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Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

Meadows SK, Dressman HK, Daher P, Himburg H, Russell JL, Doan P, Chao NJ, Lucas J, Nevins JR, Chute JP - PLoS ONE (2010)

Bottom Line: Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice.These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice.These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

View Article: PubMed Central - PubMed

Affiliation: Division of Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina, United States of America.

ABSTRACT
In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16-43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

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Gene expression profiles of partial body irradiation poorly predict the status of mice irradiated to disparate anatomic sites.A single variable plot is shown of the leave one out cross validation analysis performed in which the gene expression profiles of (A) AH irradiation were utilized to predict the status of mice irradiated to PH or HL at the identical dose levels (0.5 Gy, top; 2 Gy, middle; 10 Gy, bottom). (B) PB signatures of PH irradiation were tested against mice irradiated to AH and HL at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). (C) PB signatures of HL were tested against mice irradiated to AH and PH at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). Positive prediction of radiation status is defined by plotting of the sample above the ROC curve-defined cutoff (dotted line). Each dot represents a PB sample from an individual mouse.
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pone-0011535-g002: Gene expression profiles of partial body irradiation poorly predict the status of mice irradiated to disparate anatomic sites.A single variable plot is shown of the leave one out cross validation analysis performed in which the gene expression profiles of (A) AH irradiation were utilized to predict the status of mice irradiated to PH or HL at the identical dose levels (0.5 Gy, top; 2 Gy, middle; 10 Gy, bottom). (B) PB signatures of PH irradiation were tested against mice irradiated to AH and HL at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). (C) PB signatures of HL were tested against mice irradiated to AH and PH at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). Positive prediction of radiation status is defined by plotting of the sample above the ROC curve-defined cutoff (dotted line). Each dot represents a PB sample from an individual mouse.

Mentions: We next sought to determine if PB signatures of partial body irradiation were capable of predicting the status of other partially irradiated mice in which different parts of the body had been irradiated. The predictors of partial irradiation to AH, PH and HL (nā€Š=ā€Š25-50 genes from Figure 1) were utilized to predict radiation status by anatomic site. Surprisingly, the PB signatures of partial body irradiation demonstrated low accuracy in predicting the radiation status of other mice irradiated at the same dose level to other parts of the body (Figure 2). For example, the PB signature of 10 Gy AH failed to predict the status of 57% and 86% the PB samples from mice irradiated with 10 Gy to the PH or HL, respectively. This lack of accuracy in predicting radiation status of PB samples from partially irradiated mice was irrespective of dose level and anatomic location; for example, the PB signature of 2 Gy HL exposure failed to predict the radiation status of 66% and 71% of the PB samples from mice irradiated with 2 Gy to the AH or PH, respectively. Consistent with these results, we found little overlap in genes represented within the AH, PH or HL radiation groups at any dose level and only 1 gene which overlapped between all 3 conditions (RIKEN cDNA 6330579B17) at the 10 Gy dose level (Table S2). Taken together, these data demonstrate that ionizing radiation induces distinct PB molecular responses as a function of the anatomic site of exposure, rather than a redundant molecular response based upon the percentage of body surface area that is irradiated.


Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

Meadows SK, Dressman HK, Daher P, Himburg H, Russell JL, Doan P, Chao NJ, Lucas J, Nevins JR, Chute JP - PLoS ONE (2010)

Gene expression profiles of partial body irradiation poorly predict the status of mice irradiated to disparate anatomic sites.A single variable plot is shown of the leave one out cross validation analysis performed in which the gene expression profiles of (A) AH irradiation were utilized to predict the status of mice irradiated to PH or HL at the identical dose levels (0.5 Gy, top; 2 Gy, middle; 10 Gy, bottom). (B) PB signatures of PH irradiation were tested against mice irradiated to AH and HL at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). (C) PB signatures of HL were tested against mice irradiated to AH and PH at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). Positive prediction of radiation status is defined by plotting of the sample above the ROC curve-defined cutoff (dotted line). Each dot represents a PB sample from an individual mouse.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2902517&req=5

pone-0011535-g002: Gene expression profiles of partial body irradiation poorly predict the status of mice irradiated to disparate anatomic sites.A single variable plot is shown of the leave one out cross validation analysis performed in which the gene expression profiles of (A) AH irradiation were utilized to predict the status of mice irradiated to PH or HL at the identical dose levels (0.5 Gy, top; 2 Gy, middle; 10 Gy, bottom). (B) PB signatures of PH irradiation were tested against mice irradiated to AH and HL at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). (C) PB signatures of HL were tested against mice irradiated to AH and PH at 0.5 Gy (top), 2 Gy (middle) and 10 Gy (bottom). Positive prediction of radiation status is defined by plotting of the sample above the ROC curve-defined cutoff (dotted line). Each dot represents a PB sample from an individual mouse.
Mentions: We next sought to determine if PB signatures of partial body irradiation were capable of predicting the status of other partially irradiated mice in which different parts of the body had been irradiated. The predictors of partial irradiation to AH, PH and HL (nā€Š=ā€Š25-50 genes from Figure 1) were utilized to predict radiation status by anatomic site. Surprisingly, the PB signatures of partial body irradiation demonstrated low accuracy in predicting the radiation status of other mice irradiated at the same dose level to other parts of the body (Figure 2). For example, the PB signature of 10 Gy AH failed to predict the status of 57% and 86% the PB samples from mice irradiated with 10 Gy to the PH or HL, respectively. This lack of accuracy in predicting radiation status of PB samples from partially irradiated mice was irrespective of dose level and anatomic location; for example, the PB signature of 2 Gy HL exposure failed to predict the radiation status of 66% and 71% of the PB samples from mice irradiated with 2 Gy to the AH or PH, respectively. Consistent with these results, we found little overlap in genes represented within the AH, PH or HL radiation groups at any dose level and only 1 gene which overlapped between all 3 conditions (RIKEN cDNA 6330579B17) at the 10 Gy dose level (Table S2). Taken together, these data demonstrate that ionizing radiation induces distinct PB molecular responses as a function of the anatomic site of exposure, rather than a redundant molecular response based upon the percentage of body surface area that is irradiated.

Bottom Line: Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice.These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice.These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

View Article: PubMed Central - PubMed

Affiliation: Division of Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina, United States of America.

ABSTRACT
In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16-43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

Show MeSH
Related in: MedlinePlus