Sex-specific effects on the heart from combined exposure to simulated galactic cosmic radiation and hindlimb unloading

Future long duration space missions will expose astronauts to higher doses of galactic cosmic radiation (GCR) than those experienced on the international space station. Recent studies have demonstrated astronauts may be at risk for cardiovascular complications due to increased radiation exposure and fluid shift from microgravity. However, there is a lack of direct evidence on how the cardiovascular system is affected by GCR and microgravity since no astronauts have been exposed to exploratory mission relevant GCR doses. Therefore, we utilized a ground-based mouse model to determine the cardiovascular risks for space radiation exposure while the mice were simultaneously hindlimb suspended to mimic microgravity. 6-month-old male and female C57BL/6 mice were exposed to an absorbed dose of 0 Gy, 0.5 Gy, or 1.5 Gy simulated GCR (GCRsim) that comprised beams of 5 ions at NASA's Space Radiation Laboratory. Subcohorts of mice were hindlimb unloaded (HLU), starting 5 days before GCRsim until the completion of radiation exposure. GCRsim + HLU was performed over 8 hours (0.5 Gy) or 24 hours (1.5 Gy). After completion of GCRsim and HLU, mice were shipped to UAMS for long-term observation. Cardiac function was measured using high resolution ultrasound at 6 and 9 months after exposure. Tissues were collected after the final ultrasound and prepared for further analysis. Female mice exposed to 1.5 Gy + HLU demonstrated a significant increase in body weight compared to ground controls months after GCR exposure; however, there was no change in male body weights. Cardiac ultrasound revealed 0.5 Gy GCRsim decreased left ventricular (LV) mass, LV posterior wall thickness in diastole, and systole in males 6 months after exposure. In females, 1.5 Gy + HLU significantly increased LV posterior wall thickness in diastole and systole at 6 months. These changes in ultrasound measurements were no longer seen at 9 months. Moreover, at 9 months there was no change in total collagen content or density of the capillary network in the heart. Lastly, the combination of GCRsim and HLU influenced immune cell markers in the heart of female mice. These data suggest that combined simulated GCR and microgravity result in minor, yet statistically significant sex-dependent changes to body weight and cardiac structure.