Simulated Microgravity and Low-Dose/Low-Dose-Rate Radiation Induces Oxidative Damage in the Mouse Brain

Abstract

Microgravity and radiation are stressors unique to the spaceflight environment that can have an impact on the central nervous system (CNS). These stressors could potentially lead to significant health risks to astronauts, both acutely during the course of a mission or chronically, leading to long-term, post-mission decrements in quality of life. The CNS is sensitive to oxidative injury due to high concentrations of oxidizable, unsaturated lipids and low levels of antioxidant defenses. The purpose of this study was to evaluate oxidative damage in the brain cortex and hippocampus in a ground-based model for spaceflight, which includes prolonged unloading and low-dose radiation. Whole-body low-dose/low-dose-rate (LDR) gamma radiation using (57)Co plates (0.04 Gy at 0.01 cGy/h) was delivered to 6 months old, mature, female C57BL/6 mice (n = 4-6/group) to simulate the radiation component. Anti-orthostatic tail suspension was used to model the unloading, fluid shift and physiological stress aspects of the microgravity component. Mice were hindlimb suspended and/or irradiated for 21 days. Brains were isolated 7 days or 9 months after irradiation and hindlimb unloading (HLU) for characterization of oxidative stress markers and microvessel changes. The level of 4-hydroxynonenal (4-HNE) protein, an oxidative specific marker for lipid peroxidation, was significantly elevated in the cortex and hippocampus after LDR + HLU compared to controls (P < 0.05). The combination group also had the highest level of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression compared to controls (P < 0.05). There was a significant decrease in superoxide dismutase (SOD) expression in the animals that received HLU only or combined LDR + HLU compared to control (P < 0.05). In addition, 9 months after LDR and HLU exposure, microvessel densities were the lowest in the combination group, compared to age-matched controls in the cortex (P < 0.05). Our data provide the first evidence that prolonged exposure to simulated microgravity and LDR radiation is associated with increased oxidative stress biomarkers that may increase the likelihood of brain injury and reduced antioxidant defense. NOX2-containing nicotinamide adenosine dinucleotide phosphate (NADPH oxidase) may contribute to spaceflight environment-induced oxidative stress.

High Dose Gamma Radiation Selectively Reduces GABAA-slow Inhibition

“…Similarily, a dose-dependent loss of neurons is noticed when looking at both neurogenesis and cellular differentiation of neurons in the hippocampal region of the brain [5]. Also, a study looking at the oxidative damage of brain tissue after a prolonged exposure (21 days before brain tissue isolation) of low-dose (0.04 Gy) radiation exposure observed an increase in oxidative stress biomarkers that could possibly lead to brain injury [6]. In contrast, a more recent histological study has shown that tissue integrity or neuron distribution was not changed a year after irradiation of 45 Gy delivered with 5 Gy fractions twice per week for 4.5 weeks [7].…”

NADPH Oxidase Activation Contributes to Heavy Ion Irradiation–Induced Cell Death

“…29 Similarly, low-dose γ irradiation is capable of upregulating NADPH oxidase in central nervous system in mice. 30 Increased NADPH oxidase expression is possible sources of increased ROS production mirrored by an increase in DNA damage. Further investigation on the NOX’s activities in endogenous ROS production will help to clarify the additive effects of radiation-induced DNA damage.…”

Effects of low-dose rate γ-irradiation combined with simulated microgravity on markers of oxidative stress, DNA methylation potential, and remodeling in the mouse heart

“…All mice were handled and sacrificed by our co-author, XW Mao, at Loma Linda University under AUP 8130028 in a previous study [31]. All data were obtained from cardiac tissue samples collected from that previous study.…”

“…Furthermore, increased oxidative stress coupled with impairment of antioxidant mechanisms and inflammation have been shown in skeletal muscle following exposure to simulated microgravity [30]. Recently, Mao et al showed that a combined exposure to hindlimb unloading (HU) and low-dose rate γ-radiation may increase oxidative damage and decrease antioxidant protein content in the mouse brain [31]. To be able to model simultaneous HU and exposure to low-dose rate ionizing radiation, Mao et al placed cages of hind-limb unloaded mice onto Co-57 plates that emitted ionizing radiation in the form of γ-rays at an average dose rate of 0.01 cGy/h.…”

“…Since, the combined effects of low-dose rate radiation exposure and microgravity on the heart are largely unknown, the purpose of the current study was to evaluate indicators of oxidative stress and tissue remodeling in cardiac tissue obtained from the mice in the study of Mao et al [31]. …”