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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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Partial body irradiation and TBI cause significantly different changes in PB cell distributions.(A) The mean numbers of PB MNCs are shown in non-irradiated (untreated) mice versus mice irradiated with TBI, AH, PH or HL irradiation. *P = 0.02 for comparison with non-irradiated mice; ∧ P = 0.007, ∧∧P = 0.004, ∧∧∧P = 0.02 for comparison with non-irradiated mice; #P = 0.03, ##P = 0.03, ###P = 0.007 for comparison with non-irradiated mice; ΔP = 0.0005, ΔΔP = 0.03, ΔΔΔP = 0.004 for comparison with non-irradiated mice. (B) TBI causes a significant decrease in PB B cells (B220+) at increasing dose levels. *P = 0.04, **P = 0.03; AH and PH irradiation decrease PB B cells at 10 Gy, ∧P = 0.03; HL irradiation increases PB B cell content at all doses, #P = 0.003. (C) TBI causes a modest decrease in PB T cells (Thy 1.2+) at 10 Gy; AH, PH and HL irradiation uniformly cause an increase in PB T cells compared to non-irradiated controls, *P = 0.01, **P = 0.04, #P = 0.01, ∧P = 0.01, ∧∧P = 0.04, ∧∧∧P = 0.01. (D) TBI causes no significant change in PB myeloid (Mac-1+) cells; mice irradiated to AH, PH or HL demonstrated an increase in PB myeloid cells at 6 hours, *P = 0.03, ∧P = 0.04, ∧∧P = 0.03, #P = 0.02, ##P = 0.02, ###P = 0.009.
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pone-0011535-g004: Partial body irradiation and TBI cause significantly different changes in PB cell distributions.(A) The mean numbers of PB MNCs are shown in non-irradiated (untreated) mice versus mice irradiated with TBI, AH, PH or HL irradiation. *P = 0.02 for comparison with non-irradiated mice; ∧ P = 0.007, ∧∧P = 0.004, ∧∧∧P = 0.02 for comparison with non-irradiated mice; #P = 0.03, ##P = 0.03, ###P = 0.007 for comparison with non-irradiated mice; ΔP = 0.0005, ΔΔP = 0.03, ΔΔΔP = 0.004 for comparison with non-irradiated mice. (B) TBI causes a significant decrease in PB B cells (B220+) at increasing dose levels. *P = 0.04, **P = 0.03; AH and PH irradiation decrease PB B cells at 10 Gy, ∧P = 0.03; HL irradiation increases PB B cell content at all doses, #P = 0.003. (C) TBI causes a modest decrease in PB T cells (Thy 1.2+) at 10 Gy; AH, PH and HL irradiation uniformly cause an increase in PB T cells compared to non-irradiated controls, *P = 0.01, **P = 0.04, #P = 0.01, ∧P = 0.01, ∧∧P = 0.04, ∧∧∧P = 0.01. (D) TBI causes no significant change in PB myeloid (Mac-1+) cells; mice irradiated to AH, PH or HL demonstrated an increase in PB myeloid cells at 6 hours, *P = 0.03, ∧P = 0.04, ∧∧P = 0.03, #P = 0.02, ##P = 0.02, ###P = 0.009.

Mentions: Since partial body irradiation produced significantly different PB gene expression profiles compared to TBI, we analyzed PB from partially irradiated versus TBI-mice to determine if changes in PB cell content contributed to these differences. TBI caused a 33% decrease in PB MNCs within 6 hours of exposure (Figure 4), but partial body exposures caused an increase in PB MNCs compared to non-irradiated mice (Figure 4). TBI caused a modest increase in PB Mac-1+ myeloid cells and a modest decrease in Thy1.2+ T cells but both populations doubled in the PB following partial body irradiation to AH or PH. B220+ B lymphocytes decreased by >10-fold in the PB in response to TBI and were predominantly not affected by partial body irradiation. Taken together, these results suggest a model in which TBI causes a rapid and significant shift in the proportion of circulating PB cells which contribute to the PB gene expression profile (myeloid and T cells >>>> B cells) compared to partially irradiated mice. These differences between PB cell content in TBI- and partial body irradiated-mice may be explained, in part, by the generalized mobilization of hematopoietic cell subsets which occurs following partial body irradiation [21]. Since AH irradiation spares both femurs and PH irradiation spares the hematopoietic spleen, it is not surprising that mice irradiated to AH or PH would sustain PB cell counts whereas TBI-treated mice would not. These differences in PB cell content may also reflect the capacity for BM progenitor cells to mobilize into the PB in response to injury at distant anatomic sites [21], [22].


