Cosmic Radiation and Spaceflight Factors

Besides the radiation environment, microgravity is another important source of potentially detrimental effects during spaceflight. In response to microgravity, several essential cellular functions are impaired, such as signal transduction, gene transfer, and immune response (Moore and Cogoli 1996) (see Chapter 4). Microgravity also affects the physiology of the cardiovascular, respiratory, interstitial, endocrine, immune, and muscular and bone systems in humans (see Hinghofer-Szallcay 1996 and Clement 2005 for review). In addition, spaceflight travelers as well as every organic or inorganic material are subjected to a multitude of factors of various kinds and intensities. These factors are both environmental (e.g., ambient gas medium, temperature, limited space, and cabin microflora) and body internal (e.g., physiological and health status, altered circadian rhythms, emotional stress, and drugs). These different factors rarely act individually. Spaceflight factors that act over extended periods of time, such as microgravity, radiation and those which depend on stay in a closed environment, are of particular interest with respect to combined influences. A potential interaction of radiation and microgravity has been observed in studies involving cell, plant (seeds as well as whole plants), and animal material (insect eggs, larvae, pupae and adults, and rats) (see Horneck 1999 for review).

4.2.1 Definitions

The interaction between two or more factors can be additive, synergistic, antagonistic, or independent. The terms may be more stringently defined in mathematical terms. For example, if a and b are doses of the two agents yielding the same effect if given separately, the effect x (a + b) of the combined action may be as follows (Equations 9 to 12):

Additive: One agent is able to replace the other if the dose scales are appropriately adjusted x (a + b) = x (b + a)

Synergistic: One agent sensitizes the system to the other agent.

Antagonistic: One agent reduces the sensitivity to the other agent.

Independent: Both agents act independently of each other, x (a +b ) = x (a) • x (b)

4.2.2 Methods

Various methods have been applied to disentangle the complex interplay of the parameters of space encountered by humans or any other living being in space. In order to test the influence of microgravity on radiation response, an onboard 1-g centrifuge has been used in parallel, and in some cases in addition, with methods to localize the heavy ions hits in the biological system, e.g., the Biostack concept (see Figure 7-10).

In other experiments, the controlled application of additional radiation during spaceflight was used. This method was first used during Gemini missions, when chromosomal aberrations were studied in human blood cells irradiated with P-rays from 32P. Later on, during the Biosatellite-II mission, plants and insects were irradiated in-flight with relatively high doses from a 85Sr source. The biosatellite Cosmos-690 mission carried an onboard irradiation source (137Cs) to irradiate rats with doses up to 8 Gy. Recently, yeast cells were irradiated in-flight during the Space Shuttle mission STS-84. Biological samples were also irradiated before or after spaceflight. This method was extensively applied during the Cosmos-368, -782 and Salyut missions and in DNA repair studies with cellular systems within the ESA Biorack during the Spacelab missions IML-1, IML-2, and SMM-03.

I 15

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Stage of Development

206 33 151 4

Figure 7-13. Frequency of developmental anomalies observed in larvae of Carausius morosus exposed at different embryonic stages to spaceflight conditions, either in microgravity (¡jg) or in the onboard centrifuge (lg), and analyzed with the Biostack method. Age of eggs during spaceflight: Stage I (16-23 days), Stage II (30-37 days), Stage III (45-52 days). N = number of larvae investigated.

4.2.3 Results

The combined effects of microgravity and individual cosmic ray HZE particles were investigated on embryogenesis and organogenesis of the stick insect Carausius morosus using Biostack and an onboard 1-g centrifuge. The combined influence of an HZE particle hit and microgravity acted synergistically on early embryonic stages of development. Evidences were reduced hatching rate, the presence of body anomalies, such as deformities of abdomen and antennae (Figure 7-13), and an increase in mortality. Malformations were observed in the early development stages of fruit fly Drosophila melanogaster exposed to 85Sr y-rays (up to 14.32 Gy) during spaceflight. In larvae and adults of Drosophila, genetic effects included lethal mutations, visible mutations at specific loci, chromosome translocations, and chromosome non-disjunctions. Synergism of spaceflight factors and radiation was also observed in chromosome translocations and thorax deformations. These effects have been suggested to be due to an increase in chromosome breakage followed by a loss or exchange of genetic information. It has further been suggested that, under conditions of spaceflight, some repair or recovery mechanisms, usually operating on Earth, may fail. From these results it can be concluded that embryonic systems appear to be especially susceptible to a synergistic interaction of radiation and microgravity.

