Radiation Metabolomics. 5. Identification of Urinary Biomarkers of Ionizing Radiation Exposure in Nonhuman Primates by Mass Spectrometry-Based Metabolomics

Abstract

Mass spectrometry-based metabolomics has previously demonstrated utility for identifying biomarkers of ionizing radiation exposure in cellular, mouse and rat in vivo radiation models. To provide a valuable link from small laboratory rodents to humans, γ-radiation-induced urinary biomarkers were investigated using a nonhuman primate total-body-irradiation model. Mass spectrometry-based metabolomics approaches were applied to determine whether biomarkers could be identified, as well as the previously discovered rodent biomarkers of γ radiation. Ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry analysis was carried out on a time course of clean-catch urine samples collected from nonhuman primates (n = 6 per cohort) exposed to sham, 1.0, 3.5, 6.5 or 8.5 Gy doses of 60Co γ ray (~0.55 Gy/min) ionizing radiation. By multivariate data analysis, 13 biomarkers of radiation were discovered: N-acetyltaurine, isethionic acid, taurine, xanthine, hypoxanthine, uric acid, creatine, creatinine, tyrosol sulfate, 3-hydroxytyrosol sulfate, tyramine sulfate, N-acetylserotonin sulfate, and adipic acid. N-Acetyltaurine, isethionic acid, and taurine had previously been identified in rats, and taurine and xanthine in mice after ionizing radiation exposure. Mass spectrometry-based metabolomics has thus successfully revealed and verified urinary biomarkers of ionizing radiation exposure in the nonhuman primate for the first time, which indicates possible mechanisms for ionizing radiation injury.

Comparative Analysis of Transcriptional Gene Regulation Indicates Similar Physiologic Response in Mouse Tissues at Low Absorbed Doses from Intravenously Administered211At

“…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).…”

CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation

“…7A). Increased urinary excretion of creatine and its catabolite creatinine are biomarkers of whole body irradiation in rats (44), and creatine was identified as a urinary radiation biomarker in a nonhuman primate (11). Notably, baseline creatine levels were much higher in CD47(Ϫ) cells and persisted after irradiation (Fig.…”

Novel metabolites and roles for α-tocopherol in humans and mice discovered by mass spectrometry–based metabolomics

“…This was to obtain the actual concentration of each metabolite normalized to the endogenous creatinine concentration. Standard calibration curves were made, and the following MRM transitions were monitored for creatinine Endogenous liver metabolites were quantitated by using an ACQUITY UPLC H-class coupled to a XEVOG2 QTOFMS with Quantof technology (Waters Corp), as recently described (8). Standard calibration curves of 0 to 35 mmol/L of linoleic acid, linolenic acid, adrenic acid, oleic acid, DHA, arachidonic acid, and palmitic acid were made by using authentic standards.…”