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)

Partial body irradiation and TBI cause significantly different changes in PB cell distributions.(A) The mean numbers of PB MNCs are shown in non-irradiated (untreated) mice versus mice irradiated with TBI, AH, PH or HL irradiation. *P = 0.02 for comparison with non-irradiated mice; ∧ P = 0.007, ∧∧P = 0.004, ∧∧∧P = 0.02 for comparison with non-irradiated mice; #P = 0.03, ##P = 0.03, ###P = 0.007 for comparison with non-irradiated mice; ΔP = 0.0005, ΔΔP = 0.03, ΔΔΔP = 0.004 for comparison with non-irradiated mice. (B) TBI causes a significant decrease in PB B cells (B220+) at increasing dose levels. *P = 0.04, **P = 0.03; AH and PH irradiation decrease PB B cells at 10 Gy, ∧P = 0.03; HL irradiation increases PB B cell content at all doses, #P = 0.003. (C) TBI causes a modest decrease in PB T cells (Thy 1.2+) at 10 Gy; AH, PH and HL irradiation uniformly cause an increase in PB T cells compared to non-irradiated controls, *P = 0.01, **P = 0.04, #P = 0.01, ∧P = 0.01, ∧∧P = 0.04, ∧∧∧P = 0.01. (D) TBI causes no significant change in PB myeloid (Mac-1+) cells; mice irradiated to AH, PH or HL demonstrated an increase in PB myeloid cells at 6 hours, *P = 0.03, ∧P = 0.04, ∧∧P = 0.03, #P = 0.02, ##P = 0.02, ###P = 0.009.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2902517&req=5

pone-0011535-g004: Partial body irradiation and TBI cause significantly different changes in PB cell distributions.(A) The mean numbers of PB MNCs are shown in non-irradiated (untreated) mice versus mice irradiated with TBI, AH, PH or HL irradiation. *P = 0.02 for comparison with non-irradiated mice; ∧ P = 0.007, ∧∧P = 0.004, ∧∧∧P = 0.02 for comparison with non-irradiated mice; #P = 0.03, ##P = 0.03, ###P = 0.007 for comparison with non-irradiated mice; ΔP = 0.0005, ΔΔP = 0.03, ΔΔΔP = 0.004 for comparison with non-irradiated mice. (B) TBI causes a significant decrease in PB B cells (B220+) at increasing dose levels. *P = 0.04, **P = 0.03; AH and PH irradiation decrease PB B cells at 10 Gy, ∧P = 0.03; HL irradiation increases PB B cell content at all doses, #P = 0.003. (C) TBI causes a modest decrease in PB T cells (Thy 1.2+) at 10 Gy; AH, PH and HL irradiation uniformly cause an increase in PB T cells compared to non-irradiated controls, *P = 0.01, **P = 0.04, #P = 0.01, ∧P = 0.01, ∧∧P = 0.04, ∧∧∧P = 0.01. (D) TBI causes no significant change in PB myeloid (Mac-1+) cells; mice irradiated to AH, PH or HL demonstrated an increase in PB myeloid cells at 6 hours, *P = 0.03, ∧P = 0.04, ∧∧P = 0.03, #P = 0.02, ##P = 0.02, ###P = 0.009.
Mentions: Since partial body irradiation produced significantly different PB gene expression profiles compared to TBI, we analyzed PB from partially irradiated versus TBI-mice to determine if changes in PB cell content contributed to these differences. TBI caused a 33% decrease in PB MNCs within 6 hours of exposure (Figure 4), but partial body exposures caused an increase in PB MNCs compared to non-irradiated mice (Figure 4). TBI caused a modest increase in PB Mac-1+ myeloid cells and a modest decrease in Thy1.2+ T cells but both populations doubled in the PB following partial body irradiation to AH or PH. B220+ B lymphocytes decreased by >10-fold in the PB in response to TBI and were predominantly not affected by partial body irradiation. Taken together, these results suggest a model in which TBI causes a rapid and significant shift in the proportion of circulating PB cells which contribute to the PB gene expression profile (myeloid and T cells >>>> B cells) compared to partially irradiated mice. These differences between PB cell content in TBI- and partial body irradiated-mice may be explained, in part, by the generalized mobilization of hematopoietic cell subsets which occurs following partial body irradiation [21]. Since AH irradiation spares both femurs and PH irradiation spares the hematopoietic spleen, it is not surprising that mice irradiated to AH or PH would sustain PB cell counts whereas TBI-treated mice would not. These differences in PB cell content may also reflect the capacity for BM progenitor cells to mobilize into the PB in response to injury at distant anatomic sites [21], [22].

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