Project description: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.

Project description:BackgroundCesium-137 (137Cs) is one of the major and most clinically relevant radionuclides of concern in a radiological dispersal device, "dirty bomb" scenario as well as in nuclear accidents and detonations. In this exposure scenario, a significant amount of soluble radionuclide(s) may be dispersed into the atmosphere as a component of fallout. The objectives of the present study were to investigate the effect of protracted 137Cs radionuclide exposures on DNA damage in mouse blood and spleen mononuclear cells (MNCs) in vivo using the γ-H2AX biomarker, and to develop a mathematical formalism for these processes.ResultsC57BL/6 mice were injected with a range of 137CsCl activities (5.74, 6.66, 7.65 and 9.28 MBq) to achieve total-body committed doses of ~ 4 Gy at Days 3, 5, 7, and 14. Close to 50% of 137Cs was excreted by day 5, leading to a slower rate of decay for the remaining time of the study; 137Cs excretion kinetics were independent of activity level within the tested range, and the absorbed radiation dose was determined by injected activity and time after injection. Measurements of γ-H2AX fluorescence in blood and spleen MNCs at each time point were used to develop a new biodosimetric mathematical formalism to estimate injected activity based on γ-H2AX fluorescence and time after injection. The formalism performed reasonably well on blood data at 2-5 days after injection: Pearson and Spearman's correlation coefficients between actual and predicted activity values were 0.857 (p = 0.00659) and 0.929 (p = 0.00223), respectively.ConclusionsDespite the complicated nature of the studied biological system and the time-dependent changes in radiation dose and dose rate due to radionuclide excretion and other processes, we have used the γ-H2AX repair kinetics to develop a mathematical formalism, which can relatively accurately predict injected 137Cs activity 2-5 days after initial exposure. To determine the assay's usefulness to predict retrospective absorbed dose for medical triage, further studies are required to validate the sensitivity and accuracy of the γ-H2AX response after protracted exposures.

Project description:Background The radioactive isotope Strontium-90 (90Sr) may be released as a component of fallout from nuclear accidents, or in the event of a radiological incident such as detonation of an improvised nuclear device, and if ingested poses a significant health risk to exposed individuals. In order to better understand the response to 90Sr, using an easily attainable and standard biodosimetry sample fluid, we analyzed the global transcriptomic response of blood cells in an in vivo model system. Methods We injected C57BL/6 mice with a solution of 90SrCl2 and followed them over a 30-day period. At days 4, 7, 9, 25 and 30, we collected blood and isolated RNA for microarray analyses. These days corresponded to target doses in a range from 1 to 5 Gy. We investigated changes in mRNA levels using microarrays, and changes in specific microRNA (miRNA) predicted to be involved in the response using qRT-PCR. Results We identified 8082 differentially expressed genes in the blood of mice exposed to 90Sr compared with controls. Common biological functions were affected throughout the study, including apoptosis of B and T lymphocytes, and atrophy of lymphoid organs. Cellular functions such as RNA degradation and lipid metabolism were also affected during the study. The broad down regulation of genes observed in our study suggested a potential role for miRNA in gene regulation. We tested candidate miRNAs, mmu-miR-16, mmu-miR-124, mmu-miR-125 and mmu-mir-21; and found that all were induced at the earliest time point, day 4. Conclusions Our study is the first to report the transcriptomic response of blood cells to the internal emitter 90Sr in mouse and a possible role for microRNA in gene regulation after 90Sr exposure. The most dramatic effect was observed on gene expression related to B-cell development and RNA maintenance. These functions were affected by genes that were down regulated throughout the study, suggesting severely compromised antigen response, which may be a result of the deposition of the radioisotope proximal to the hematopoietic compartment in bone.

Project description:Background The radioactive isotope Strontium-90 (90Sr) may be released as a component of fallout from nuclear accidents, or in the event of a radiological incident such as detonation of an improvised nuclear device, and if ingested poses a significant health risk to exposed individuals. In order to better understand the response to 90Sr, using an easily attainable and standard biodosimetry sample fluid, we analyzed the global transcriptomic response of blood cells in an in vivo model system. Methods We injected C57BL/6 mice with a solution of 90SrCl2 and followed them over a 30-day period. At days 4, 7, 9, 25 and 30, we collected blood and isolated RNA for microarray analyses. These days corresponded to target doses in a range from 1 to 5 Gy. We investigated changes in mRNA levels using microarrays, and changes in specific microRNA (miRNA) predicted to be involved in the response using qRT-PCR. Results We identified 8082 differentially expressed genes in the blood of mice exposed to 90Sr compared with controls. Common biological functions were affected throughout the study, including apoptosis of B and T lymphocytes, and atrophy of lymphoid organs. Cellular functions such as RNA degradation and lipid metabolism were also affected during the study. The broad down regulation of genes observed in our study suggested a potential role for miRNA in gene regulation. We tested candidate miRNAs, mmu-miR-16, mmu-miR-124, mmu-miR-125 and mmu-mir-21; and found that all were induced at the earliest time point, day 4. Conclusions Our study is the first to report the transcriptomic response of blood cells to the internal emitter 90Sr in mouse and a possible role for microRNA in gene regulation after 90Sr exposure. The most dramatic effect was observed on gene expression related to B-cell development and RNA maintenance. These functions were affected by genes that were down regulated throughout the study, suggesting severely compromised antigen response, which may be a result of the deposition of the radioisotope proximal to the hematopoietic compartment in bone. Radiation induced gene expression in mouse blood was measured at 4, 7, 9, 25 and 30 days after 90Sr injection. Six independent experiments were performed at each time point.

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Serum Metabolomic Alterations Associated with Cesium-137 Internal Emitter Delivered in Various Dose Rates.

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Serum Metabolomic Alterations Associated with Cesium-137 Internal Emitter Delivered in Various Dose Rates.

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