Tebuconazole induces liver injury coupled with ROS-mediated hepatic metabolism disorder

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Tebuconazole, the most widely used fungicide, is reported to cause various environmental problems and have serious health risks in humans. Despite numerous advances in toxicity studies, its internal metabolic process and the underlying mechanisms have not been systemically studied. The present study administered low doses (0.02 g/kg bw and 0.06 g/kg bw) of tebuconazole to C57BL/6 mice in vivo. The high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed and validated to analyze the tebuconazole in different organs, and our data revealed that tebuconazole mainly accumulated in the liver and that histopathological damage were exhibited in this organ. Tebuconazole significantly dysregulated phase Ⅰ- and phase II-metabolizing enzymes, ATP-binding cassette (ABC) efflux transporters (Abcc2 and Abcc3) and fatty acid metabolism-related genes (Cdkn1a and Fasn), thereby directly causing liver hypertrophy and steatosis. Importantly, the excessive induction of reactive oxygen species (ROS) and oxidative stress partially accounted for the metabolic abnormalities mediated by tebuconazole. Moreover, these alterations were related to the abnormal transcriptional levels of peroxisome proliferator-activated receptor α (PPAR-α) and liver x receptor α (LXR-α), which were predicted to bind to tebuconazole via hydrogen bonding interactions. The current findings provide new insight into the molecular mechanisms of metabolic abnormalities induced by tebuconazole at low concentration, and are conducive to a better understanding of the environmental risk posed by this fungicide.