Acute Risks of Space Radiation
The space radiation environment consists of highly charged and energetic particles that include high-energy protons released from the sun during solar particle events (SPEs). SPEs that are above 25–30 mega-electron volts (MeV) can penetrate the shielding on the International Space Station (ISS) and present a major challenge for the National Aeronautics and Space Administration (NASA). During long-term deep space missions, it is anticipated that multiple SPEs will be encountered. Such exposures are a significant radiation hazard to astronauts and spacecraft. Indeed, exposure to SPEs may place astronauts at risk for acute radiation sickness (ARS), prodromal effects, skin damage, hematological/immune deficits, and changes in other body compartments. The timing of symptom onset varies with radiation dose, dose rate, quality, and individual sensitivity.
Overview of ARS Following Acute Exposure Due to SPEs
During an SPE, the sun releases a large amount of energetic particles. Although the particle composition varies slightly from event to event, on average these particles consist of 96% protons, 4% helium ions, and a small fraction of heavier ions (Cucinotta 1999; Kim et al. 2009; NCRP 1989; Townsend et al. 1994).
Because SPEs generally have much lower energies than galactic cosmic rays (GCRs), their effects can be greatly mitigated with the proper amount of shielding. However, SPE exposures are sporadic and occur over a relatively short period of time (hours to days) with little warning. Because of their unpredictable nature, an astronaut performing an extravehicular activity (EVA) could receive a debilitating or even fatal dose of radiation if unable to reach shelter in time (NRC 2008). An SPE may result in a whole-body dose up to 2 gray (Gy) with dose rate up to 0.5 Gy/h (Hu et al. 2009; Kennedy 2014). Astronauts on long-duration space missions outside of low Earth orbit (LEO) could be exposed to multiple SPEs of unpredictable magnitudes. Furthermore, an SPE dose may also exacerbate biological effects from the concurrent protracted GCR radiation exposure (Chancellor et al. 2014). Exposure to an SPE poses a critical and acute health risk to astronaut crews and can have a serious impact on all biomedical aspects of space exploration.
Humans who are exposed to gamma- or X-rays at doses above 0.5 Gy are known to experience ARS (Anno et al. 1989). ARS appears in various forms and has different threshold onset doses for biological effects, depending on the cell or tissue type. The threshold whole-body dose for ARS is about 0.1–0.2 Gy for acute exposures (i.e., dose rates >1 Gy/h) (NCRP 1989, 2000, 2006; Wu et al. 2013). While ARS has been well defined for gamma- and X-ray exposures, less is known about the acute effects from whole-body exposures to SPE protons, which are characterized by dynamic changes in energy distribution and dose rates at specific locations in the human body (Wu et al. 2013).
ARS could lead to decrements in crew performance, increasing the risk for partial or total mission failure. Because radiation exposure can affect multiple organs and physiological systems in complex ways, recovery from ARS can be hindered by long-term changes in immune status, skin burns, blood loss, and slower wound healing. Although predicting the biological risks associated with a given radiation dose is a complicated process, many ground-based research models have been utilized in an attempt to better understand and potentially prevent, or at least ameliorate, the acute radiation response (Chancellor et al. 2014).
Gastrointestinal (GI) Tract Damage
The first symptoms of ARS manifest in the GI system, which together with bone marrow are the most sensitive parts of the body (Grammaticos et al. 2013). This will occur within a matter of hours to days (Donnelly et al. 2010). Emesis and retching are known prodromal outcomes which are early symptoms following exposures to high doses of radiation and can be detrimental, especially in the confined environment of an EVA suit. Animal studies performed using a ferret model indicate that retching and vomiting occur at doses as low as 0.5 Gy and can be expected from SPE radiation exposure at doses of 2 Gy (King 1988; Sanzari et al. 2013b). The mechanisms by which radiation induces nausea and vomiting are not well understood. It is known that radiation induces the secretion of serotonin in the GI tract. In turn, the binding of serotonin to receptors in the brain mediates vomiting (Wu et al. 2013).
