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• Alam, T
• Neerathilingam, M
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• Sarkar, S
• Luxon, B
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Metabolites 2012, 2(3), 479-495; doi:10.3390/metabo2030479

Article

¹H Nuclear Magnetic Resonance (NMR) Metabolomic Study of Chronic Organophosphate Exposure in Rats

Todd M. Alam ^1,* , Muniasamy Neerathilingam ^2,† , M. Kathleen Alam ³ , David E. Volk ^2,4 , G. A. Shakeel Ansari ⁵ , Swapna Sarkar ²  and Bruce A. Luxon ²

¹ Department of Electronic and Nanostructured Materials, Sandia National Laboratories, Albuquerque, NM 87185, USA ² Department of Biochemistry and Molecular Biology, School of Medicine, University of Texas Medical Branch, Galveston, TX, 77555, USA ³ Energetics Characterization Department, Sandia National Laboratories, Albuquerque, NM 87185, USA ⁴ Institute for Molecular Medicine for the Prevention of Human Diseases, Centers for Proteomics & System Biology, University of Texas Health Science Center Houston, 1825 Pressler, Houston, TX 77555, USA ⁵ Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA ^† Present address: Center of Cellular Molecular Platforms, National Center for Biological Sciences, GKVK, Bellary Road, Bangalore -65, India

* Author to whom correspondence should be addressed.

Received: 18 April 2012; in revised form: 26 June 2012 / Accepted: 5 July 2012 / Published: 24 July 2012

(This article belongs to the Special Issue Feature Papers)

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Abstract: ¹H NMR spectroscopy and chemometric analysis were used to characterize rat urine obtained after chronic exposure to either tributyl phosphate (TBP) or triphenyl phosphate (TPP). In this study, the daily dose exposure was 1.5 mg/kg body weight for TBP, or 2.0 mg/kg body weight for TPP, administered over a 15-week period. Orthogonal signal correction (OSC) -filtered partial least square discriminant analysis (OSC-PLSDA) was used to predict and classify exposure to these organophosphates. During the development of the model, the classification error was evaluated as a function of the number of latent variables. NMR spectral regions and corresponding metabolites important for determination of exposure type were identified using variable importance in projection (VIP) coefficients obtained from the OSC-PLSDA analysis. As expected, the model for classification of chronic (1.5–2.0 mg/kg body weight daily) TBP or TPP exposure was not as strong as the previously reported model developed for identifying acute (15–20 mg/kg body weight) exposure. The set of majorly impacted metabolites identified for chronic TBP or TPP exposure was slightly different than those metabolites previously identified for acute exposure. These metabolites were then mapped to different metabolite pathways and ranked, allowing the metabolic response to chronic organophosphate exposure to be addressed.

Keywords: NMR; metabolomics; tributyl phosphate, triphenyl phosphate, chemometrics

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