Rats were y-irradiated from an onboard 137Cs source with doses up to 8 Gy on day 10 of the 20-day spaceflight of the biosatellite Cosmos-690 in order to study radiosensitivity and radiation injury under the combined action of ionizing radiation and microgravity. Endpoints under investigation were mortality, changes in mobility, weight, behavior, hemopoietic system, metabolism, muscles, and morpho-histology. For the majority of endpoints studied, the effectiveness of y-radiation in microgravity was similar to that in normal gravity on Earth. However, after irradiation in-flight, the regeneration of the hemopoietic system was remarkably delayed compared to the animals irradiated on the ground. From these experiments, it was inferred that the modifying effects of microgravity on the radiation response of whole animals might be moderate. However, the delayed recovery process observed during the period of re-adaptation to terrestrial conditions might be a point of concern.

4.2.4 Repair Process

It has been conjectured that microgravity might interfere with the operation of some cellular repair processes, thereby resulting in an augmentation of the radiation response (Figure 7-14). Experimental support in favor of this hypothesis has been provided in a space experiment utilizing a temperature-conditional repair mutant of the yeast Saccharomyces cerevisiae in which the extent of repair of DNA Double Strand Breaks (DSBs) was reduced by approximately a factor of two compared to the ground control. However, this observation could not be confirmed in a follow-up experiment.

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Figure 7-14. Time scale of the radiobiological chain of events and possible impairment of DNA repair by microgravity.

Examining several different repair pathways in different unicellular systems that were irradiated prior to the space mission, evidence was provided that cells in the microgravity environment possess almost normal ability to repair radiation-induced DNA damage (Figure 7-15). In this study, the following repair functions were investigated:

a. The kinetics of rejoining of radiation-induced DNA strand breaks in Escherichia coli and human fibroblasts;

b. The induction of the SOS response7 in E. coli;

c. The efficiency of repair in cells of Bacillus subtilis of different repair capacity.

The enzymatic repair reactions were identical in cells that were allowed to repair in microgravity and those in normal gravity (both onboard 1-g centrifuge and corresponding ground controls) (Figure 7-15). Although after being irradiated on ground, the samples were kept inactive (e.g., frozen, as spores, or at a repair-prohibiting temperature) until incubation in space, it

7 The SOS response is the synthesis of a whole set of DNA repair, recombination, and replication proteins in bacteria containing severely damaged DNA, e.g., following exposure to radiation.

cannot be excluded that the very first steps of repair initiation, such as gene activation, already occurred on ground. Therefore, studies on gene activation related to DNA repair require irradiating of cells directly in space.

If however, the synergistic effects of microgravity and radiation in biological systems, which has been observed in several instances, cannot be explained by a disturbance of DNA repair in microgravity, other mechanisms must be considered:

a. At the molecular level, as consequences of a convection-free environment;

b. At the cellular level, as impact on signal transduction, on receptors, on the metabolic/physiological state, on the chromatin, or on the membrane structure;

c. At the tissue and organ level, as modification of self assembly, intercellular communication, cell migration, pattern formation or differentiation.

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Figure 7-15. Repair of radiation-induced DNA damage under microgravity conditions. A: Rejoining of DNA strand breaks in cells of E. coli B/r. B: Rejoining of DNA strand breaks in human fibroblasts. C: Induction of SOS response in cells of E. coli PQ37.

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Figure 7-15. Repair of radiation-induced DNA damage under microgravity conditions. A: Rejoining of DNA strand breaks in cells of E. coli B/r. B: Rejoining of DNA strand breaks in human fibroblasts. C: Induction of SOS response in cells of E. coli PQ37.

60 120 180 240

Incubation Time (min)

60 120 180 240

Incubation Time (min)

Further studies are required to interpret the synergistic effects of microgravity and radiation observed preferentially in embryonic systems, using both an onboard radiation source under well-defined conditions and appropriate controls. These studies can be expected to involve both cellular systems as well as whole organisms including mammals.

As far as radiation protection of astronauts is concerned, it must be kept in mind that several defense mechanisms against radiation damage operate above the cellular level, i.e., on the tissue or immune system level. The established physiological changes brought about by microgravity, in particular in the humoral system, may well modify the response to radiation, especially late response after long-duration missions. So far, this aspect has not been addressed experimentally.

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Figure 7-16. Effective radiation doses measured during LEO and Moon missions.

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