The GI tract contains over 1012 types of bacteria whose functions include carbohydrate fermentation and absorption, repression of pathogenic microbial growth, metabolic activity, and continuous and dynamic effects on the gut and systemic immune system (Ni et al. 2011). Injury to the intestinal mucosa or impaired host immune defenses promotes the migration of bacteria or bacterial products from the intestinal lumen to extraintestinal sites in a process known as bacteria translocation. Studies show that SPE-like radiation exposure causes bacterial product translocation across the GI tract. Irradiation with 2 Gy of 50 or 70 MeV protons leads to transient increases in immune activation at 1 day postirradiation. This is associated with increases in circulating lipopolysaccharide (LPS), suggesting an increased risk for pathological changes to the GI tract (Kennedy 2014).
Members of the intestinal microbiota are known to modulate the immune system, involving a variety of pro-inflammatory and anti-inflammatory mechanisms (Maier et al. 2014). The prolonged inflammatory responses associated with high oxidative stress are believed to lead to bacteria-associated carcinogenesis. Although this is a relatively new field of study, research has begun on the impact of radiation-induced oxidative stress on intestinal bacterial communities, using both conventional intestinal microbiota (CM) and restricted microbial composition (RM) mouse models. One study shows that high linear energy transfer (LET) radiation, at doses as low as 1 Gy, can cause persistent DNA double-strand breaks and increased oxidative stress in RM mice several weeks after exposure (Maier et al. 2014). Studies have also shown that space-relevant doses of radiation, including low-LET radiation, can have a significant impact on murine colon microbiota and mucosal homeostasis (Ritchie et al. 2015).
Adverse Effects on Hematopoietic Cells/Immune System
Of all physiological systems known to be affected by low-dose radiation, the immune system is, perhaps, the most unique. At the most fundamental level, its primary functions include removal of normally dying cells in the body, surveillance, and host defense. However, various immune cells have also been shown to play critically important roles in a variety of nonimmune-specific functions such as bone turnover, metabolism, and behavior. Indeed, immune populations are mobile and distributed throughout all organ systems and tissues. Furthermore, immunocytes tend to be highly radiosensitive compared to most other cell types. This means that even low doses of radiation could result in a systemic response mediated at least partly by immune populations.
Previous work by our group and others has shown that the spaceflight environment as a whole can have a dramatic influence on immunity. Virtually all immune populations are reduced after spaceflight (Baqai et al. 2009; Gridley et al. 2003; Pecaut et al. 2003). Studies in both animal models and humans have shown that the spaceflight environment can influence total body, thymus and spleen mass (Baqai et al. 2009; Gridley et al. 2013b; Pecaut et al. 2000), mitogen-induced proliferation, cytokine production and reactivity (Baqai et al. 2009; Crucian et al. 2011, 2013), and leukocyte subpopulation distributions (Crucian et al. 2013; Pecaut et al. 2000; Stowe et al. 2011).
Important immune organs such as the spleen and thymus are radiosensitive at spaceflight-relevant doses, and changes in organ weights can be considered general indicators of overall immune status. Organ weights are typically reduced in mice 4 days after 1.7–2 Gy low-LET protons for both acute exposures (Luo-Owen et al. 2012) and chronic, 36 h “simulated SPE” (sSPE) exposures (Gridley et al. 2008b, 2010). However, these decreases are not noted after doses below 1.5 Gy, nor are they evident 17–21 days after exposure (Gridley et al. 2008b, 2010; Luo-Owen et al. 2012; Rizvi et al. 2011). For higher LET exposures, spleen and thymus mass generally decrease 4 days after exposure to 0.5 Gy 56Fe, though not always to the level of statistical significance (Gridley et al. 2002b; Pecaut et al. 2006; Pecaut and Gridley 2010). This decrease is no longer present at 30 days (Pecaut and Gridley 2010).
