Instantaneous dose rate as a crucial factor in reducing mortality and normal tissue toxicities in murine total-body irradiation: a comparative study of dose rate combinations

Abstract

Abstract Purpose The ultra-high dose rate (UHDR) radiation shows promise in eradicating tumors while reducing normal tissue toxicities. However, the biological outcomes of UHDR are influenced by various factors, particularly the mean dose rate and instantaneous dose rate. Additionally, the UHDR response at large field sizes is lacking. This study aimed to explore the impact of different dose rate combinations on gastrointestinal biological outcomes following total-body irradiations (TBI) and to examine the involved molecular signaling pathways. Method Female C57BL6/J mice received 10 Gy TBI using three modes: ultra-high mean and ultra-high instantaneous dose rate irradiation (HH mode), low mean and ultra-high instantaneous dose rate irradiation (LH mode), and low mean and low instantaneous dose rate irradiation (LL mode). Mice were euthanized at 3 h and 48 h post irradiation to assess acute normal tissue damage and perform transcriptome sequencing. Furthermore, a subset of mice was monitored for 30 days to evaluate survival. Results We found that when the instantaneous dose rate is sufficiently high (> 105 Gy/s), both ultra-high or low mean dose rate irradiation reduced mice mortality, myelosuppression, DNA damage, and cell apoptosis. The survival probabilities 30 days after 10 Gy TBI were 4/7, 4/6, and 0/6 in the HH, LH, and LL groups, respectively. Myelosuppression was lower at 3 h and 48 h post HH and LH irradiations than LL irradiation. The better regulated inflammatory response was evident at 48 h post HH and LH irradiation compared to LL irradiation. Additionally, DNA damages and cell apoptosis in the intestinal tissue were significantly reduced after HH and LH irradiations compared to LL irradiation. Transcriptome sequencing of intestinal tissues revealed that HH irradiation activated immune response pathways and suppressed mitochondrial related pathways compared to LL irradiation. Conclusion Our findings underscore the pivotal role of instantaneous dose rate in reducing radiation damages. When the instantaneous dose rate is sufficiently high (> 105 Gy/s), both ultra-high or low mean dose rate irradiation (HH and LH mode) reduced mice mortality, myelosuppression, DNA damage, and cell apoptosis. Understanding these dose rate effects and biological responses are crucial for optimizing radiotherapy strategies and exploring the potential benefits of UHDR irradiation.