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Urinary metabolomic phenotyping of nickel induced acute toxicity in rat: an NMR spectroscopy approach

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Abstract

The metabolomic approach has been widely used in toxicology to investigate mechanisms of toxicity. To understand the mammalian system’s response to nickel exposure, we analysed the NiCl2 induced metabolomic changes in urine of rats using 1H nuclear magnetic resonance (1H NMR) spectroscopy together with clinically relevant biochemical parameters. Male Sprague–Dawley rats were administered intraperitoneally with NiCl2 at doses of 4, 10 and 20 mg/kg body weight. Urine samples were collected at 8, 16, 24, 72, 96 and 120 h post treatment. The metabolomic profile of rat urine showed prominent changes in citrate, dimethylamine, creatinine, choline, trimethylamine oxide (TMAO), phenyl alanine and hippurate at all doses. Principal component analysis of urine 1H NMR spectra demonstrated the dose and time dependent development of toxicity. The metabolomic time trajectory, based on pattern recognition analysis of 1H NMR spectra of urine, illustrated clear separation of pre and post treatments (temporal). Only animals treated with a low dose of NiCl2 returned to normal physiology. The 1H NMR spectral data correlated well with the clinically relevant nephrotoxic biomarkers. The urinary metabolomic phenotyping for NiCl2 induced nephrotoxicity was defined according to the predictive ability of the known metabolite biomarkers, creatinine, citrate and TMAO. The current approach demonstrates that metabolomics, one of the most important platform in system biology, may be a promising tool for identifying and characterizing biochemical responses to toxicity.

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References

  • Beutler, E., Duron, O., & Kelly, B. M. (1963). Improved method for the determination of blood glutathione. Journal of Laboratory and Clinical Medicine, 61, 882–888.

    PubMed  CAS  Google Scholar 

  • Boudonck, K. J., Mitchell, M. W., Nemet, L., et al. (2009). Discovery of metabolomics biomarker for early detection of nephrotoxicity. Toxicologic Pathology, 37, 280–292.

    Article  PubMed  CAS  Google Scholar 

  • Das, K. K., Das, S. N., & Dhundasi, S. A. (2008). Nickel, its adverse health effects and oxidative stress. Indian Journal of Medical Research, 128, 412–425.

    PubMed  CAS  Google Scholar 

  • Feng, J., Li, X., Pei, F., et al. (2002). 1H NMR analysis for metabolites in serum and urine from rats administered chronically with La (NO3)3. Analytical Biochemistry, 301, 1–7.

    Article  PubMed  CAS  Google Scholar 

  • Garrod, S., Humpher, E., Connor, S. C., et al. (2001). High-resolution 1H NMR and magic angle spinning NMR spectroscopic investigation of the biochemical effects of 2-bromoethanamine in intact renal and hepatic tissue. Magnetic Resonance in Medicine, 45, 781–790.

    Article  PubMed  CAS  Google Scholar 

  • Gavaghan, C. L., Nicholson, J. K., Connor, S. C., et al. (2001). Directly coupled high-performance liquid chromatography and nuclear magnetic resonance spectroscopic with chemometric studies on metabolic variation in Sprague–Dawley rats. Analytical Biochemistry, 291, 245.

    Article  PubMed  CAS  Google Scholar 

  • Griffin, J. L., Walker, L. A., Shore, R. F., et al. (2001). Metabolic profiling of chronic cadmium exposure in the rat. Chemical Research in Toxicology, 14, 1428–1434.

    Article  PubMed  CAS  Google Scholar 

  • Hauet, T., Baumert, H., Amor, I. B., et al. (2000). Pharmacological limitation of damage to renal medulla after cold storage and transplantation by trimetazidine. Journal of Pharmacology and Experimental Therapeutics, 292, 254–260.

    PubMed  CAS  Google Scholar 

  • Holmes, E., Nicholls, A. W., Lindon, J. C., et al. (2000). Chemometric models for toxicity classification based on NMR spectra of biofluids. Chemical Research in Toxicology, 13, 471–478.

    Article  PubMed  CAS  Google Scholar 

  • Holmes, E., Nicolson, J. K., Bonner, F. W., et al. (1992). Mapping the biochemical trajectory of nephrotoxicity by pattern recognition of NMR urinanalysis. NMR in Biomedicine, 5, 368–372.

