Toxicometabolomics approach to urinary biomarkers for mercuric chloride (HgCl)-induced nephrotoxicity using proton nuclear magnetic resonance ((1)H NMR) in rats.

摘要

The primary objective of this study was to determine and characterize surrogate biomarkers that can predict nephrotoxicity induced by mercuric chloride (HgCl) using urinary proton nuclear magnetic resonance ((1)H NMR) spectral data. A procedure for (1)H NMR urinalysis using pattern recognition was proposed to evaluate nephrotoxicity induced by HgCl in Sprague-Dawley rats. HgCl at 0.1 or 0.75 mg/kg was administered intraperitoneally (i.p.), and urine was collected every 24 h for 6 days. Animals (n=6 per group) were sacrificed 3 or 6 days post-dosing in order to perform clinical blood chemistry tests and histopathologic examinations. Urinary (1)H NMR spectroscopy revealed apparent differential clustering between the control and HgCl treatment groups as evidenced by principal component analysis (PCA) and partial least square (PLS)-discriminant analysis (DA). Time- and dose-dependent separation of HgCl-treated animals from controls was observed by PCA of (1)H NMR spectral data. In HgCl-treated rats, the concentrations of endogenous urinary metabolites of glucose, acetate, alanine, lactate, succinate, and ethanol were significantly increased, whereas the concentrations of 2-oxoglutarate, allantoin, citrate, formate, taurine, and hippurate were significantly decreased. These endogenous metabolites were selected as putative biomarkers for HgCl-induced nephrotoxicity. A dose response was observed in concentrations of lactate, acetate, succinate, and ethanol, where severe disruption of the concentrations of 2-oxoglutarate, citrate, formate, glucose, and taurine was observed at the higher dose (0.75 mg/kg) of HgCl. Correlation of urinary (1)H NMR PLS-DA data with renal histopathologic changes suggests that (1)H NMR urinalysis can be used to predict or screen for HgCl-induced nephrotoxicity.