Similarly, changes in total circulating and spleen white blood cell (WBC) counts are indicators of overall immune health. Lower counts generally mean a reduced ability to respond to an immune challenge. As with organ masses, WBC counts decrease 4 days after 0.5–2 Gy protons (Gridley et al. 2002a, 2008b; Luo-Owen et al. 2012; Sanzari et al. 2013a) or 1–4 days after 1.7–2 Gy sSPE (Gridley et al. 2008b, 2010; Romero-Weaver et al. 2014; Sanzari et al. 2014). For the higher, 1.7–2 Gy dose range, WBC counts are generally still reduced 17–21 days after exposure (Gridley et al. 2008b, 2010, 2013c; Luo-Owen et al. 2012; Romero-Weaver et al. 2014), but not always (Sanzari et al. 2013a). In contrast, there are no significant differences for any major leukocyte population in either compartment 0, 4, or 21 days after a chronic, up to 2-week exposure to low-dose protons (0.01–0.1 Gy) (Gridley et al. 2009). For higher LET radiation, WBC counts generally decrease 4 days after exposure to up to 0.5 Gy 56Fe (Gridley et al. 2002b; Pecaut et al. 2006; Pecaut and Gridley 2010), but are no longer different from controls by day 30 (Pecaut and Gridley 2010).
Spontaneous blastogenesis is a measure of the proliferative status of immune populations. Increases in this measure are generally associated with an overall activation of the immune system or a recovery response due to a loss of immune cells. The decreases in cell counts noted above are generally coincident with increased spontaneous blastogenesis in both blood and spleen 4 days after an acute 2 Gy proton exposure (Gridley et al. 2008b; Luo-Owen et al. 2012) and 2 Gy sSPE (Gridley et al. 2008b) but not 0.01–1.5 Gy (Gridley et al. 2009; Pecaut et al. 2002). This enhanced spontaneous blastogenesis is still present in splenocytes isolated from mice 17 days after exposure to 2 Gy protons (Luo-Owen et al. 2012), but absent in both compartments by day 21 for both acute and chronic exposures (Gridley et al. 2008b, 2009). Interestingly, despite decreases in cell counts, this measure is not significantly changed in leukocytes isolated from either the blood or spleen 4–30 days after 0.5 Gy 56Fe (Gridley et al. 2002b, 2006; Pecaut and Gridley 2010).
There are two major branches of the immune system: innate and adaptive. Describing how spaceflight-relevant radiation impacts immune function depends largely on which branch is being discussed.
The innate immune system includes monocytes/macrophages (MΦ), neutrophils, and natural killer (NK) cells. These populations are the “first responders” in the event of an infection or tissue damage, and their responses are fairly nonspecific. As part of their normal response to infection or damaged tissues, these cells produce and release a variety of cytokines, enzymes, and reactive oxygen/nitrogen species to eliminate infectious agents and clear out damaged or dying cells. As many of these reactive species are identical to those generated by radiation, these populations tend to be more radioresistant compared to other immune phenotypes.
Blood and spleen ΜΦ counts are low 4 days after proton doses of 1.5–2 Gy, regardless of dose rate (Gridley et al. 2002a, 2008b, 2010; Luo-Owen et al. 2012). Although there are no differences in circulating granulocyte counts 1–4 days after up to 1.5 Gy protons (Gridley et al. 2002a; Sanzari et al. 2014), these counts decrease in both blood and spleen 4 days after 2 Gy (Gridley et al. 2008b; Luo-Owen et al. 2012; Romero-Weaver et al. 2014). While decreases in both of these populations are typically no longer evident 17–21 days after exposure (Gridley et al. 2008b, 2010; Luo-Owen et al. 2012), there is at least one report of reductions in granulocyte counts up to 18 days post-2 Gy sSPE (Romero-Weaver et al. 2014). In contrast, lower, chronic exposures (e.g., 2-week exposure to 0.01–0.1 Gy protons) do not appear to have any impact on the counts of either of these populations in either compartment at 0, 4, or 21 days (Gridley et al. 2009).
Similarly, for higher LET exposures, blood and splenic granulocyte and MΦ counts do not change significantly 4–30 days after up to 0.5 Gy 56Fe (Gridley et al. 2002b; Pecaut et al. 2006; Pecaut and Gridley 2010). Nor are there any changes in certain types of MΦ or granulocytes in either the blood or spleen 4 days after up to 0.5 Gy 56Fe (Gridley et al. 2006; Pecaut and Gridley 2010).
Finally, there are no consistent changes in NK cell counts in either the blood or spleen 4–21 days after exposure up to 2 Gy protons, regardless of dose rate (Gridley et al. 2002a, 2008b, 2009; Luo-Owen et al. 2012). Similarly, there are no changes in NK cell counts in either the blood or spleen 4 days after exposure to up to 0.5 Gy 56Fe (Gridley et al. 2002b; Pecaut et al. 2006).
