Prothioconazole and prothioconazole-desthio induced different hepatotoxicities via interfering with glycolipid metabolism in mice

Prothioconazole (PTA), a new triazole fungicide, has been widely used worldwide. A recent study has confirmed that PTA and its main metabolite prothioconazole-desthio (dPTA) interfere with the liver metabolism in reptiles. However, little is known about liver toxicity of these two pollutants in mammals. Here, female mice were orally exposed to PTA (1.5 mg/kg body weight/day) and dPTA (1.5 mg/kg body weight/day) for 30 days. Additionally, growth phenotype and indexes related to serum and liver function were examined. Using metabolomics and gene expression analysis, PTA- and dPTA-induced hepatotoxicity was studied to clarify its potential underlying mechanism of action. Together, the results indicated that PTA and dPTA exposure caused changes in growth phenotypes, including elevated blood glucose levels, triglyceride accumulation, and damage of liver function. Additionally, exposure to PTA and dPTA caused changes in genes and metabolites related to glycolipid metabolism in female mice, thereby interfering with the pyruvate metabolism and glycolysis/gluconeogenesis pathways, ultimately leading to hepatic metabolism disorders. In particular, the effect of dPTA on hepatotoxicity has been proven to be more significant than that of PTA. Thus, these findings help us understand the underlying mechanism of action of PTA and dPTA exposure-induced hepatotoxicity in mammals and possibly humans.