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

Abstract

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 doseresponse 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.

Comparative Analysis of Transcriptional Gene Regulation Indicates Similar Physiologic Response in Mouse Tissues at Low Absorbed Doses from Intravenously Administered 211At

“…Radiation metabolomics has shown the feasibility of metabolites as biomarkers for ionizing radiation exposure, suggesting that regulation profiles of metabolic processes have indicative potential. Recently, Johnson et al (33) identified several urinary biomarkers in nonhuman primates, among which taurine and xanthine had been identified previously in the mouse (34,35). In fact, responses in genes associated with taurine and xanthine metabolization were regulated in some instances (data not shown).…”

Dealing with the unknown: Metabolomics and Metabolite Atlases

“…These were then identified using authentic standards and tandem mass spectrometry. In another study, Tyburski et al used LC/MS metabolomics to study the response of mice to ␥-radiation exposure [37]. MarkerLynx was used for feature identification.…”

“…However, in many cases it is not possible to separate sufficient quantities due to sample availability and/or complexity. In these cases, it is necessary to synthesize libraries of related hypothetical molecules and compare features (e.g., m/z, fragmentation masses, and method specific retention time) with the unknown metabolite [37,40].…”

Fourier Transform Infrared Microspectroscopy and Multivariate Methods for Radiobiological Dosimetry

“…Recently, methods which analyse concentration changes in metabolites have also been applied to this problem, identifying biomarkers of radiobiological effect in various biological media (17)(18)(19). The vibrational microspectroscopy modalities (Raman and FTIR microspectroscopy (FTIRM)) are techniques that can rapidly and noninvasively measure the spatially-resolved chemistry of the cell (20) and of tissue (21) with minimal sample preparation.…”