Metabolomic Analysis of Mice Exposed to Gamma Radiation Reveals a Systemic Understanding of Total-Body Exposure

Abstract

Diagnostic markers are needed for accidental or deliberate radiation exposure that could cause acute and chronic radiation toxicity. Biomarkers of temporal, dose-dependent, aging-attenuated and multiple radiation exposures have been previously described by others. However, the physiological origin and biochemical networks that generate these biomarkers and their association at the molecular level have yet to be explored. Hence, the discovery and identification of total-body-irradiation-induced tissue specific biomarkers remains an enormous challenge within radiation biodosimetry research. To determine the tissue level response of total-body exposure (6 Gy), metabolomics analysis was carried out on radiosensitive tissues bone marrow, ileum, liver, muscle and lung as well as serum and on urine within 12 h postirradiation. Differences in the metabolic signatures between the sham and gamma-irradiated groups were analyzed by hydrophilic interaction liquid chromatography (HILIC)-based ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS). A panel of 67 biomarkers identified in radiosensitive tissues and biofluids (serum and urine) at a 6 Gy dose. Among the identified biomarkers, 3-methylglutarylcarnitine (3-MGC) was found to be a novel metabolite in liver, serum and urine that could potentially be an early radiation response marker. The degree of metabolic changes among different tissues showed perturbations in pathways including DNA methylation, energy, nucleic acid, amino acid, glutathione and bile acid metabolism. These results highlight metabolomics as a potential novel approach to understand functional alterations in the metabolome that could be adapted for use in the rapid assessment of radiation exposure and triage protocols in the case of nuclear incidents.

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…The utility of 5-oxoproline as a biomarker for NASH is doubtful, as it is often found to be elevated in relation to hepatic oxidative stress. We have recently reported a highly statistically significant upregulation of 5-oxoproline in HepG2 cells treated with the experimental anti-HCV drug [193], in the liver of whole-body γ-irradiated mice [194] and in γ-irradiated HepG2 cells [195].…”

microRNA and Metabolite Signatures Linked to Early Consequences of Lethal Radiation

“…In addition, human serum samples have been analyzed in individuals following radiotherapy 26,27 ; these studies indicated upregulation of biomarkers corresponding to energy metabolism including increased branched chain amino acid synthesis and protein biosynthesis 27 . C57BL/6 mouse biosamples including bone marrow, ileum, muscle, lung, serum, and urine have been analyzed within 12 hours of 6 Gy irradiation and demonstrated differences in DNA methylation pattern, energy expenditure and metabolism of amino acid, glutathione, and bile, respectively 28 . Unlike miRNA profiling, radiation-induced metabolite profiles at various time points relative to radiation exposure warrants further study.…”

Early metabolic characterization of brain tissues after whole body radiation based on gas chromatography–mass spectrometry in a rat model

“…Different tissues displayed substantial radiosensitivity. The metabolic signatures were focused on radiosensitive organs in most earlier reports, such as bone marrow, ileum, lung, jejunum and spleen (Golla et al, ; Jang et al, ; Xiao et al, ). Nevertheless, there were few studies on the early metabolic signatures in the brain following irradiation.…”

“…Furthermore, novel diagnostic biomarkers and therapeutic targets for clinical applications are also involved in the tissues (Huang et al, ). In recent years, metabolic changes in various tissues including bone marrow, ileum, liver, muscle, lung, jejunum and spleen after ionizing radiation based on liquid chromatography–mass spectrometry (LC–MS) or NMR have been reported (Golla et al, ; Jang et al, ; Xiao, Hu, Liu, & Hu, ). Because of the heterogeneity in chemical properties and wide dynamic range of the metabolites in organism, a single analytical technique is adequate to obtain a global metabolic signature (Wu et al, ).…”