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γ-H2AX Kinetic Profile in Mouse Lymphocytes Exposed to the Internal Emitters Cesium-137 and Strontium-90.

Turner HC, Shuryak I, Weber W, Doyle-Eisele M, Melo D, Guilmette R, Amundson SA, Brenner DJ - PLoS ONE (2015)

Bottom Line: In order to measure the kinetic profile for γ-H2AX, peripheral blood samples were drawn at 5 specific timed dose points over the 30-day study period and the total γ-H2AX nuclear fluorescence per lymphocyte was determined using image analysis software.A mechanistically-motivated model was used to analyze the temporal kinetics of γ-H2AX fluorescence.The complexity of the observed responses to internal irradiation is likely caused by the interplay between continual production and repair of DNA damage, cell cycle effects and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.

ABSTRACT
In the event of a dirty bomb scenario or an industrial nuclear accident, a significant dose of volatile radionuclides such as 137Cs and 90Sr may be dispersed into the atmosphere as a component of fallout and inhaled or ingested by hundreds and thousands of people. To study the effects of prolonged exposure to ingested radionuclides, we have performed long-term (30 day) internal-emitter mouse irradiations using soluble-injected 137CsCl and 90SrCl2 radioisotopes. The effect of ionizing radiation on the induction and repair of DNA double strand breaks (DSBs) in peripheral mouse lymphocytes in vivo was determined using the γ-H2AX biodosimetry marker. Using a serial sacrifice experimental design, whole-body radiation absorbed doses for 137Cs (0 to 10 Gy) and 90Sr (0 to 49 Gy) were delivered over 30 days following exposure to each radionuclide. The committed absorbed doses of the two internal emitters as a function of time post exposure were calculated based on their retention parameters and their derived dose coefficients for each specific sacrifice time. In order to measure the kinetic profile for γ-H2AX, peripheral blood samples were drawn at 5 specific timed dose points over the 30-day study period and the total γ-H2AX nuclear fluorescence per lymphocyte was determined using image analysis software. A key finding was that a significant γ-H2AX signal was observed in vivo several weeks after a single radionuclide exposure. A mechanistically-motivated model was used to analyze the temporal kinetics of γ-H2AX fluorescence. Exposure to either radionuclide showed two peaks of γ-H2AX: one within the first week, which may represent the death of mature, differentiated lymphocytes, and the second at approximately three weeks, which may represent the production of new lymphocytes from damaged progenitor cells. The complexity of the observed responses to internal irradiation is likely caused by the interplay between continual production and repair of DNA damage, cell cycle effects and apoptosis.

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Related in: MedlinePlus

Observed and fitted cumulative probability distributions of cellular γ-H2AX fluorescence values at different times after administration of radioactive material.A shift to the right represents a “peak” of the fluorescence signal and a shift to the left, a trough.
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pone.0143815.g003: Observed and fitted cumulative probability distributions of cellular γ-H2AX fluorescence values at different times after administration of radioactive material.A shift to the right represents a “peak” of the fluorescence signal and a shift to the left, a trough.

Mentions: For all analyzed radionuclide doses and times after administration, the cumulative probability distribution of cellular γ-H2AX fluorescence values was well approximated by a stretched exponential function [32] described in Materials and Methods. Both 137Cs and 90Sr the best-fit values of the shape parameter b were always less than unity (Table 2). Consequently, the function reproduced the following observed data patterns: (1) the modal γ-H2AX fluorescence value was equal to zero, i.e. many cells had no fluorescent foci at all even when a large radionuclide dose was accumulated; (2) there was a prominent “tail” of the probability distribution extending towards large fluorescence values (Fig 3), i.e. quite a few cells had large numbers of fluorescent foci per cell. This “tail” may represent cells that are likely to proceed to apoptosis. Examination of these cumulative probability distributions suggested that the temporal kinetics for γ-H2AX fluorescence after administration of either radionuclide were not monotonic, but exhibited two “peaks” separated by a “trough”. For 137Cs, the trough occurred on Day 5 after administration–the cumulative probability distribution for that day was visibly shifted to the left, towards smaller fluorescence values (red line in 137Cs panel of Fig 3). Consequently, the two peaks occurred before and after the trough. For 90Sr the trough was not so apparent, but there was a clear peak on Day 7 (i.e. a shift of the cumulative probability distribution to the right) at both low and high doses (blue lines in 90Sr panel of Fig 3).


