Toxicometabolomics approach to urinary biomarkers for mercuric chloride (HgCl₂)-induced nephrotoxicity using proton nuclear magnetic resonance (¹H NMR) in rats.
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.
Kim
Kyu-Bong
KB
Korea Food and Drug Administration, 5-Nokbun-dong, Eunpyung-gu, Seoul 122-704, Republic of Korea. kyubong@inje.ac.kr
Um
So Young
SY
Chung
Myeon Woo
MW
Jung
Seung Chul
SC
Oh
Ji Seon
JS
Kim
Seon Hwa
SH
Na
Han Sung
HS
Lee
Byung Mu
BM
Choi
Ki Hwan
KH
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
D015415:Biomarkers; D008627:Mercuric Chloride