Immunocytes involved in adaptive immunity include T and B lymphocytes. Tasked with eliminating damaged/mutated cells (e.g., due to viruses or carcinogenesis) or invading pathogens (e.g., bacteria), responses involving these cells tend to be far more specific compared to innate responses. Furthermore, T and B cells are major components of immunological memory. Of all immune cell types, T and B cells tend to be the most radiosensitive.
With acute exposures, there are slight decreases in total lymphocyte counts in the blood 1 day after 0.1–2 Gy protons, but this does not always reach the level of statistical significance (Gridley and Pecaut 2011; Sanzari et al. 2014). However, by day 4, total blood and splenic lymphocyte counts are reduced after 0.5–2 Gy protons for both acute and sSPE exposures (Gridley et al. 2002a, 2008b, 2010; Luo-Owen et al. 2012; Romero-Weaver et al. 2014). Furthermore, slight decreases are still present in both compartments 17–30 days postexposure, though not always large enough to reach statistical significance (Gridley et al. 2008b, 2010, 2013c; Gridley and Pecaut 2011; Luo-Owen et al. 2012; Romero-Weaver et al. 2014). Chronic, very low-dose proton exposures do not appear to have a great impact on lymphocyte counts in either compartment 0, 4, or 21 days after a 2-week exposure to 0.01–0.1 Gy (Gridley et al. 2009). For higher LET radiation, lymphocyte counts decrease in both the blood and spleen 4 days after 0.5 Gy 56Fe (Gridley et al. 2002b; Pecaut et al. 2006).
Within the lymphocyte subsets, both T and B cell counts are generally reduced in both the blood and spleen 4 days after irradiation with 0.5–2 Gy protons (Gridley et al. 2002a, 2008b; Luo-Owen et al. 2012; Sanzari et al. 2013a, 2013c) or 1.7–2 Gy sSPE (Gridley et al. 2008b, 2010). For acute exposures to 2 Gy protons (but not a 1.7 Gy sSPE), counts remain low for these populations in the spleen through day 17 (Luo-Owen et al. 2012), recovering in both compartments by day 21 (Gridley et al. 2008b, 2010). While B cell counts are generally reduced in both compartments 4 days after exposure to 0.5 Gy 56Fe, this reaches the level of significance only in the blood (Gridley et al. 2002b; Pecaut et al. 2006).
Similarly, while slightly decreased, T cell counts are not significantly different in blood and spleen 4 days after irradiation with 0.5 Gy 56Fe (Gridley et al. 2002b; Pecaut et al. 2006). Nor are there any significant differences in activated T cell counts (CD3+/CD71+ or CD3+/CD25+) in either the spleen or bone marrow (Gridley et al. 2006).
Within the T cell subsets, T-helper (Th) cell counts are reduced in both compartments 4 days after acute exposures to 1.5–2 Gy protons (Gridley et al. 2002a, 2008b; Luo-Owen et al. 2012). This decrease is also typically present after 1.7–2 Gy sSPE (Gridley et al. 2008b, 2010). With cytotoxic T cell (Tc) counts, there are no significant changes in either compartment 0, 4, or 21 days after 0.01–0.1 Gy low-dose-rate exposures (Gridley et al. 2009). However, there are reductions after acute exposures to 0.5–2 Gy protons (Gridley et al. 2002a; Luo-Owen et al. 2012). While the decreases in both of these populations are still evident in both compartments 17–21 days postexposure, the changes are not always significant (Gridley et al. 2008b, 2010; Luo-Owen et al. 2012). There are no significant effects on Th or Tc cell counts in either compartment 4 days after 0.5 Gy 56Fe (Gridley et al. 2002b; Pecaut et al. 2006).