    Article  PubMed  CAS  Google Scholar 

  • Holmes, E., Nicolson, J. K., Nicholls, A. W., et al. (1998). The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine. Chemometrics and Intelligent Laboratory Systems, 44, 245–255.

    Article  CAS  Google Scholar 

  • Khan, A. R., Rana, P., Tyagi, R., et al. (2011). NMR spectroscopy based metabolic profiling of urine and serum for investigation of physiological perturbations during radiation sickness. Metabolomics, 7, 583–592.

    Google Scholar 

  • Lenz, E. M., Bright, J., Knight, R., et al. (2005). Metabonomics with 1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamycin-induced nephrotoxicity in the rat. Biomarkers, 10, 173–187.

    Article  PubMed  CAS  Google Scholar 

  • Lindon, J. C., Nicholson, J. K., & Everett, J. R. (1999). NMR spectroscopy of biofluid. Annual Reports on NMR Spectroscopy, 38, 1–88.

    Article  CAS  Google Scholar 

  • Nicholls, A. W., Mortishire-Smith, R. J., & Nicholson, J. K. (2003). NMR spectroscopic-based metabonomic studies of urinary metabolite variation in acclimatizing germ-free rats. Chemical Research in Toxicology, 6, 1395–1404.

    Article  Google Scholar 

  • Nicholson, J. K., Connelly, J., Lindon, J. C., et al. (2002). Metabonomics: a platform for studying drug toxicity and gene function. Nature Reviews, 1, 153–161.

    Article  PubMed  CAS  Google Scholar 

  • Nicholson, J. K., & Wilson, I. D. (1989). High-resolution proton magnetic resonance spectroscopy of biological fluids. Progress in Nuclear Magnetic Resonance Spectroscopy, 21, 449–501.

    Article  CAS  Google Scholar 

  • Peiqiu, L., Lai, W., Huifeng, W., et al. (2009). Biochemical effects of gadolinium chloride in rats liver and kidney studied by 1H NMR metabolomics. Journal of Rare Earths, 27, 280–287.

    Article  Google Scholar 

  • Phipps, A. N., Stewart, J., Wright, B., et al. (1998). Effect of diet on the urinary excretion of hippuric acid and other dietary-derived aromatics in rat, a complex interaction between diet, gut microflora and substrate specificity. Xenobiotica, 28, 527–537.

    Article  PubMed  CAS  Google Scholar 

  • Portilla, D., Li, S., Nagothu, K. K., et al. (2006). Metabolomic study of cisplatin-induced nephrotoxicity. Kidney International, 69, 2194–2204.

    Article  PubMed  CAS  Google Scholar 

  • Rezuke, W. N., Knight, J. A., & Sunderman, F. W., Jr. (1987). Reference values for nickel concentrations in human tissues and bile. American Journal of Industrial Medicine, 11, 419–426.

    Google Scholar 

  • Robosky, L. C., Wells, D. F., Egnash, L. A., et al. (2005). Metabonomic identification of two distinct phenotypes in Sprague–Dawley (Crl:CD(SD)) rats. Toxicological Sciences, 87, 277.

    Article  PubMed  CAS  Google Scholar 

  • Singh, K. K. (2006). Oxidative stress, disease and cancer. London: Imperial College Press.

    Book  Google Scholar 

  • Singla, A., Kaur, J., & Mahmood, A. (2006). Alterations in the expression of intestinal enzymes in rats exposed to nickel. Journal of Applied Toxicology, 26, 397–401.

    Article  PubMed  CAS  Google Scholar 

  • Sun, J., Schnackenberg, L. K., Holland, R. D., et al. (2008). Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS. Journal of Chromatography B, 871, 328–340.

    Article  CAS  Google Scholar 

  • Trygg, J., Holmes, E., & Lundstedt, T. (2007). Chemometrices in metabonomics. Journal of Proteome Research, 6, 469–479.

    Article  PubMed  CAS  Google Scholar 

  • Trygg, J., & Wold, S. (2002). Orthogonal projections to latent structures (O-PLS). Journal of chemometrices, 16, 119–128.

