Positive impact of low-dose, high-energy radiation on bone in partial- and/or full-weightbearing mice

Astronauts traveling beyond low Earth orbit will be exposed to galactic cosmic radiation (GCR); understanding how high energy ionizing radiation modifies the bone response to mechanical unloading is important to assuring crew health. To investigate this, we exposed 4-mo-old female Balb/cBYJ mice to an acute space-relevant dose of 0.5 Gy 56Fe or sham (n = ~8/group); 4 days later, half of the mice were also subjected to a ground-based analog for 1/6 g (partial weightbearing) (G/6) for 21 days. Microcomputed tomography (µ-CT) of the distal femur reveals that 56Fe exposure resulted in 65-78% greater volume and improved microarchitecture of cancellous bone after 21 d compared to sham controls. Radiation also leads to significant increases in three measures of energy absorption at the mid-shaft femur and an increase in stiffness of the L4 vertebra. No significant effects of radiation on bone formation indices are detected; however, G/6 leads to reduced % mineralizing surface on the inner mid-tibial bone surface. In separate groups allowed 21 days of weightbearing recovery from G/6 and/or 56Fe exposure, radiation-exposed mice still exhibit greater bone mass and improved microarchitecture vs. sham control. However, femoral bone energy absorption values are no longer higher in the 56Fe-exposed WB mice vs. sham controls. We provide evidence for persistent positive impacts of high-LET radiation exposure preceding a period of full or partial weightbearing on bone mass and microarchitecture in the distal femur and, for full weightbearing mice only and more transiently, cortical bone energy absorption values

Can Acute Galactic Cosmic Radiation-Induced Bone Loss Be Mitigated By Dietary Modulation Of Inflammatory Cytokines?

The space environment includes weightlessness and galactic cosmic radiation (GCR), both of which can have a negative impact on bone parameters. In particular, acute exposures to space-relevant doses (2 Gy or less) of simulated GCR lead to a rapid acceleration of bone resorption activity and suppression of bone forming osteoblasts, resulting in diminished bone mineral density (BMD), strength and altered microarchitecture. A key mechanism driving these changes may be a radiation-induced increase in pro-inflammatory cytokines, such as TNF-α. Consuming a diet rich in omega-3 fatty acids has been associated with attenuated reductions in bone parameters in astronauts, mice and elderly humans with corresponding reductions in circulating inflammatory cytokines. PURPOSE: To test the hypothesis thata diet high in omega-3 fatty acids will mitigate radiation-induced bone loss and reduce inflammatory cytokines in bone osteocytes and serum. METHODS: Adult (30- to 50-week-old) female Lgr5-EGFP C57BL/6 mice (n=4-6 per group) were acclimated to a corn oil/cellulose (COC) or fish oil/pectin (FOP) diet for 3 weeks. Animals were subsequently randomized to total body low dose high-energy radiation (0.1, 0.25, 0.5 Gy of 1000 MeV/n 56Fe at 25 cGy/min at Brookhaven National Lab) or non-irradiated control (sham) and euthanized 8 weeks later. MicroCT (ScanCo, Switzerland) analyses were performed to assess bone geometry and microarchitecture at the mid-shaft and distal end of the femur. Significance was assessed using an αof 0.10. RESULTS:There was a significant main effect of diet on mid-shaft femur periosteal diameter (Peri.Dm) (p=0.001) and endocortical diameter (Endo. Dm.) (p\u3c0.001). The FOP diet led to larger Peri.Dm. (p\u3c0.051 for all) and Endo.Dm. (p\u3c0.41 for all) than did the COC diet at all doses. We could not detect an impact of 56Fe on cortical area or cancellous bone volume at the distal femur. Irradiation with 0.25 and 0.5 Gy in the FOP mice showed significant increases in distal femur volumetric BMD (p=0.014, p=0.063) and trabecular thickness (p=0.058, p=0.028), as compared with sham FOP mice. CONCLUSION: Though we did not detect a significant impact of radiation on bone parameters, these early data analyses suggest some modest benefits from a diet high in omega-3 fatty acids on cortical and cancellous bone parameters