In addition to overall cell survival, radiation can also impact the function of surviving cell populations. One way to examine changes in function is to activate certain immune populations with mitogens. For example, phytohemagglutinin (PHA) and concanavalin A (ConA) are mitogens that are commonly used to assess T cell proliferative capacity and cytokine production. LPS is a mitogen used to assess immune cell response to Gram-negative bacteria. Interestingly, PHA-, ConA-, and LPS-induced blastogenesis are not significantly different in splenocytes isolated from mice 4 days after up to 1.5 Gy protons (Pecaut et al. 2002). Similarly, none of these parameters are affected in mice 4 days after 0.5 Gy 56Fe (Gridley et al. 2002b, 2006; Pecaut and Gridley 2010), nor are there any differences at 30 days (Pecaut and Gridley 2010).
Another way to assess function is to look at the ability of cells to produce pro- and anti-inflammatory cytokines in response to activation. Cytokines are how the various immune populations communicate among themselves and with other cells/tissues. Stimulation with antibodies that bind to CD3/CD28 (surface receptors on T cells) is often used to assess T cell function in this way. There are significant differences in the ability to secrete interleukin-2 (IL-2), but not several other cytokines, in splenocytes isolated from mice 4 days after exposure to 2 Gy protons and then activated with antibodies against these surface receptors. There are no significant changes in any of the quantified cytokines 17 days after exposure (Luo-Owen et al. 2012).
Similarly, there are no significant differences in splenocytes stimulated with anti-CD3 alone in IL-2 and two other cytokines at 21 days after a 2 Gy sSPE (Gridley et al. 2013c; Rizvi et al. 2011). However, anti-CD3 stimulated the production of eight additional cytokines (Gridley et al. 2013c; Rizvi et al. 2011), while two others are decreased (Rizvi et al. 2011) at this time point. Overall this indicates that radiation can modify the expression patterns of numerous cytokines.
Adverse Effect on Liver
The liver has long been known for activities such as detoxification of drugs, regulation of glycogen storage, and synthesis of digestive biochemicals. Much more recently it has been recognized as an important immunological organ in which lymphocytes and antigen-presenting cells reside (Racanelli and Rehermann 2006). The liver is also of interest because it functions in innate immunity via production of complement and acute-phase proteins that enhance phagocytosis of microbes. Suboptimal function could increase risk for serious infections. Studies of crew members on shuttle missions and the MIR space station find depressed protein synthesis in plasma (Stein et al. 2000; Stein and Schluter 2006) and high IL-6 level in urine (Stein and Schluter 1994), indicating a spaceflight effect on the liver. Liver abnormalities have also been reported in rodents subjected to spaceflight (Gridley et al. 2012; Grindeland 1990; Jonscher et al. 2015).
Although specific underlying factors responsible for the abnormalities remain elusive, radiation is likely to be a major contributor. In a study of livers from mice irradiated with low-dose/low-dose-rate (LDR) γ-rays (0.01 Gy at 0.03 cGy/h), with and without subsequent exposure to acute 2 Gy proton or gamma radiation, numerous differences are noted in apoptosis-related genes and oxygen radical production on day 56 postexposure compared to nonirradiated controls, as well as among the various radiation regimens (Gridley et al. 2013a). This study also reveals gene expression differences between acute radiation alone and LDR preexposure combined with acute radiation.
These and other findings led to the evaluation of liver status using sSPE (Gridley et al. 2008a). In this study, C57BL/6 mice are whole-body irradiated with 2 Gy sSPE protons over 36 h, both with and without preexposure to LDR photons (57Co, 0.049 Gy total at 0.024 cGy/h). Livers collected immediately after irradiation (day 0) and on day 21 are analyzed for 84 oxidative stress-related genes. Some significantly upregulated (>twofold) and downregulated genes are noted on day 0. However, a much greater effect is noted by day 21, and exposure to LDR photons + sSPE upregulated completely different genes than those upregulated after either LDR photons or sSPE alone. There are many downregulated genes in all irradiated groups, with very little overlap among groups. This study also shows that oxygen radical production by phagocytic cells in the liver is significantly enhanced by LDR photons on day 21.
Damage in Lungs
Studies performed as part of the NASA Spacelab series of missions found that pulmonary function in astronauts is greatly altered, e.g., increased diffusing capacity and reduced residual volume are among the changes noted (West et al. 1997). A study of lung tissue from mice collected within a few hours after returning from a 13-day space shuttle mission (STS-118) found that spaceflight leads to significant changes in extracellular matrix (ECM), cell adhesion, and pro-fibrotic molecules (Tian et al. 2010). Genetic and apoptotic changes are also noted in the lungs of mice shortly after return from another 13-day mission in space (STS-135) (Gridley et al. 2015).
