1H NMR-based metabonomic investigation of tributyl phosphate exposure in rats

Muniasamy Neerathilingam, David E. Volk, Swapna Sarkar, Todd M. Alam, M. Kathleen Alam, G. A.Shakeel Ansari, Bruce A. Luxon

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Tributyl phosphate (TBP) is a toxic organophosphorous compound widely used in many industrial applications, including significant usage in nuclear processing. The industrial application of this chemical is responsible for occupational exposure and environmental pollution. In this study, 1H NMR-based metabonomics has been applied to investigate the metabolic response to TBP exposure. Male Sprague-Dawley rats were given a TBP-dose of 15mg/kg body weight, followed by 24h urine collection, as was previously demonstrated for finding most of the intermediates of TBP. High-resolution 1H NMR spectroscopy of urine samples in conjunction with statistical pattern recognition and compound identification allowed for the metabolic changes associated with TBP treatment to be identified. Discerning NMR spectral regions corresponding to three TBP metabolites, dibutyl phosphate (DBP), N-acetyl-(S-3-hydroxybutyl)-l-cysteine and N-acetyl-(S-3-oxobutyl)-l-cysteine, were identified in TBP-treated rats. In addition, the 1H NMR spectra revealed TBP-induced variations of endogenous urinary metabolites including benzoate, urea, and trigonelline along with metabolites involved in the Krebs cycle including citrate, cis-aconitate, trans-aconitate, 2-oxoglutarate, succinate, and fumarate. These findings indicate that TBP induces a disturbance to the Krebs cycle energy metabolism and provides a biomarker signature of TBP exposure. We show that three metabolites of TBP, dibutylphosphate, N-acetyl-(S-3-hydroxybutyl)-l-cysteine and N-acetyl-(S-3-oxobutyl)-l-cysteine, which are not present in the control groups, are the most important factors in separating the TBP and control groups (p<0.0023), while the endogenous compounds 2-oxoglutarate, benzoate, fumarate, trigonelline, and cis-aconetate were also important (p<0.01).

Original languageEnglish (US)
Pages (from-to)10-16
Number of pages7
JournalToxicology Letters
Volume199
Issue number1
DOIs
StatePublished - Nov 1 2010

    Fingerprint

Keywords

  • Dibutyl phosphate (DBP)
  • Metabonomics
  • Nuclear magnetic resonance (NMR)
  • Rat
  • Tributyl phosphate (TBP)
  • Urine

ASJC Scopus subject areas

  • Toxicology

Cite this

Neerathilingam, M., Volk, D. E., Sarkar, S., Alam, T. M., Alam, M. K., Ansari, G. A. S., & Luxon, B. A. (2010). 1H NMR-based metabonomic investigation of tributyl phosphate exposure in rats. Toxicology Letters, 199(1), 10-16. https://doi.org/10.1016/j.toxlet.2010.07.013