Sex-Specific Responses of Human Hematopoietic Progenitors to Neutron Irradiation

Biological sex is among the most defining traits influencing cellular radiation responses, yet the mechanisms underlying these differences remain poorly characterized. This is particularly true for high linear energy transfer (LET) exposures relevant to deep space travel. Interactions between galactic cosmic radiation and spaceflight hardware can propagate secondary neutrons, a major component of the space radiation risk associated with human travel to the moon and Mars. Radiation-induced damage to the human bone marrow (BM) is a specific concern in space travel, as injury to sensitive hematopoietic stem/progenitor cells (HSPCs) can trigger acute radiation syndrome. We investigated sex-dependent responses of primary human BM-derived HSPCs after exposure to 0.5 Gy of neutrons, modeling the high-LET contributions expected during a Mars-class mission. After radiation exposure, CD34+ HSPCs from male and female donors were cultured in suspension and analyzed by flow cytometry at 48 h, 1 week, and 2 weeks after exposure to capture both acute injury and the regenerative dynamics of the blood system. While acute (48 h) responses were comparable between males and females, male-derived HSPCs exhibited increased sensitivity over time, with a significant reduction in CD34+ progenitor frequencies at 1 week relative to female cells. In addition, cultures from males showed a sustained expansion of CD11b+ myeloid cells compared with untreated controls at both 1 and 2 weeks after irradiation, an effect that was subdued in female cells by week 2. These findings indicate that high-LET exposures may drive sexual dimorphism in HSPC maintenance and lineage commitment. Our study establishes biological sex as a critical factor in human blood and immune cell responses to neutron radiation and underscores the need to incorporate astronaut-specific considerations in countermeasure development for deep space exploration.