A metabolomics study unravels the hepatotoxic mechanism of diuron in zebrafish: Disruption of glutathione synthesis and mitochondrial energy metabolism.

The liver plays a central role in xenobiotic metabolism and is consequently highly vulnerable to chemical-induced injury. Nevertheless, the mechanisms underlying diuron-induced hepatotoxicity remain poorly understood. Zebrafish (Danio rerio) were exposed to diuron at concentrations of 50 and 500 μg/L for 21 days, with subsequent analysis of the induced hepatotoxicity employing a combination of physiological, biochemical, and metabolomic techniques. Results showed that diuron significantly bioaccumulated in zebrafish, with bioconcentration factor (BCF) values ranging from 14.0 to 40.49 L/kg. Tissue distribution analysis indicated that the liver was the primary site of accumulation (491.48 ± 19.48 ng/g), while the brain also showed substantial accumulation (334.84 ± 10.90 ng/g) at an exposure concentration of 500 μg/L. Further examination of diuron metabolism in the liver identified 13 metabolites produced through demethylation, hydrolysis, oxidation, and C-N bond cleavage. These metabolic alterations correlated with histopathological damage, oxidative stress, and lipid peroxidation. Untargeted metabolomics further revealed a significant disruption in key metabolic pathways, particularly in arginine metabolism and the TCA cycle. Mechamistically, diuron-induced hepatotoxicity in zebrafish is characterized by the downregulation of key metabolites, namely gamma-Glutamyltyrosine, Leucylproline, and Malate, collectively contributing to the disruption of the tricarboxylic acid cycle alongside arachidonic acid, glutathione, and arginine metabolic pathways. These disturbances may represent the core mechanisms underlying hepatotoxicity. These findings will improve understanding of metabolic disorders in the liver and provide valuable insights into ecological risk assessments related to chemicals, and provide novel mechanistic insights into diuron induced hepatotoxicity.