Long Bones Exhibit Adaptive Responses to Chronic Low-Dose-Rate Ionizing Radiation Despite Its Lifespan-Shortening and Carcinogenic Effects on C57BL/6 Mice

Ionizing radiation (IR) is a well-known carcinogen. High-dose-rate (HDR) IR is known to damage long bones (in terms of mass and structure), but the relationships among dose rates (particularly low-dose-rate [LDR] IR), long-bone condition, cancer incidence, and lifespan shortening remain elusive. The aim of this study was to elucidate the effects of LDR-IR on long-bone condition by comparing the long-term consequences of HDR- and LDR-IR exposure in mice. We utilized micro-computed tomography (μCT) scans of the long bones at similar ages (mean 77-96 weeks) to compare mice receiving approximately equivalent total doses of internal LDR-IR or external HDR-IR starting at 4 weeks of age, and their respective control groups. The lifespan-shortening effects of LDR-IR and HDR-IR were similar in these mixed-sex cohorts. Notably, compared to HDR-IR mice, mice internally exposed to chronic LDR-IR with continuous hypohematopoiesis showed a significantly higher trabecular bone connective density [femur: 247% ( = 0.0042), tibia: 169% ( = 0.0005)] and midshaft cortical bone thickness/area (femur: 130% [ = 0.0079]/120% [ = 0.021], tibia: 148% [ = 0.0004]/129% [ = 0.002]). Consistent with this result, when comparing 26-32 weeks post-IR with 2-8 weeks post-IR, compared to HDR-IR-treated mice, LDR-IR-treated mice exhibited higher levels of an osteoblast marker (OPG;  = 0.67 for HDR-IR,  = 0.068 for LDR-IR) and lower levels of an osteoclast marker (CTX-I;  = 0.0079 for HDR-IR,  = 0.72 for LDR-IR) despite significantly higher levels of inflammatory markers (CCL2 and CXCL1;  = 0.36-0.8 for HDR-IR,  = 0.013-0.041 for LDR-IR). These results suggest that long bones under chronic LDR-IR stress may exhibit an adaptive response to stresses such as chronic inflammation associated with IR-induced lifespan shortening. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.