Dose and LET-dependence of gastric cancer risk in Apc^1638N/+ mice exposed to space-relevant radiation types

Exposure to high-linear energy transfer (LET) heavy ions (Z > 2) present in galactic cosmic radiation (GCR) is predicted to pose a significant but uncertain risk of gastric (stomach) cancer among astronauts. Uncertainties in current risk estimate models are primarily attributed to the lack of in vivo radiobiological data on dose- and LET-responses of high-LET heavy-ions. To address this gap, we investigated dose- and LET-dependent gastric tumorigenesis in male Apc^1638N/+ mice following exposure to γ rays and ²⁸Si ions (69 keV/μm) at doses of 5, 10, and 50 cGy. Additionally, a separate cohort of mice were exposed to 10 cGy of ⁴He (1.6 keV/μm), ⁵⁶Fe (148 keV/μm), and 50 cGy of sequentially delivered 4-ions (60 % ¹H, 20 % ⁴He, 10 % ¹⁶O, and 10 % ²⁸Si ions) GCR simulation (GCRsim). Animals were euthanized at 5 months post-exposure and formalin-fixed hematoxylin and eosin-stained gastric tissues sections were used for tumor counting as well as for carcinoma identification. Both γ and ²⁸Si induced a dose-dependent increase in tumor burden, with ²⁸Si producing a more pronounced tumorigenic and carcinogenic response. Additionally, the relative risk of carcinoma in the 50 cGy GCRsim group was 12.25, that far exceed the relative risk of 3.5 noted after 50 cGy γ radiation. Further we demonstrate exposure to 69 keV/μm ²⁸Si-ion radiation as a more potent driver of gastric tumorigenesis exceeding those of both γ (∼0.2 keV/μm) and 148 keV/μm ⁵⁶Fe-ion radiation, suggesting a non-linear response. These findings underscore the potentially disproportionate biological impact of intermediate high-LET ions, such as ²⁸Si, within the complex GCR environment.