A metabolomic-based study on disturbance of bile acids metabolism induced by intratracheal instillation of nickel oxide nanoparticles in rats

Nickel oxide nanoparticles (Nano NiO) evoke hepatotoxicity, while whether it affects the hepatic metabolism remains unclear. The aim of this study was to explore the differential metabolites and their metabolic pathways in rat serum and to further verify the potential mechanism of bile acids' (BAs) metabolism dysregulation after Nano NiO exposure. Sixteen male Wistar rats were intratracheally instilled with Nano NiO (0.24 mg/kg body weight) twice a week for 9 weeks. Liquid chromatography/mass spectrometry was applied to filter the differentially expressed metabolites in rat serum. Western blot was employed to detect the protein contents. Twenty-one differential metabolites that associated with BAs, lipid and phospholipid metabolism pathways were identified in rat serum after Nano NiO exposure. Decreased cholic acid and deoxycholic acid implied that the BAs metabolism was disturbed. The nickel content increased in liver after Nano NiO exposure. The protein expression of cholesterol 7α-hydroxylase (CYP7A1) was down-regulated, and the bile salt export pump was up-regulated after Nano NiO administration in rat liver. Moreover, dehydroepiandrosterone sulphotransferase (SULT2A1) and cytochrome P450 (CYP) 3A4 were elevated in the exposure group. In conclusion, Nano NiO might trigger the disturbances of BAs, lipid and phospholipid metabolism pathways in rats. The diminished serum BAs induced by Nano NiO might be related to the down-regulation of synthetase and to the overexpression of transmembrane protein and detoxification enzymes in BAs metabolism.