    Article  CAS  Google Scholar 

  • Tyagi, R., Rana, P., Gupta, M., et al. (2011a). Differential biochemical response of rat kidney towards low and high doses of NiCl2 as revealed by NMR spectroscopy. Journal of Applied Toxicology, in press. doi:10.1002/jat.1730.

  • Tyagi, R., Rana, P., Khan, A. R., et al. (2011b). Study of acute biochemical effects of thallium toxicity in mouse urine by NMR spectroscopy. Journal of Applied Toxicology, 31, 663–670.

    Google Scholar 

  • Wang, Y., Bollard, M. E., Nicholson, J. K., et al. (2006). Exploration of the direct metabolic effects of mercury II chloride on the kidney of Sprague–Dawley rats using high-resolution magic angle spinning 1H NMR spectroscopy of intact tissue and pattern recognition. Journal of Pharmaceutical and Biomedical Analysis, 40, 375–381.

    Article  PubMed  CAS  Google Scholar 

  • Wei, L., Liao, P., Wu, H., et al. (2008). Toxicological effects of cinnabar in rats by NMR-based metabolic profiling of urine and serum. Toxicology and Applied Pharmacology, 227, 417–429.

    Article  PubMed  CAS  Google Scholar 

  • Wu, H., Zhang, X., Li, X., et al. (2006). Investigation on acute biochemical effects of Ce(NO3)3 on liver and kidney tissues by MAS 1H NMR spectroscopic-based metabonomic approach. Journal of Rare Earths, 24, 357–363.

    Article  Google Scholar 

  • Wu, H., Zhang, X., Liao, P., et al. (2005). NMR spectroscopic-based metabonomic investigation on the acute biochemical effects induced by Ce(NO3)3 in rats. Journal of Inorganic Biochemistry, 99, 2151–2160.

    Article  PubMed  CAS  Google Scholar 

  • Xu, L. (2004). Methods of chemometrics. Beijing: Science Press.

    Google Scholar 

Download references

Acknowledgments

This work was performed as a part of Defence Research & Development Organization (DRDO) sponsored R & D project INM-308. The authors are thankful for the financial support provided by DRDO, Ministry of Defence, India.

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Authors and Affiliations

  1. NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), S. K Mazumdar Road, Timarpur, Delhi, 110054, India

    Ritu Tyagi, Poonam Rana, Mamta Gupta, Ahmad Raza Khan, M. Memita Devi, Rajendra P. Tripathi & Subash Khushu

  2. Department of Biochemistry, Devi Ahilya Vishwavidyalaya, Indore, India

    Deepak Bhatnagar

  3. Centre of Biomedical Magnetic Resonance, SGPGI Campus, Lucknow, India

    Raja Roy

Authors
  1. Ritu Tyagi
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  2. Poonam Rana
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  3. Mamta Gupta
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  4. Ahmad Raza Khan
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  5. M. Memita Devi
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  6. Deepak Bhatnagar
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  7. Raja Roy
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  8. Rajendra P. Tripathi
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  9. Subash Khushu
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Corresponding author

Correspondence to Subash Khushu.

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Supplementary Fig. 1a: Representative 1H NMR spectra of serum. (TIFF 103 kb)

11306_2011_390_MOESM2_ESM.tif

Supplementary Fig. 1b: Relative change in the integral value of lactate from rat exposed to three doses of (4, 10 and 20 mg/kg b.w.) NiCl2 at 24 h. (TIFF 23 kb)

11306_2011_390_MOESM3_ESM.tif

Supplementary Fig. 2: PCA Scores plot of 1H NMR spectra of urine sampled at 96 h from control rats (○, n = 5) and NiCl2 doses with 4 (●, n = 5); 10 (■, n = 5); and 20 (▲, n = 5) mg/kg body weight dose. (TIFF 37 kb)

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Tyagi, R., Rana, P., Gupta, M. et al. Urinary metabolomic phenotyping of nickel induced acute toxicity in rat: an NMR spectroscopy approach. Metabolomics 8, 940–950 (2012). https://doi.org/10.1007/s11306-011-0390-4

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  • DOI: https://doi.org/10.1007/s11306-011-0390-4

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