Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System.

Joshua Alwood,Luan Tran,Ruth Globus,Akhilesh Kumar,Candice Tahimic,Yasaman Shirazi-Fard,Diane Hilton,Ann-Sofie Schreurs

doi:10.3390/ijms18102117

Joshua Alwood, Luan Tran + Show 6 more

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https://doi.org/10.3390/ijms18102117

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Abstract

Space radiation may pose a risk to skeletal health during subsequent aging. Irradiation acutely stimulates bone remodeling in mice, although the long-term influence of space radiation on bone-forming potential (osteoblastogenesis) and possible adaptive mechanisms are not well understood. We hypothesized that ionizing radiation impairs osteoblastogenesis in an ion-type specific manner, with low doses capable of modulating expression of redox-related genes. 16-weeks old, male, C57BL6/J mice were exposed to low linear-energy-transfer (LET) protons (150 MeV/n) or high-LET 56Fe ions (600 MeV/n) using either low (5 or 10 cGy) or high (50 or 200 cGy) doses at NASA’s Space Radiation Lab. Five weeks or one year after irradiation, tissues were harvested and analyzed by microcomputed tomography for cancellous microarchitecture and cortical geometry. Marrow-derived, adherent cells were grown under osteoblastogenic culture conditions. Cell lysates were analyzed by RT-PCR during the proliferative or mineralizing phase of growth, and differentiation was analyzed by imaging mineralized nodules. As expected, a high dose (200 cGy), but not lower doses, of either 56Fe or protons caused a loss of cancellous bone volume/total volume. Marrow cells produced mineralized nodules ex vivo regardless of radiation type or dose; 56Fe (200 cGy) inhibited osteoblastogenesis by more than 90% (5 weeks and 1 year post-IR). After 5 weeks, irradiation (protons or 56Fe) caused few changes in gene expression levels during osteoblastogenesis, although a high dose 56Fe (200 cGy) increased Catalase and Gadd45. The addition of exogenous superoxide dismutase (SOD) protected marrow-derived osteoprogenitors from the damaging effects of exposure to low-LET (137Cs γ) when irradiated in vitro, but had limited protective effects on high-LET 56Fe-exposed cells. In sum, either protons or 56Fe at a relatively high dose (200 cGy) caused persistent bone loss, whereas only high-LET 56Fe increased redox-related gene expression, albeit to a limited extent, and inhibited osteoblastogenesis. Doses below 50 cGy did not elicit widespread responses in any parameter measured. We conclude that high-LET irradiation at 200 cGy impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss.

Highlights

Structural degradation and oxidative stress following exposure to space radiation potentially endangers skeletal health of astronauts, both during the mission and later in life
For exploration missions into deep space, galactic cosmic-rays (GCR) are of particular concern because of the high-energy and densely ionizing pattern of energy deposition from heavy ions [2,3,4], which can induce oxidative stress [5,6] in various tissues. Both solar particle-emissions (SPE) and GCR contribute to the mixed composition of low-energy radiation, high linear-energy-transfer (LET) particles, and secondary constituents, such as Bremmstrahlung, fragmentation products, and neutrons [4,7]
Taken together with gene expression data, these findings suggest that irradiation induced persistent oxidative stress that impaired colony formation via reduced proliferation leading to lower extent of mineralization

Summary

Introduction

Structural degradation and oxidative stress following exposure to space radiation potentially endangers skeletal health of astronauts, both during the mission and later in life. For exploration missions into deep space, galactic cosmic-rays (GCR) are of particular concern because of the high-energy and densely ionizing pattern of energy deposition from heavy ions [2,3,4], which can induce oxidative stress [5,6] in various tissues. Both solar particle-emissions (SPE) and GCR contribute to the mixed composition of low-energy radiation (such as protons and γ rays), high linear-energy-transfer (LET) particles (such as ionized 56Fe- and 12C-nuclei), and secondary constituents, such as Bremmstrahlung, fragmentation products, and neutrons [4,7]. Risk of exposure-induced death from a fatal cancer drives the NASA astronaut career radiation-exposure limit [10], though NASA is investigating additional risks associated with acute and late tissue degeneration following radiation exposure [11]

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