Development of urinary biomarkers for internal exposure by cesium-137 using a metabolomics approach in mice

Cesium-137 is a fission product of uranium and plutonium in nuclear reactors and is released in large quantities during nuclear explosions or detonation of an improvised device containing this isotope. This environmentally persistent radionuclide undergoes radioactive decay with the emission of beta particles as well as gamma radiation. Exposure to (137)Cs at high doses can cause acute radiation sickness and increase risk for cancer and death. The serious health risks associated with (137)Cs exposure makes it critical to understand how it affects human metabolism and whether minimally invasive and easily accessible samples such as urine and serum can be used to triage patients in case of a nuclear disaster or a radiologic event. In this study, we have focused on establishing a time-dependent metabolomic profile for urine collected from mice injected with (137)CsCl. The samples were collected from control and exposed mice on days 2, 5, 20 and 30 after injection. The samples were then analyzed by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC/TOFMS) and processed by an array of informatics and statistical tools. A total of 1,412 features were identified in ESI(+) and ESI(-) modes from which 200 were determined to contribute significantly to the separation of metabolomic profiles of controls from those of the different treatment time points. The results of this study highlight the ease of use of the UPLC/TOFMS platform in finding urinary biomarkers for (137)Cs exposure. Pathway analysis of the statistically significant metabolites suggests perturbations in several amino acid and fatty acid metabolism pathways. The results also indicate that (137)Cs exposure causes: similar changes in the urinary excretion levels of taurine and citrate as seen with external-beam gamma radiation; causes no attenuation in the levels of hexanoylglycine and N-acetylspermidine; and has unique effects on the levels of isovalerylglycine and tiglylglycine.