Radiation Metabolomics. 1. Identification of Minimally Invasive Urine Biomarkers for Gamma-Radiation Exposure in Mice

Abstract Tyburski, J. B., Patterson, A. D., Krausz, K. W., Slavík, J., Fornace, A. J., Jr., Gonzalez, F. J. and Idle, J. R. Radiation Metabolomics. 1. Identification of Minimally Invasive Urine Biomarkers for Gamma-Radiation Exposure in Mice. Radiat. Res. 170, 1–14 (2008). Gamma-radiation exposure has both short- and long-term adverse health effects. The threat of modern terrorism places human populations at risk for radiological exposures, yet current medical countermeasures to radiation exposure are limited. Here we describe metabolomics for γ-radiation biodosimetry in a mouse model. Mice were γ-irradiated at doses of 0, 3 and 8 Gy (2.57 Gy/min), and urine samples collected over the first 24 h after exposure were analyzed by ultra-performance liquid chromatography–time-of-flight mass spectrometry (UPLC–TOFMS). Multivariate data were analyzed by orthogonal partial least squares (OPLS). Both 3- and 8-Gy exposures yielded distinct urine metabolomic phenotypes. The top 22 ions for 3 and 8 Gy were analyzed further, including tandem mass spectrometric comparison with authentic standards, revealing that N-hexanoylglycine and β-thymidine are urinary biomarkers of exposure to 3 and 8 Gy, 3-hydroxy-2-methylbenzoic acid 3-O-sulfate is elevated in urine of mice exposed to 3 but not 8 Gy, and taurine is elevated after 8 but not 3 Gy. Gene Expression Dynamics Inspector (GEDI) self-organizing maps showed clear dose–response relationships for subsets of the urine metabolome. This approach is useful for identifying mice exposed to γ radiation and for developing metabolomic strategies for noninvasive radiation biodosimetry in humans.

[1]  Weiling Zhao,et al.  Knocking Out Peroxisome Proliferator-Activated Receptor (PPAR) α Inhibits Radiation-Induced Apoptosis in the Mouse Kidney through Activation of NF-κB and Increased Expression of IAPs , 2007, Radiation research.

[2]  A. Fernie,et al.  Metabolite profiling: from diagnostics to systems biology , 2004, Nature Reviews Molecular Cell Biology.

[3]  H. Smith,et al.  Alterations in tryptophan metabolism in man after irradiation. , 1966, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[4]  J. Lindon,et al.  An hypothesis for a mechanism underlying hepatotoxin-induced hypercreatinuria , 2003, Archives of Toxicology.

[5]  L. G. Hoffman,et al.  On the mechanism of radiation-induced emesis: the role of serotonin. , 1994, International journal of radiation oncology, biology, physics.

[6]  C. N. Coleman,et al.  Discovering clinical biomarkers of ionizing radiation exposure with serum proteomic analysis. , 2006, Cancer research.

[7]  Sui Huang,et al.  Gene Expression Dynamics Inspector (GEDI): for integrative analysis of expression profiles , 2003, Bioinform..

[8]  Donald E. Ingber,et al.  Towards a Holistic, Yet Gene-Centered Analysis of Gene Expression Profiles: A Case Study of Human Lung Cancers , 2006, Journal of biomedicine & biotechnology.

[9]  Huaixia Chen,et al.  [HPLC-ESI/MS analysis of stachydrine and its metabolites in rat urine]. , 2006, Yao xue xue bao = Acta pharmaceutica Sinica.

[10]  J. Griffin.  The Cinderella story of metabolic profiling: does metabolomics get to go to the functional genomics ball? , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[11]  H. Claycamp,et al.  Absence of pyrimidine salvage and prevention of thymineless radiosensitization in Escherichia coli thyA cells fed dihydrothymine or thymine glycol. , 1988, Radiation research.

[12]  E. Hall,et al.  Radiobiology for the radiologist , 1973 .

[13]  V. Garaj-vrhovac,et al.  The alkaline Comet assay as biomarker in assessment of DNA damage in medical personnel occupationally exposed to ionizing radiation. , 2003, Mutagenesis.

[14]  V. Bihari,et al.  DNA-protein crosslinks as a biomarker of exposure to solar radiation: a preliminary study in brick-kiln workers , 2003, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[15]  L. Gros,et al.  The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway. , 2004, Nucleic acids research.

[16]  M. Randić,et al.  Urinary excretion of 5-hydroxyindolacetic acid after a single whole-body x-irradiation in normal and adrenalectomized rats. , 1961, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[17]  E. Hall,et al.  Radiobiology for the Radiologist, 6th Edition , 2006 .

[18]  E. L. Green,et al.  Biology of the Laboratory Mouse , 1942 .

