Multiple simulated spaceflight stressors impact cardiac fibrosis, calcium dynamics, immune function, cytokines and gene variants in rat, Rattus norvegicus.

Space radiation and microgravity pose significant health risks for astronauts conducting deep space exploration. The impact of galactic cosmic radiation (GCR) and weightlessness alone, and their combined effects on cardiac disease, the immune system, cytokines and calcium dynamics should be understood before undertaking such missions. Male WAG/RijCmcr rats, Rattus norvegicus, 8-9 months old were hind limb unloaded (HLU) to simulate exposure to microgravity for 5 days before, during, and 25 days after whole-body exposure to a simplified GCR simulation (simGCRsim) dose of 1.5 Gy that was administered rapidly. Other rats maintained normal weight-bearing. Exposure to 1.5 Gy of simGCRsim with or without HLU increased cardiac perivascular collagen content, the primary endpoint, compared to sham-irradiated no HLU rats after 270 days. The extent of cardiac fibrosis present in the two irradiated groups could not be distinguished, indicating no interaction between the two space flight stressors. A series of secondary endpoints were also measured. Sham irradiation with HLU increased blood lymphocytes but not myeloid cells compared with non-HLU, an outcome that was inhibited by simGCRsim with HLU, indicating an interaction between spaceflight stressors at this high dose-rate. HLU alone decreased multiple circulating cytokines and depleted CD56+ cells in the spleen. Notably, simGCRsim and HLU alone and in combination did not disrupt calcium homeostasis. An exposure to 1.5 Gy simGCRsim no HLU revealed distinct genomic alterations in circulating nucleated blood cells as compared with sham-irradiated subjects no HLU, and identified mutations, frameshifts, and deletions in genes that contribute to human disease in the irradiated cohort. A limited follow-on study involved exposure to 0.75 Gy simGCRsim with no HLU with appropriate controls. This radiation dose, a dose relevant to human missions to Mars, caused cardiac perivascular fibrosis at an extended follow up period of after 360 days. Taken together, our findings show exposure to simGCRsim, representing the composition of GCR behind spacecraft shielding, caused cardiac perivascular fibrosis and gene variants. Simulated microgravity (HLU) alone engaged the immune system and decreased cytokine production. We conclude that exposure of rats to simGCRsim and/or HLU results in persistent health effects with limited interactions between the two spaceflight stressors.