Global metabolomic responses in urine from Atm deficient mice in response to LD50/30 gamma irradiation doses
Evagelia C. Laiakis, Tytus D. Mak, Steven J. Strawn, Yi-Wen Wang, Bo-Hyun Moon, Pelagie Ake, Albert J. Fornace
Exposures to ionizing radiation (IR) may either be accidental or intentional, for medical purposes or even through terrorist actions. As certain populations emerge to be more radiosensitive than others, it is imperative to assess those individuals and treat them accordingly. To demonstrate the feasibility of rapid identification of such cases, we utilized the highly radiosensitive mouse model Atm-/- in the C57BL/6 background, and evaluated the urinary responses in 8-10 wk old male mice at early time points (4, 24, and 48h) after exposure to their respective LD50/30 doses [4 Gy for Atm-/-, and 8 Gy for wild type (WT)]. Urinary profiles from heterozygous animals exhibited remarkably similar responses to WT before and after radiation exposure. However, genotypic differences (WT or Atm-/-) were the primary driver to responses to radiation. Putative metabolites were validated through tandem mass spectrometry and included riboflavin, uric acid, D-ribose, D-glucose, pantothenic acid, taurine, kynurenic acid, xanthurenic acid, 2-oxoadipic acid, glutaric acid, 5-deoxy-5-methylthioadenosine, and hippuric acid. These metabolites mapped to several interconnected metabolic pathways which suggest that radiosensitive mouse models have underlying differences significantly impacting overall metabolism, which is further amplified by ionizing radiation at different time points. This study further emphasizes that genetically based radiosensitivity is reflected in the metabolic processes, and can be directly observed in urine. These differences in turn can potentially be used to identify individuals that may require altered medical treatment in an emergency radiological situation or modification of a regimen during a radiotherapy session.