Fenitrothion exposure induces hyperglycemia in juvenile rats: Impeded glycolysis and promoted gluconeogenesis mediated by acetyl-CoA and oxaloacetate metabolism dysregulation

Abstract

Fenitrothion (FNT), an organophosphorus insecticide widely used in agriculture and household pest control, is closely associated with several glucose metabolism diseases. However, scientific knowledge about the mechanisms of FNT disturbance of glucose metabolism in puberty models remains poorly understood. Here, we show that 4-week-old SD rats exposed to 3.7 or 37 mg/kg bw/day FNT for 28 days exhibited hyperglycemia and hyperphagia, as well as impaired glucose tolerance and insulin resistance, which resulted from FNT's interference with insulin secretion, inhibition of glycolysis, and promotion of gluconeogenesis. Interestingly, FNT interferes with the TCA cycle, the final oxidation pathway of glucose, with significant sex differences. For males, FNT impedes pyruvate catabolism, and accelerates the conversion of α-ketoglutaric acid to oxaloacetate and enhancement of hepatic glucose production. For females, FNT retards the conversion of acetyl-CoA to citrate and promotes the conversion of fatty acids to acetyl-CoA, which leads to accumulation of acetyl-CoA and inhibits glucose breakdown. It is evident that FNT interferes with the metabolism of acetyl-CoA and oxaloacetate, thereby obstructing the TCA cycle, which is a key step in exacerbating metabolic disorders. Our research reveals novel molecular pathways through which environmental FNT exposure disrupts glucose metabolic balance. These mechanistic findings carry significant public health implications, underscoring FNT as an underrecognized environmental risk factor that could exacerbate hyperglycemia and related conditions, particularly among vulnerable populations such as adolescents undergoing rapid metabolic changes.

Keywords: Fenitrothion; Glucose metabolism; Multi-omics; Tricarboxylic acid cycle.