A lipidomic and metabolomic serum signature from nonhuman primates exposed to ionizing radiation
- 385 Downloads
Due to dangers associated with potential accidents from nuclear energy and terrorist threats, there is a need for high-throughput biodosimetry to rapidly assess individual doses of radiation exposure. Lipidomics and metabolomics are becoming common tools for determining global signatures after disease or other physical insult and provide a “snapshot” of potential cellular damage.
The current study assesses changes in the nonhuman primate (NHP) serum lipidome and metabolome 7 days following exposure to ionizing radiation (IR).
Serum sample lipids and metabolites were extracted using a biphasic liquid–liquid extraction and analyzed by ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry. Global radiation signatures were acquired in data-independent mode.
Radiation exposure caused significant perturbations in lipid metabolism, affecting all major lipid species, including free fatty acids, glycerolipids, glycerophospholipids and esterified sterols. In particular, we observed a significant increase in the levels of polyunsaturated fatty acids (PUFA)-containing lipids in the serum of NHPs exposed to 10 Gy radiation, suggesting a primary role played by PUFAs in the physiological response to IR. Metabolomics profiling indicated an increase in the levels of amino acids, carnitine, and purine metabolites in the serum of NHPs exposed to 10 Gy radiation, suggesting perturbations to protein digestion/absorption, biological oxidations, and fatty acid β-oxidation.
This is the first report to determine changes in the global NHP serum lipidome and metabolome following radiation exposure and provides information for developing metabolomic biomarker panels in human-based biodosimetry.
KeywordsLipidomics Metabolomics Ionizing Radiation Nonhuman Primate
The authors acknowledge Lombardi Comprehensive Cancer Proteomics and Metabolomics Shared Resource (PMSR) for data acquisition. Content is the responsibility of authors and does not necessarily represent official views of NCI/NIH.
National Institutes of Health (National Institute of Allergy and Infectious Diseases) grant 1R01AI101798 (P.I. Albert J. Fornace, Jr.) and Lombardi Comprehensive Cancer Proteomics and Metabolomics Shared Resource (PMSR); partial support National Cancer Institute grant P30CA051008 (P.I. Louis Weiner).
Compliance with ethical standards
Conflict of Interest
Evan L. Pannkuk, Evagelia C. Laiakis, Tytus D. Mak, Giuseppe Astarita, Simon Authier, Karen Wong, and Albert J. Fornace Jr. declare that they have no conflict of interest.
NHP studies were conducted by CiToxLAB: North America Safety and Health Research Laboratories (Laval, Québec, Canada; study # 5013-0193) and was approved by the Institutional Animal Care and Use Committee.
- Goudarzi, M., Weber, W. M., Mak, T. D., Chung, J., Doyle-Eisele, M., Melo, D. R., et al. (2015). Metabolomic and Lipidomic Analysis of Serum from Mice Exposed to an Internal Emitter, Cesium-137, Using a Shotgun LC-MSE Approach. Journal of Proteome Research, 14(1), 374–384.CrossRefPubMedPubMedCentralGoogle Scholar
- Hall, E. C., & Giaccia, A. J. (2012). Radiobiology for the Radiologist (7th ed.). Philadelphia: Lippincott Williams & Wilkins.Google Scholar
- Johnson, C. H., Patterson, A. D., Krausz, K. W., Kalinich, J. F., Tyburski, J. B., Kang, D. W., et al. (2012). Radiation metabolomics. 5. Identification of urinary biomarkers of ionizing radiation exposure in nonhuman primates by mass spectrometry-based metabolomics. Radiation Research, 178(4), 328–340.CrossRefPubMedPubMedCentralGoogle Scholar
- Jones, J. W., Tudor, G., Bennett, A., Farese, A. M., Moroni, M., Booth, C., et al. (2014). Development and validation of a LC-MS/MS assay for quantitation of plasma citrulline for application to animal models of the acute radiation syndrome across multiple species. Analytical and Bioanalytical Chemistry, 406(19), 4663–4675.CrossRefPubMedGoogle Scholar
- Khan, A. R., Rana, P., Devi, M. M., Chaturvedi, S., Javed, S., Tripathi, R. P., et al. (2011). Nuclear magnetic resonance spectroscopy-based metabonomic investigation of biochemical effects in serum of gamma-irradiated mice. International Journal of Radiation Biology, 87(1), 91–97.CrossRefPubMedGoogle Scholar
- Lanz, C., Patterson, A. D., Slavik, J., Krausz, K. W., Ledermann, M., Gonzalez, F. J., et al. (2009). Radiation metabolomics. 3. Biomarker discovery in the urine of gamma-irradiated rats using a simplified metabolomics protocol of gas chromatography-mass spectrometry combined with random forests machine learning algorithm. Radiation Research, 172(2), 198–212.CrossRefPubMedPubMedCentralGoogle Scholar
- Li, H. H., Tyburski, J. B., Wang, Y. W., Strawn, S., Moon, B. H., Kallakury, B. V., et al. (2014). Modulation of fatty acid and bile acid metabolism by peroxisome proliferator-activated receptor alpha protects against alcoholic liver disease. Alcoholism, Clinical and Experimental Research, 38(6), 1520–1531.CrossRefPubMedPubMedCentralGoogle Scholar
- Macvittie, T. J., Bennett, A., Booth, C., Garofalo, M., Tudor, G., Ward, A., et al. (2012a). The prolonged gastrointestinal syndrome in rhesus macaques: the relationship between gastrointestinal, hematopoietic, and delayed multi-organ sequelae following acute, potentially lethal, partial-body irradiation. Health Physics, 103(4), 427–453.CrossRefPubMedPubMedCentralGoogle Scholar
- Manna, S. K., Patterson, A. D., Yang, Q., Krausz, K. W., Li, H., Idle, J. R., et al. (2010). Identification of noninvasive biomarkers for alcohol-induced liver disease using urinary metabolomics and the Ppara-null mouse. Journal of Proteome Research, 9, 4176–4188.CrossRefPubMedPubMedCentralGoogle Scholar
- Schrier, R. W. (2006). Diseases of the kidney and urinary tract (diseases of the kidney [Schrier]). Philadelphia: Lippincott Williams & Wilkins.Google Scholar
- Tyburski, J. B., Patterson, A. D., Krausz, K. W., Slavik, J., Fornace, A. J, Jr, Gonzalez, F. J., et al. (2008). Radiation metabolomics. 1. Identification of minimally invasive urine biomarkers for gamma-radiation exposure in mice. Radiation Research, 170(1), 1–14.CrossRefPubMedPubMedCentralGoogle Scholar
- Zhang, G., Panigrahy, D., Mahakian, L. M., Yang, J., Liu, J. Y., Stephen Lee, K. S., et al. (2013). Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 110(16), 6530–6535.CrossRefPubMedPubMedCentralGoogle Scholar