Although the primary emphasis on pulmonary function has been related to microgravity effects (Prisk 2014), other factors such as radiation and inhalation of potentially pathogenic microbes could compromise the function of this vital organ. An in vitro study using rat lung epithelial cells exposed to high-energy (250 MeV) protons at doses ranging from 0.1 to 4 Gy shows significant dose-dependent activation of reactive oxygen species (ROS), repression of antioxidants glutathione and superoxide dismutase, and increasing activities of apoptosis-related genes with corresponding increases in DNA fragmentation (Baluchamy et al. 2010).
Ionizing radiation is well known to cause acute inflammation that can sometimes progress to pulmonary fibrosis that is very difficult to control. A mouse lung study has been conducted comparing effects of total-body irradiation with acute 2 Gy protons versus photons, both with and without preexposure to 0.01 LDR γ-rays at 0.03 cGy/h (Tian et al. 2011). The data on days 21 and 56 shows numerous radiation-induced changes compared to 0 Gy in expression of genes involved in stem cell differentiation and regulation, increased Clara cell secretory protein, and high number of alveolar type 2 cells positive for prosurfactant protein C. Many differences are also noted among the various radiation regimens and time points.
Lung response after whole-body irradiation with sSPE protons has been compared to response after acutely delivered protons and photons (Tian et al. 2009). In this study total dose is 2 Gy. However, the sSPE group is irradiated over 36 h; acute protons and photons (57Co γ-rays) are delivered at 0.9 Gy/min and 0.7 Gy/min, respectively. Lung tissue is collected on days 4 and 21 postirradiation and has been assessed using real-time polymerase chain reaction (RT-PCR) and histological and immunohistochemical (IHC) techniques. The most striking findings are (a) upregulation of transforming growth factor-β1 (TGF-β1) by sSPE and photons, but not protons, at both time points, (b) matrix metalloproteinase 2 (MMP-2) enhancement by sSPE and photons, (c) upregulation of tissue inhibitor of metalloproteinase 1 (TIMP-1) by photons at both times, and (d) more collagen accumulation after exposure to either sSPE or photons than after exposure to protons.
In a mouse study that combined 2 Gy SPE-like radiation with hindlimb suspension to model both the radiation and microgravity components of the spaceflight environment, investigators reported decreases in the ability to clear a common bacteria, Klebsiella pneumoniae, from the lungs and an increase in morbidity (Li et al. 2014). These results further support the possibility that irradiation during a strong SPE could increase an astronaut’s risk for respiratory tract complications.
The skin is a large organ made up of multiple layers that protect underlying cells and tissues. Injury to the skin can lead to infection, entry of allergens, inflammation, and other pathologies (Brandt and Sivaprasad 2011; Proksch et al. 2008). Unstable oxygen radicals that are induced directly by ionizing radiation, as well as by inflammatory cells that migrate to injured sites, can easily damage DNA. The skin is an early responder to environmental insults such as radiation.
One parameter associated with ARS is cutaneous radiation syndrome (CRS). The CRS includes all deterministic effects on the skin and visible parts of the mucosa from ionizing radiation. The intensity and duration of radiation-induced skin symptoms depend on the kind and quality of ionizing radiation. Accidental exposure of the human skin to single doses of ionizing radiation greater than 3 Gy results in a distinct clinical feature, which is characterized by a transient and faint erythema after a few hours and then followed by severe erythema, blistering, and necrosis. Even years and decades after exposure, atrophy of epidermis, sweat and sebaceous glands, telangiectasia, and dermal and subcutaneous fibrosis may be found and even continue to progress (Peter 2013).
