title: Toxicometabolomics approach to urinary biomarkers for mercuric chloride (HgCl₂)-induced nephrotoxicity using proton nuclear magnetic resonance (¹H NMR) in rats.
abstract: The primary objective of this study was to determine and characterize surrogate biomarkers that can predict nephrotoxicity induced by mercuric chloride (HgCl₂) using urinary proton nuclear magnetic resonance (¹H NMR) spectral data. A procedure for (1)H NMR urinalysis using pattern recognition was proposed to evaluate nephrotoxicity induced by HgCl₂ in Sprague-Dawley rats. HgCl₂ 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 ¹H NMR spectroscopy revealed apparent differential clustering between the control and HgCl₂ treatment groups as evidenced by principal component analysis (PCA) and partial least square (PLS)-discriminant analysis (DA). Time- and dose-dependent separation of HgCl₂-treated animals from controls was observed by PCA of ¹H NMR spectral data. In HgCl₂-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 HgCl₂-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 HgCl₂. Correlation of urinary (1)H NMR PLS-DA data with renal histopathologic changes suggests that ¹H NMR urinalysis can be used to predict or screen for HgCl₂-induced nephrotoxicity.
authors.affiliation: Korea Food and Drug Administration, 5-Nokbun-dong, Eunpyung-gu, Seoul 122-704, Republic of Korea. kyubong@inje.ac.kr
authors.forename: Kyu-Bong
authors.initials: KB
authors.lastname: Kim
authors.forename: So Young
authors.initials: SY
authors.lastname: Um
authors.forename: Myeon Woo
authors.initials: MW
authors.lastname: Chung
authors.forename: Seung Chul
authors.initials: SC
authors.lastname: Jung
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Oh
authors.forename: Seon Hwa
authors.initials: SH
authors.lastname: Kim
authors.forename: Han Sung
authors.initials: HS
authors.lastname: Na
authors.forename: Byung Mu
authors.initials: BM
authors.lastname: Lee
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Choi
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced* / Q000652:urine*; D000818:Animals; D015415:Biomarkers / Q000652:urine; D004305:Dose-Response Relationship, Drug; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008627:Mercuric Chloride / Q000097:blood / Q000633:toxicity* / Q000652:urine*; D055432:Metabolomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008627:Mercuric Chloride