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Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice.

Chang J, Luo Y, Wang Y, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L - PLoS ONE (2016)

Bottom Line: HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE).Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays.These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage.

View Article: PubMed Central - PubMed

Affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.

ABSTRACT
One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic system from space radiation.

No MeSH data available.


Related in: MedlinePlus

16O TBI causes sustained reduction of HSC clonogenic function.(A–C) At 2 weeks after TBI, BM-MNCs were isolated from irradiated and sham-irradiated (CTL) mice. A CFC assay was performed, and the results are presented as mean CFUs per 1x105 BM-MNCs (n = 5). (D and E) Total BM cells (BMCs) were analyzed by CAFC assays, and the numbers of two and five week CAFCs were expressed as mean ± SD (n = 3 mice per group) per 1x105 BMCs. The statistical significance for the difference between the control group and each of the irradiated groups is indicated by asterisks. *p<0.05, **p<0.01, ***p<0.001 as determined by one-way ANOVA.
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pone.0158097.g003: 16O TBI causes sustained reduction of HSC clonogenic function.(A–C) At 2 weeks after TBI, BM-MNCs were isolated from irradiated and sham-irradiated (CTL) mice. A CFC assay was performed, and the results are presented as mean CFUs per 1x105 BM-MNCs (n = 5). (D and E) Total BM cells (BMCs) were analyzed by CAFC assays, and the numbers of two and five week CAFCs were expressed as mean ± SD (n = 3 mice per group) per 1x105 BMCs. The statistical significance for the difference between the control group and each of the irradiated groups is indicated by asterisks. *p<0.05, **p<0.01, ***p<0.001 as determined by one-way ANOVA.

Mentions: We further examined whether 16O irradiation may not only alter the frequency and number, but also the function of HPCs and HSCs. Firstly, we used a colony forming unit assay and showed that the frequencies of BFU-Es, CFU-GMs, and CFU-GEMMs were significantly reduced in all irradiated mice compared to those in sham-irradiated controls (Fig 3A–3C, p<0.05-p<0.001), indicating that the abilities of hematopoietic progenitor cells (HPCs) to differentiate into granulocytes, erythrocytes, monocytes and/or megakaryocytes were dramatically decreased upon 16O exposure. Hematopoietic stem cells (HSCs) were then analyzed with a CAFC assay, a widely used in vitro surrogate assay of HSC function. The frequencies of functional HSCs at 2- and 5-week CAFCs were significantly lower in irradiated mice, particularly in the 0.25 and 1.0 Gy groups (Fig 3D and 3E, p<0.05-p<0.001). These findings clearly demonstrate that exposure to 16O irradiation causes acute damage to HPCs and HSCs.


Low Doses of Oxygen Ion Irradiation Cause Acute Damage to Hematopoietic Cells in Mice.

Chang J, Luo Y, Wang Y, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L - PLoS ONE (2016)

16O TBI causes sustained reduction of HSC clonogenic function.(A–C) At 2 weeks after TBI, BM-MNCs were isolated from irradiated and sham-irradiated (CTL) mice. A CFC assay was performed, and the results are presented as mean CFUs per 1x105 BM-MNCs (n = 5). (D and E) Total BM cells (BMCs) were analyzed by CAFC assays, and the numbers of two and five week CAFCs were expressed as mean ± SD (n = 3 mice per group) per 1x105 BMCs. The statistical significance for the difference between the control group and each of the irradiated groups is indicated by asterisks. *p<0.05, **p<0.01, ***p<0.001 as determined by one-way ANOVA.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4930193&req=5

pone.0158097.g003: 16O TBI causes sustained reduction of HSC clonogenic function.(A–C) At 2 weeks after TBI, BM-MNCs were isolated from irradiated and sham-irradiated (CTL) mice. A CFC assay was performed, and the results are presented as mean CFUs per 1x105 BM-MNCs (n = 5). (D and E) Total BM cells (BMCs) were analyzed by CAFC assays, and the numbers of two and five week CAFCs were expressed as mean ± SD (n = 3 mice per group) per 1x105 BMCs. The statistical significance for the difference between the control group and each of the irradiated groups is indicated by asterisks. *p<0.05, **p<0.01, ***p<0.001 as determined by one-way ANOVA.
Mentions: We further examined whether 16O irradiation may not only alter the frequency and number, but also the function of HPCs and HSCs. Firstly, we used a colony forming unit assay and showed that the frequencies of BFU-Es, CFU-GMs, and CFU-GEMMs were significantly reduced in all irradiated mice compared to those in sham-irradiated controls (Fig 3A–3C, p<0.05-p<0.001), indicating that the abilities of hematopoietic progenitor cells (HPCs) to differentiate into granulocytes, erythrocytes, monocytes and/or megakaryocytes were dramatically decreased upon 16O exposure. Hematopoietic stem cells (HSCs) were then analyzed with a CAFC assay, a widely used in vitro surrogate assay of HSC function. The frequencies of functional HSCs at 2- and 5-week CAFCs were significantly lower in irradiated mice, particularly in the 0.25 and 1.0 Gy groups (Fig 3D and 3E, p<0.05-p<0.001). These findings clearly demonstrate that exposure to 16O irradiation causes acute damage to HPCs and HSCs.

Bottom Line: HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE).Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays.These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage.

View Article: PubMed Central - PubMed

Affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.

ABSTRACT
One of the major health risks to astronauts is radiation on long-duration space missions. Space radiation from sun and galactic cosmic rays consists primarily of 85% protons, 14% helium nuclei and 1% high-energy high-charge (HZE) particles, such as oxygen (16O), carbon, silicon, and iron ions. HZE particles exhibit dense linear tracks of ionization associated with clustered DNA damage and often high relative biological effectiveness (RBE). Therefore, new knowledge of risks from HZE particle exposures must be obtained. In the present study, we investigated the acute effects of low doses of 16O irradiation on the hematopoietic system. Specifically, we exposed C57BL/6J mice to 0.1, 0.25 and 1.0 Gy whole body 16O (600 MeV/n) irradiation and examined the effects on peripheral blood (PB) cells, and bone marrow (BM) hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) at two weeks after the exposure. The results showed that the numbers of white blood cells, lymphocytes, monocytes, neutrophils and platelets were significantly decreased in PB after exposure to 1.0 Gy, but not to 0.1 or 0.25 Gy. However, both the frequency and number of HPCs and HSCs were reduced in a radiation dose-dependent manner in comparison to un-irradiated controls. Furthermore, HPCs and HSCs from irradiated mice exhibited a significant reduction in clonogenic function determined by the colony-forming and cobblestone area-forming cell assays. These acute adverse effects of 16O irradiation on HSCs coincided with an increased production of reactive oxygen species (ROS), enhanced cell cycle entry of quiescent HSCs, and increased DNA damage. However, none of the 16O exposures induced apoptosis in HSCs. These data suggest that exposure to low doses of 16O irradiation induces acute BM injury in a dose-dependent manner primarily via increasing ROS production, cell cycling, and DNA damage in HSCs. This finding may aid in developing novel strategies in the protection of the hematopoietic system from space radiation.

No MeSH data available.


Related in: MedlinePlus