γ-H2AX Kinetic Profile in Mouse Lymphocytes Exposed to the Internal Emitters Cesium-137 and Strontium-90.

Turner HC, Shuryak I, Weber W, Doyle-Eisele M, Melo D, Guilmette R, Amundson SA, Brenner DJ - PLoS ONE (2015)

Observed and fitted cumulative probability distributions of cellular γ-H2AX fluorescence values at different times after administration of radioactive material.A shift to the right represents a “peak” of the fluorescence signal and a shift to the left, a trough.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664397&req=5

pone.0143815.g003: Observed and fitted cumulative probability distributions of cellular γ-H2AX fluorescence values at different times after administration of radioactive material.A shift to the right represents a “peak” of the fluorescence signal and a shift to the left, a trough.
Mentions: For all analyzed radionuclide doses and times after administration, the cumulative probability distribution of cellular γ-H2AX fluorescence values was well approximated by a stretched exponential function [32] described in Materials and Methods. Both 137Cs and 90Sr the best-fit values of the shape parameter b were always less than unity (Table 2). Consequently, the function reproduced the following observed data patterns: (1) the modal γ-H2AX fluorescence value was equal to zero, i.e. many cells had no fluorescent foci at all even when a large radionuclide dose was accumulated; (2) there was a prominent “tail” of the probability distribution extending towards large fluorescence values (Fig 3), i.e. quite a few cells had large numbers of fluorescent foci per cell. This “tail” may represent cells that are likely to proceed to apoptosis. Examination of these cumulative probability distributions suggested that the temporal kinetics for γ-H2AX fluorescence after administration of either radionuclide were not monotonic, but exhibited two “peaks” separated by a “trough”. For 137Cs, the trough occurred on Day 5 after administration–the cumulative probability distribution for that day was visibly shifted to the left, towards smaller fluorescence values (red line in 137Cs panel of Fig 3). Consequently, the two peaks occurred before and after the trough. For 90Sr the trough was not so apparent, but there was a clear peak on Day 7 (i.e. a shift of the cumulative probability distribution to the right) at both low and high doses (blue lines in 90Sr panel of Fig 3).

Bottom Line: In order to measure the kinetic profile for γ-H2AX, peripheral blood samples were drawn at 5 specific timed dose points over the 30-day study period and the total γ-H2AX nuclear fluorescence per lymphocyte was determined using image analysis software.A mechanistically-motivated model was used to analyze the temporal kinetics of γ-H2AX fluorescence.The complexity of the observed responses to internal irradiation is likely caused by the interplay between continual production and repair of DNA damage, cell cycle effects and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.

ABSTRACT
In the event of a dirty bomb scenario or an industrial nuclear accident, a significant dose of volatile radionuclides such as 137Cs and 90Sr may be dispersed into the atmosphere as a component of fallout and inhaled or ingested by hundreds and thousands of people. To study the effects of prolonged exposure to ingested radionuclides, we have performed long-term (30 day) internal-emitter mouse irradiations using soluble-injected 137CsCl and 90SrCl2 radioisotopes. The effect of ionizing radiation on the induction and repair of DNA double strand breaks (DSBs) in peripheral mouse lymphocytes in vivo was determined using the γ-H2AX biodosimetry marker. Using a serial sacrifice experimental design, whole-body radiation absorbed doses for 137Cs (0 to 10 Gy) and 90Sr (0 to 49 Gy) were delivered over 30 days following exposure to each radionuclide. The committed absorbed doses of the two internal emitters as a function of time post exposure were calculated based on their retention parameters and their derived dose coefficients for each specific sacrifice time. In order to measure the kinetic profile for γ-H2AX, peripheral blood samples were drawn at 5 specific timed dose points over the 30-day study period and the total γ-H2AX nuclear fluorescence per lymphocyte was determined using image analysis software. A key finding was that a significant γ-H2AX signal was observed in vivo several weeks after a single radionuclide exposure. A mechanistically-motivated model was used to analyze the temporal kinetics of γ-H2AX fluorescence. Exposure to either radionuclide showed two peaks of γ-H2AX: one within the first week, which may represent the death of mature, differentiated lymphocytes, and the second at approximately three weeks, which may represent the production of new lymphocytes from damaged progenitor cells. The complexity of the observed responses to internal irradiation is likely caused by the interplay between continual production and repair of DNA damage, cell cycle effects and apoptosis.

Show MeSH
Related in: MedlinePlus