Abstract
Exposure of individuals to ionizing radiation (IR), as in the case of astronauts exploring space or radiotherapy cancer patients, increases their risk of developing secondary cancers and other health-related problems. Bone marrow (BM), the site in the body where hematopoietic stem cell (HSC) self-renewal and differentiation to mature blood cells occurs, is extremely sensitive to low-dose IR, including irradiation by high-charge and high-energy particles. Low-dose IR induces DNA damage and persistent oxidative stress in the BM hematopoietic cells. Inefficient DNA repair processes in HSC and early hematopoietic progenitors can lead to an accumulation of mutations whereas long-lasting oxidative stress can impair hematopoiesis itself, thereby causing long-term damage to hematopoietic cells in the BM niche. We report here that low-dose 1H- and 56Fe-IR significantly decreased the hematopoietic early and late multipotent progenitor (E- and L-MPP, respectively) cell numbers in mouse BM over a period of up to 10 months after exposure. Both 1H- and 56Fe-IR increased the expression of pluripotent stem cell markers Sox2, Nanog, and Oct4 in L-MPPs and 10 months post-IR exposure. We postulate that low doses of 1H- and 56Fe-IR may induce endogenous cellular reprogramming of BM hematopoietic progenitor cells to assume a more primitive pluripotent phenotype and that IR-induced oxidative DNA damage may lead to mutations in these BM progenitors. This could then be propagated to successive cell lineages. Persistent impairment of BM progenitor cell populations can disrupt hematopoietic homeostasis and lead to hematologic disorders, and these findings warrant further mechanistic studies into the effects of low-dose IR on the functional capacity of BM-derived hematopoietic cells including their self-renewal and pluripotency.
Highlights
Exposure to ionizing radiation (IR), high-energy protons (1H) and ions with high charge and high energy (HZE particles), is one of the major risks during spaceflight beyond low Earth orbit (LEO) [1, 2]
Such clustered DNA damage caused by high-linear energy transfer (LET) radiation can lead to double strand breaks (DSBs) in DNA and mutations in the absence of proper DNA repair processes [18]
It should be noted that cells within the bone marrow (BM) often exhibit low levels of expression of many DNA repair proteins, suggesting they may have an inherent inability to repair DNA damage induced by radiation, and are at increased risk of mutations [20]
Summary
Exposure to ionizing radiation (IR), high-energy protons (1H) and ions with high charge and high energy (HZE particles), is one of the major risks during spaceflight beyond low Earth orbit (LEO) [1, 2]. Venturing beyond the van Allen belt and into deep space, astronauts will encounter a significant amount of galactic cosmic radiation which contains high-energy 1H and alpha particles and high-LET radiation from HZE particles, such as 56Fe and 28Si [4] These high-LET HZE ions have a greater propensity for ionization and they deposit large amounts of energy along their tracks; and have greater potential for causing damage to tissues. A single high dose of radiation may induce significant tissue and cell damage; the biological effects of low-dose IR may be more relevant in disease processes, owing to IR-induced aberrations at the genetic or epigenetic levels. Studying the biological consequences of these types of radiation is of significance for understanding the consequences of both space missions and cancer therapy regimens
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