Studies on dermal response to radiation have generally employed ultraviolet (UV) radiation that is well known to be a major cause of melanoma and other types of skin cancers (Ayala et al. 2013). However, tissue response to low-dose ionizing radiation in animal models has not been extensively addressed. There is growing interest in studying the biological effects of SPE radiation, particularly when delivered at a low dose, a situation relevant to most environmental exposures (Elmore et al. 2006). Kennedy et al. utilizes mini-pig models to calculate skin effects, for high-dose-rate SPE radiation (Sanzari et al. 2015; Wilson et al. 2011). In the mini-pig, it is demonstrated that high doses of SPE-like radiation result in adverse skin effects. A consequence of this is reduced blood flow to these areas of the dermis. Such areas of reduced blood supply beneath the epidermis occur in interventional radiology patients and are known to be life-threatening (Balter et al. 2010; NCRP 2010). A study on the skin from ICR mice finds numerous differences in oxidative stress/ECM gene expression profiles after exposure to γ-rays at variable doses (0.25–1 Gy) and dose rates (0.5 Gy/h and 0.5 Gy/min) (Mao et al. 2011). A study also finds acute changes in oxidative stress and ECM-associated gene expression and metabolic significance in Space Shuttle Atlantis (STS-135) space-flown mouse skin tissues (Mao et al. 2014). Data demonstrate that spaceflight conditions lead to a shift in biological and metabolic homeostasis as the consequence of increased regulation in cellular antioxidants, ROS production, and tissue remodeling.
The effects of space radiation, which is the number one risk to astronaut health on extended exploration missions, still remain to be fully characterized. Multiple organs and physiological systems could be seriously compromised. It is critical to utilize appropriate ground-based models to understand radiobiological response of these systems and provide information required to define risk from exposure to ionizing radiation during space missions. More in-flight and ground-based studies are also needed to evaluate the impact of low-dose and low-dose-rate radiation on biological systems. Complex “omics” information should be integrated and complemented to physiological endpoint observations. Furthermore, since radiation risk is unavoidable for astronauts, research for suitable countermeasures against adverse biological effects of space radiation, especially for ARS, the most severe form of acute radiation-induced injury, is necessary for success of long-duration space missions.
- Baluchamy S, Ravichandran P, Periyakaruppan A, Ramesh V, Hall JC, Zhang Y, Jejelowo O, Gridley DS, Wu H, Ramesh GT (2010) Induction of cell death through alteration of oxidants and antioxidants in lung epithelial cells exposed to high energy protons. J Biol Chem 285(32):24769–24774. https://doi.org/10.1074/jbc.M110.138099CrossRefGoogle Scholar
- Brandt EB, Sivaprasad U (2011) Th2 cytokines and atopic dermatitis. J Clin Cell Immunol 2(3). https://doi.org/10.4172/2155-9899.1000110
- Grammaticos P, Giannoula E, Fountos GP (2013) Acute radiation syndrome and chronic radiation syndrome. Hell J Nucl Med 16(1):56–59Google Scholar
- Gridley DS, Nelson GA, Peters LL, Kostenuik PJ, Bateman TA, Morony S, Stodieck LS, Lacey DL, Simske SJ, Pecaut MJ (2003) Genetic models in applied physiology: selected contribution: effects of spaceflight on immunity in the C57BL/6 mouse. II. Activation, cytokines, erythrocytes, and platelets. J Appl Physiol 94(5):2095–2103. https://doi.org/10.1152/japplphysiol.01053.2002CrossRefGoogle Scholar
- Gridley DS, Rizvi A, Luo-Owen X, Makinde AY, Coutrakon GB, Koss P, Slater JM, Pecaut MJ (2008b) Variable hematopoietic responses to acute photons, protons and simulated solar particle event protons. In Vivo 22(2):159–169Google Scholar