Skeletal Impacts of Continuous Low-Dose-Rate Gamma Radiation Exposure During Simulated Microgravity

One of the greatest unknowns in human spaceflight is the effects of low-dose-rate galactic cosmic radiation (GCR). The majority of radiation studies deliver the total radiation dose expected on a 2-3 year mission in minutes. However, timing of radiation delivery is known to be biologically relevant. Very few studies have attempted to assess an appropriate timing, or doserate, of GCR exposure. We tested the effects of continuous low-dose-rate radiation (CIRR, dose rate of 6.25 mGy/day for 28 days) in combination with a slightly interrupted hindlimb unloading (iHU), simulated microgravity, and exercise treatments. CIRR alone led to few changes compared to the non-irradiated group. CIRR+iHU led to reductions in total body bone mineral density, lean mass, fat mass, cancellous bone volume and microarchitecture, and femoral neck ultimate load. Although exercise led to improvements in bone mass it was not able to mitigate losses when combined with CIRR and iHU. This indicates a differential response of bone to CIRR in combination with iHU. CIRR may not be detrimental to bone alone but further study is needed to understand the negative effects during iHU, which may not be rescuable by exercise. In the second experiment, we sought to assess how aging may affect the response to CIRR and HU in adult and middle-aged (astronaut aged) mice. Astronaut aged animals responded differently to CIRR and HU alone compared to adult animals. CIRR+HU diminished bone parameters beyond HU alone in both ages. Finally we conclude that young, skeletally mature animals may not be a good model for middle-aged crew members. Our results show that CIRR alone is not detrimental to bone, unlike what is normally found with acute radiation. Care on future missions should be taken to counter the combined detrimental effect of CIRR and unloading on bone. Our findings in different ages of mice suggest that the response to the combination of unloading and CIRR is conserved regardless of age and is therefore a continued life-long concern. The effects of space relevant radiation on bone continue to be a concern for future spaceflight missions, especially exploration class missions to the moon and Mars

Skeletal Impacts of Continuous Low-Dose-Rate Gamma Radiation Exposure During Simulated Microgravity

One of the greatest unknowns in human spaceflight is the effects of low-dose-rate galactic cosmic radiation (GCR). The majority of radiation studies deliver the total radiation dose expected on a 2-3 year mission in minutes. However, timing of radiation delivery is known to be biologically relevant. Very few studies have attempted to assess an appropriate timing, or doserate, of GCR exposure. We tested the effects of continuous low-dose-rate radiation (CIRR, dose rate of 6.25 mGy/day for 28 days) in combination with a slightly interrupted hindlimb unloading (iHU), simulated microgravity, and exercise treatments. CIRR alone led to few changes compared to the non-irradiated group. CIRR+iHU led to reductions in total body bone mineral density, lean mass, fat mass, cancellous bone volume and microarchitecture, and femoral neck ultimate load. Although exercise led to improvements in bone mass it was not able to mitigate losses when combined with CIRR and iHU. This indicates a differential response of bone to CIRR in combination with iHU. CIRR may not be detrimental to bone alone but further study is needed to understand the negative effects during iHU, which may not be rescuable by exercise. In the second experiment, we sought to assess how aging may affect the response to CIRR and HU in adult and middle-aged (astronaut aged) mice. Astronaut aged animals responded differently to CIRR and HU alone compared to adult animals. CIRR+HU diminished bone parameters beyond HU alone in both ages. Finally we conclude that young, skeletally mature animals may not be a good model for middle-aged crew members. Our results show that CIRR alone is not detrimental to bone, unlike what is normally found with acute radiation. Care on future missions should be taken to counter the combined detrimental effect of CIRR and unloading on bone. Our findings in different ages of mice suggest that the response to the combination of unloading and CIRR is conserved regardless of age and is therefore a continued life-long concern. The effects of space relevant radiation on bone continue to be a concern for future spaceflight missions, especially exploration class missions to the moon and Mars