37 mg/kg bw/day) for 28 days, resulting in hyperglycemia, hyperphagia, and impaired glucose tolerance at the 3.7 and 37 mg/kg doses. Multi-omics analysis revealed that inhibition of PK and IDH3 constitutes a key toxic event following FNT exposure. In males, FNT suppressed the PI3K–AKT and ChREBP pathways while activating the cAMP–PKA and AMPKα pathways, thereby downregulating Pk expression and impairing glycolysis. In females, FNT inhibited the PI3K–AKT and AMPKα–PGC1α pathways, downregulating Idh3 expression, ultimately impeding TCA cycle. These sex-specific alterations cooperatively suppressed glycolysis and oxidative metabolism, thereby causing hepatic energy imbalance, hyperglycemia, and glucose homeostasis disruption. These findings uncover novel molecular mechanisms linking FNT exposure to glucose metabolic dysregulation, providing insights into pesticide-associated risks of hyperglycemia and insulin resistance. Overall, this study highlights the endocrine-disrupting potential of organophosphorus pesticides.