Whole-Body Proton Irradiation Causes Long-Term Damage to Hematopoietic Stem Cells in Mice

Abstract

Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80% of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH oxidase 4 (NOX4) mRNA expression and reactive oxygen species (ROS) production. In addition, the increased production of ROS in HSCs was associated with a significant reduction in HSC quiescence and an increase in DNA damage. These findings indicate that exposure to proton radiation can lead to long-term HSC injury, probably in part by radiation-induced oxidative stress.

MMR Deficiency Does Not Sensitize or Compromise the Function of Hematopoietic Stem Cells to Low and High LET Radiation

“…We observed depletion of HSCs 3 months after exposure, as well as decreased repopulation capacity of the remaining stem cells in a competitive transplant assay. Previously, elevated levels of reactive oxygen species correlating with decreased HSCs have been observed at 22 weeks after exposure to proton radiation, in line with our observations here . Added mutational load, which is known to occur with MMR defects and radiation exposure , however, did not exacerbate the latent phenotype, at least regarding HSC function.…”

Radiation Protection and Mitigation by Natural Antioxidants and Flavonoids: Implications to Radiotherapy and Radiation Disasters

“…Moreover, their results showed that inhibition of NOX4 can protect mice similar to a potent radioprotector (N-acetyl cysteine) [19,20]. Other studies confirmed that continuous ROS production through stimulation of redox interactions plays a key role in the development of both early and late effect of IR [21][22][23]. Weyemi et al showed that inactivation of both NOX4 and NOX5 can mitigate ROS production and oxidative DNA damage in irradiated human fibroblast cells [24].…”

Selenium as an adjuvant for modification of radiation response

“…However, after exposure to high doses of ionizing radiation, cells may undergo massive chromosome damage, depending on cell type . Cells with high mitotic activities may undergo higher levels of DNA damage and cell death, while those with low mitosis activities, have a longer time to repair damaged DNA and show a low incidence of cell death . The production of reactive oxygen species (ROS) by ionizing radiation is responsible for two‐thirds of DNA damage immediately after exposure.…”

“…2,16 Cells with high mitotic activities may undergo higher levels of DNA damage and cell death, while those with low mitosis activities, have a longer time to repair damaged DNA and show a low incidence of cell death. [17][18][19][20] The production of reactive oxygen species (ROS) by ionizing radiation is responsible for two-thirds of DNA damage immediately after exposure. However, studies have revealed that high doses of ionizing radiation may stimulate chronic oxidative stress because of endogenous production of ROS and nitric oxide (NO) by macrophages, lymphocytes, as well as some pro-oxidants, such as nicotinamide adenine dinucleotide phosphate oxidase in other cells.…”