Effect of dose and dose rate on temporal γ-H2AX kinetics in mouse blood and spleen mononuclear cells in vivo following Cesium-137 administration

Abstract

Background Cesium-137 ( 137 Cs) 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 137 Cs 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. Results C57BL/6 mice were injected with a range of 137 CsCl 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 137 Cs was excreted by day 5, leading to a slower rate of decay for the remaining time of the study; 137 Cs 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. Conclusions Despite 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 137 Cs 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. Electronic supplementary material The online version of this article (10.1186/s12860-019-0195-2) contains supplementary material, which is available to authorized users.

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

“…However, it should be noted that the majority of the total dose received by an individual will be due to external exposure [ 8 ]. Cytogenetic analysis [ 9 ], the current gold standard for radiation assessment, remains laborious and time consuming, while newer methods, such as automated γ-H2AX foci counting and gene expression have shown potential in evaluating dose rate effects through internal emitters [ 10 , 11 , 12 ]. Recently, metabolomics has emerged as a method to determine biological dose and dose rate effects by assessing biofluids and developing biomarkers and biosignatures [ 13 ].…”

VADER: a variable dose-rate external 137Cs irradiator for internal emitter and low dose rate studies

“…The data above represent the first two runs of the VADER. Both runs utilized a dose/ time profile measured in our prior 137 Cs injection studies [15][16][17][18] tracking mice over 1 week or 1 month. Leukocyte depletion kinetics showed a nadir around day 3-7, similar to that seen for acute exposures 36 .…”

“…Over the past decade, we have utilized 137 CsCl (aq) injection in mice to study the long-term effects of ingested 137 Cs on cytogenetic 14 , 15 , transcriptomic 16 and metabolomic 17 , 18 endpoints. The difficulty of these studies lies in the fact that both the study animals and the resulting biofluids are often radioactive and require dedicated equipment to analyze, making systematic studies difficult and expensive.…”

“…At Columbia University, we had available a few dozen such sources, ranging from 3 to 35 mCi each. We describe below the construction and first two years of operation of the VADER system, including several 30-day mouse irradiations, designed to mimic the internal exposure experiments described in [15][16][17][18] .…”

DNA damage response in peripheral mouse blood leukocytesin vivoafter variable, low-dose rate exposure

“…In our earlier work, we showed the persistence of radiation-induced DNA γ-H2AX double strand breaks (DSBs) in vivo, several weeks after the administration of 137 Cs internal emitter gamma radiation which is in clear contrast to acute dose exposures where the γ-H2AX is typically decayed after 24-48 h due to DSB repair (Halm et al 2014;Turner et al 2019;Turner et al 2010;Turner et al 2015). We injected C57Bl/6 mice with a range of 137 CsCl activities to achieve totalbody committed doses of ~ 4 Gy at days 3, 5, 7, and 14 of 137 Cs exposure.…”