**5. Conclusion**

*Beyond LEO - Human Health Issues for Deep Space Exploration*

HSCs after 16O irradiation exposure.

radiation, which will be tested in our future studies.

space radiation in a mouse model to the human situation.

those findings from animal studies to human.

engraftment capacity and in vitro colony-forming ability using bone marrow cells after radiation. The importance of ROS overproduction on functional HSCs was not only supported under radiation stress condition but also supported by other genetic animal models. Deletion of Foxo3, ATM, TSC1, and Bmi-1 in mice leads to the impairment of numbers and function of HSCs along with increasing ROS production. Application of antioxidants, such as N-acetyl cysteine (NAC), on these mutant mice significantly ameliorated the HSC functional deficiency [71, 94–96]. We have provided data showing 16O-irradiated HSCs had higher levels of ROS production than nonirradiated animals in both acute and long-term studies. It is well accepted that mitochondrial oxidative phosphorylation and NADPH oxidases are two main sources to produce ROS in mammalian cells. Because HSCs reside in hypoxic environmental niche in the bone marrow and have higher expression of HIF1α in response to hypoxia, HSCs produce ROS mainly through glycolysis and NOX enzyme. We have previously shown that proton and γ-ray radiation induced significantly upregulation of NOX4 in irradiated HSCs [53, 66]. The NOX4 inhibitor diphenyliodonium can partially protect functional HSCs from γ-irradiationinduced long-term damage. Therefore, antioxidants, such as NOX4 inhibitors and NAC, should be further tested whether inhibiting ROS production can decrease 16O TBI-induced ROS production to accelerate the functional recovery of HPCs and

Under radiotherapy and chemotherapy stress conditions, dominant HSCs might be activated from quiescent status to provide the need for stressed hematopoietic system. However, frequent HSC activation might cause its loss of self-renewal ability, differentiation, and death with bone marrow failure syndrome [69, 97]. We have shown that proton and γ-irradiation can efficiently activate quiescent HSCs [53, 65], leading to the redistribution of different cell cycle phases and stem cell functional defects. Data from genetic mice models, such as depletion of FOXO3a and Lkb1, showed that HSCs had fast cycling with loss of HSC self-renewal ability and HSC exhaustion [94, 98–100]. There are fewer numbers of HSCs in G0 and higher numbers in G1/G2SM at 2 weeks after 16O TBI [51]. Additionally, we observed that around 15% of irradiated HSCs had more than two γH2AX foci per cell 2 weeks after 16O exposure [51], which is positively correlated with the increased ROS production in 16O TBI HSCs. Taken together, all of ROS production, DNA damage, and HSC cycling after 16O TBI might contribute to HSC defect induced by oxygen

1.Due to the large difference in size between mice and human subjects, the dosedepth distribution in mice exposed to protons is different from that in humans [1]. The dose to the blood-forming tissues in humans will be lower, whereas the dose to the blood-forming tissues in mice is likely very similar to the dose at the surface. This difference in dose-depth profile should be taken into considerations when translating risk of hematopoietic damage in response to

2.During long-term space flight (such as to Mars), astronauts will encounter either a chronic, fractionated dose of space radiation or they will accumulate 1–3 Gy of radiation exposure. Presently, it is impossible to achieve chronic or fractionated doses of space radiation due to the limited access to the facilities capable of producing synthetic space radiation. In most research to date, investigators have used either acute radiation exposure or higher doses of space radiation in animal models. Cautions should therefore be taken when applying

**90**

Note:

In summary, proton and oxygen space radiation have detrimental effects on the hematopoietic system even with at low doses, which will have potential implications for health outcomes during long-duration space missions. Increasing ROS production might be a major mediator on space radiation-induced HSC damage. Knowledge gained from this chapter could aid in planning countermeasure strategies to protect against hematopoietic effects of radiation exposure during space travel. To minimize the health negative effects of deep-space travel, decreasing oxidative stress might be a good approach to mitigate the adverse effects of proton and HZE particle exposure on the hematopoietic system.
