Fungicide bromuconazole has the potential to induce hepatotoxicity at the physiological, metabolomic and transcriptomic levels in rats

Highlights: • Metabolomic and transcriptome revealed the hepatic toxicity of bromuconazole in rat. • Lipid and bile acids metabolism related pathway were most altered via omics. • Bromuconazole could interact with PPAR-γ and decrease its expression in the liver. Bromuconazole (BROMU), a representative triazole fungicide, has been widely used in agriculture for its low cost and highly efficiency against various fungi. BROMU residue was often detected in the environment and food chain, even though there is indication of health risk to animals, and in humans. However, the data related to the toxicity of BROMU in animals remains unclear, and the mechanism is still not fully elucidated. Here, male adult rats were exposed to 0, 13.8, 32.8 and 65.6 mg/kg/d of BROMU for 10 days by oral gavage. It was observed that short time BROMU exposure not only caused liver histological damage, including vacuolar degeneration of hepatocytes with pyknotic nuclei, but also changed the levels of some hepatic physiological parameters, including aspartate transaminase (AST), triglyceride (TG), pyruvate and total cholesterol (TC), indicating that BROMU causes hepatotoxicity in rats. In addition, according to the transcriptomics and metabolomics analysis, a total of 58 metabolites and 259 genes significantly changed in the high-dose BROMU treated group. Although several different pathways are involved, lipid metabolism- and bile acids metabolism-related pathways were highlighted in both metabolomics and transcriptomics analysis. More importantly, further validation had proven that BROMU could not only interact with peroxisome proliferator-activated receptor γ (PPAR-γ), but also significantly decrease its protein and gene expression in the liver, supporting that BROMU decreased the TG synthesis via inhibiting the PPAR-γ pathway. These results clearly showed that BROMU exposure could result in hepatotoxicity at metabolomic and transcriptomic level in rats. These observations could provide some important steps toward understanding the mechanism underlying BROMU-induced mammalian toxicity.