- Gridley DS, Luo-Owen X, Rizvi A, Makinde AY, Pecaut MJ, Mao XW, Slater JM (2010) Low-dose photon and simulated solar particle event proton effects on Foxp3+ T regulatory cells and other leukocytes. Technol Cancer Res Treat 9(6):637–649. https://doi.org/10.3109/09553002.2012.715792CrossRefGoogle Scholar
- Gridley DS, Mao XW, Tian J, Cao JD, Perez C, Stodieck LS, Ferguson VL, Bateman TA, Pecaut MJ (2015) Genetic and apoptotic changes in lungs of mice flown on the STS-135 mission in space. In Vivo 29:423–433Google Scholar
- Jonscher KR, Alfonso-Garcia A, Suhalim J, Orlicky DJ, Potma EO, Bouxein ML, Bateman TA, Ferguson VL, Stodieck LS, Friedman JE, Gridley DS, Pecaut MJ (2015) Spaceflight activates lipogenic pathways in the liver. PLoS One 11(4):e0152877. https://doi.org/10.1371/journal.pone.0152877CrossRefGoogle Scholar
- NAS/NRC (2008) Space radiation hazards and the vision for space exploration. National Academy Press, Washington. D.C.Google Scholar
- NCRP (1989) NCRP Report 98: guidance on radiation received in space activities. National Council on Radiation Protection and Measurements, BethesdaGoogle Scholar
- NCRP (2000) NCRP report 132: radiation protection guidance for activities in low-earth orbit. National Council on Radiation Protection and Measurements, BethesdaGoogle Scholar
- NCRP (2006) NCRP report 153: information needed to make radiation protection recommendations for space missions beyond low-earth orbit. National Council on Radiation Protection and Measurements, BethesdaGoogle Scholar
- NCRP (2010) NCRP report 167: potential impact of individual genetic susceptibility and previous radiation exposure on radiation risk for astronaut. National Council on Radiation Protection and Measurements, BethesdaGoogle Scholar
- Pecaut MJ, Nelson GA, Peters LL, Kostenuik PJ, Bateman TA, Morony S, Stodieck LS, Lacey DL, Simske SJ, Gridley DS (2003) Genetic models in applied physiology: selected contribution: effects of spaceflight on immunity in the C57BL/6 mouse. I. Immune population distributions. J Appl Physiol 94(5):2085–2094. https://doi.org/10.1152/japplphysiol.01052.2002CrossRefGoogle Scholar
- Pecaut MJ, Dutta-Roy R, Smith AL, Jones TA, Nelson GA, Gridley DS (2006) Acute effects of iron radiation on immunity, part I: population distributions. Radiat Res 165(1):68–77Google Scholar
- Stein TP, Schluter MD (2006) Plasma protein synthesis after spaceflight. Aviat Space Environ Med 77(7):745–748Google Scholar
- Stein TP, Larina IM, Leskiv MJ, Schluter MD (2000). [Protein turnover during and after extended space flight) Aviakosm Ekolog Med 34(3):12–16Google Scholar
- Wilson JM, Sanzari JK, Diffenderfer ES, Yee SS, Seykora JT, Maks C, Ware JH, Litt HI, Reetz JA, McDonough J, Weissman D, Kennedy AR, Cengel KA (2011) Acute biological effects of simulating the whole-body radiation dose distribution from a solar particle event using a porcine model. Radiat Res 176(5):649–659CrossRefGoogle Scholar
- Wu H, Huff JL, Casey R, Kim MH, Cucinotta FA (2013) Evidence report: risk of acute radiation syndromes due to solar particle events. National Aeronautical and Space Agency, Houston. https://humanresearchroadmap.nasa.gov/evidence/reports/ars.pdf
- Cucinotta FA, Kim MH, Chappell LJ, Huff JL (2013) How safe is safe enough? Radiation risk for a human mission to Mars. PLoS One 8:e74988. https://doi.org/10.1371/journal.pone.0074988. eCollection 2013CrossRefGoogle Scholar
- Purgason A, Zhang Y, Hamilton SR, Gridley DS, Sodipe A, Jejelowo O, Ramesh GT, Moreno-Villanueva M, Wu H (2018) Apoptosis and expression of apoptosis-related genes in mouse intestinal tissue after whole-body proton exposure. Mol Cell Biochem 442(1–2):155–168. https://doi.org/10.1007/s11010-017-3200-0CrossRefGoogle Scholar
- Townsend LW, Adams JH, Blattnig SR, Clowdsley MS, Fry DJ, Jun I, McLeod CD, Minow JI, Moore DF, Norbury JW, Norman RB, Reames DV, Schwadron NA, Semones EJ, Singleterry RC, Slaba TC, Werneth CM, Xapsos MA (2018) Solar particle event storm shelter requirements for missions beyond low Earth orbit. Life Sci Space Res (Amst) 17:32–39CrossRefGoogle Scholar