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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

Temporal kinetics of γ-H2AX fluorescence after single administration of high and low dose 90Sr, and 137Cs.Error bars represent standard deviations.
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pone.0143815.g004: Temporal kinetics of γ-H2AX fluorescence after single administration of high and low dose 90Sr, and 137Cs.Error bars represent standard deviations.

Mentions: Table 3 and Fig 4 show a more detailed analysis of γ-H2AX fluorescence kinetics which supports the presence of two peaks at early and late times. The value of the 50th percentile (the median) indicates that 50% of the cells had fluorescence below this value. Correspondingly, the 75th and 90th percentile values indicate that 75% and 90% of cells have fluorescence below these values. For 137Cs, the first peak occurred at the shortest observation time, whereas for 90Sr it occurred at ~ Day 7 post-injection. The second peak occurred at Days 23–26 for both radionuclides. It is important to note that given the absence of blood draw time points between the two peaks (i.e. between days 9 and 23), the γ-H2AX kinetics within this time period were not observed and remain unknown. Future research is needed to test the two-peak interpretation of the γ-H2AX kinetics during protracted internal emitter exposure, which may display even more complex patterns. The initial decline in γ-H2AX yields and the subsequent trough between peaks may represent the death of mature lymphocytes that were present at the start of radiation exposure, whereas the second peak may represent the contribution of newly formed lymphocytes, which have been produced from radiation-damaged stem and/or progenitor cells.


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)

Temporal kinetics of γ-H2AX fluorescence after single administration of high and low dose 90Sr, and 137Cs.Error bars represent standard deviations.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143815.g004: Temporal kinetics of γ-H2AX fluorescence after single administration of high and low dose 90Sr, and 137Cs.Error bars represent standard deviations.
Mentions: Table 3 and Fig 4 show a more detailed analysis of γ-H2AX fluorescence kinetics which supports the presence of two peaks at early and late times. The value of the 50th percentile (the median) indicates that 50% of the cells had fluorescence below this value. Correspondingly, the 75th and 90th percentile values indicate that 75% and 90% of cells have fluorescence below these values. For 137Cs, the first peak occurred at the shortest observation time, whereas for 90Sr it occurred at ~ Day 7 post-injection. The second peak occurred at Days 23–26 for both radionuclides. It is important to note that given the absence of blood draw time points between the two peaks (i.e. between days 9 and 23), the γ-H2AX kinetics within this time period were not observed and remain unknown. Future research is needed to test the two-peak interpretation of the γ-H2AX kinetics during protracted internal emitter exposure, which may display even more complex patterns. The initial decline in γ-H2AX yields and the subsequent trough between peaks may represent the death of mature lymphocytes that were present at the start of radiation exposure, whereas the second peak may represent the contribution of newly formed lymphocytes, which have been produced from radiation-damaged stem and/or progenitor cells.

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