⁵⁶Fe-ion Exposure Increases the Incidence of Lung and Brain Tumors at a Similar Rate in Male and Female Mice

The main deterrent to long-term space travel is the risk of Radiation Exposure Induced Death (REID). The National Aeronautics and Space Administration (NASA) has adopted Permissible Exposure Levels (PELs) to limit the probability of REID to 3% for the risk of death due to radiation-induced carcinogenesis. The most significant contributor to current REID estimates for astronauts is the risk of lung cancer. Recently updated lung cancer estimates from Japan's atomic bomb survivors showed that the excess relative risk of lung cancer by age 70 is roughly fourfold higher in females compared to males. However, whether sex differences may impact the risk of lung cancer due to exposure to high charge and energy (HZE) radiation is not well studied. Thus, to evaluate the impact of sex differences on the risk of solid cancer development after HZE radiation exposure, we irradiated Rb^fl/fl, Trp53^fl/+ male and female mice infected with Adeno-Cre with various doses of 320 kVp X rays or 600 MeV/n ⁵⁶Fe ions and monitored them for any radiation-induced malignancies. We conducted complete necropsy and histopathology of major organs on 183 male and 157 female mice after following them for 350 days postirradiation. We observed that lung adenomas/carcinomas and esthesioneuroblastomas (ENBs) were the most common primary malignancies in mice exposed to X rays and ⁵⁶Fe ions, respectively. In addition, 1 Gy ⁵⁶Fe-ion exposure compared to X-ray exposure led to a significantly increased incidence of lung adenomas/carcinomas (P = 0.02) and ENBs (P < 0.0001) in mice. However, we did not find a significantly higher incidence of any solid malignancies in female mice as compared to male mice, regardless of radiation quality. Furthermore, gene expression analysis of ENBs suggested a distinct gene expression pattern with similar hallmark pathways altered, such as MYC targets and MTORC1 signaling, in ENBs induced by X rays and ⁵⁶Fe ions. Thus, our data revealed that ⁵⁶Fe-ion exposure significantly accelerated the development of lung adenomas/carcinomas and ENBs compared to X rays, but the rate of solid malignancies was similar between male and female mice, regardless of radiation quality.