[19]  R. Troiano,et al.  Comparison of estimated renal net acid excretion from dietary intake and body size with urine pH. , 2003, Journal of the American Dietetic Association.

[20]  R. T. Williams,et al.  Studies in detoxication: The metabolism of vanillin and vanillic acid in the rabbit. The identification of glucurovanillin and the structure of glucurovanillic acid. , 1941, The Biochemical journal.

[21]  M. Balzi,et al.  Polyamines as biochemical indicators of radiation injury. , 2001, Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics.

[22]  J. Idle,et al.  Metabolomic and genetic analysis of biomarkers for peroxisome proliferator-activated receptor alpha expression and activation. , 2007, Molecular endocrinology.

[23]  M. B. Grace,et al.  Human In vivo Radiation-Induced Biomarkers , 2004, Cancer Research.

[24]  James B. Mitchell,et al.  Molecular and Cellular Biology of Moderate-Dose (1–10 Gy) Radiation and Potential Mechanisms of Radiation Protection: Report of a Workshop at Bethesda, Maryland, December 17–18, 20011 , 2003, Radiation research.

[25]  P. Divry,et al.  General (medium-chain) acyl-CoA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases. , 1983, Clinica chimica acta; international journal of clinical chemistry.

[26]  M. B. Grace,et al.  Radiation exposure assessment using cytological and molecular biomarkers. , 2001, Radiation protection dosimetry.

[27]  James Armitage,et al.  Medical Management of the Acute Radiation Syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group , 2004, Annals of Internal Medicine.

[28]  C. Waterfield,et al.  Taurine, a possible urinary marker of liver damage: a study of taurine excretion in carbon tetrachloride-treated rats , 2005, Archives of Toxicology.

[29]  Russ Greiner,et al.  Investigations of the effects of gender, diurnal variation, and age in human urinary metabolomic profiles. , 2007, Analytical chemistry.

[30]  Pataje G S Prasanna,et al.  Early-response biological dosimetry--recommended countermeasure enhancements for mass-casualty radiological incidents and terrorism. , 2005, Health physics.

[31]  R. Scheline,et al.  The metabolism of vanillin and isovanillin in the rat. , 1975, Xenobiotica; the fate of foreign compounds in biological systems.

[32]  B. Ames,et al.  Thymine glycol and thymidine glycol in human and rat urine: a possible assay for oxidative DNA damage. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[33]  R. Wolfram,et al.  Radioiodine therapy induces dose-dependent in vivo oxidation injury: evidence by increased isoprostane 8-epi-PGF(2 alpha). , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[34]  V. Yushmanov.  Evaluation of radiation injury by 1H and 31P NMR of human urine , 1994, Magnetic resonance in medicine.

[35]  U. Plappert,et al.  Changes in the repair capacity of blood cells as a biomarker for chronic low‐dose exposure to ionizing radiation , 1997, Environmental and molecular mutagenesis.

[36]  E Holmes,et al.  Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. , 1998, Chemical research in toxicology.

[37]  William F. Morgan,et al.  Genomic instability in Gadd45a-deficient mice , 1999, Nature Genetics.

[38]  Danka Periči,et al.  Excretion of metabolites of biogenic amines in patients with irradiated brain tumours. , 1976 .

[39]  S. Straus,et al.  The uptake, excretion, and radiation hazards of tritiated thymidine in humans. , 1977, Cancer research.

[40]  Su-Jae Lee,et al.  Possible Biomarkers for Ionizing Radiation Exposure in Human Peripheral Blood Lymphocytes , 2003, Radiation research.

[41]  Ž. Deanović,et al.  The metabolites of catecholamines in urine of patients irradiated therapeutically. , 1976, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[42]  C. Berg,et al.  Urinary biomarkers in radiation therapy of cancer. , 1990, Advances in experimental medicine and biology.

[43]  M. Randić,et al.  RELATIONSHIP BETWEEN THE DOSE OF WHOLE-BODY X-IRRADIATION AND THE URINARY EXCRETION OF 5-HYDROXYINDOLEACETIC ACID IN RATS. , 1963, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[44]  P. Sever,et al.  Unequivocal synthesis and characterisation of dopamine 3- and 4-O-sulphates. , 1982, Biochemical pharmacology.

[45]  Isoprostane levels in the urine of patients with prostate cancer receiving radiotherapy are not elevated. , 2004, International journal of radiation oncology, biology, physics.

[46]  I. Wilson,et al.  Understanding 'Global' Systems Biology: Metabonomics and the Continuum of Metabolism , 2003, Nature Reviews Drug Discovery.

[47]  Jennifer H Granger,et al.  A rapid screening approach to metabonomics using UPLC and oa-TOF mass spectrometry: application to age, gender and diurnal variation in normal/Zucker obese rats and black, white and nude mice. , 2005, The Analyst.