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At least 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
NASA NTRS2003

Fundamental space radiobiology

The unique feature of the space radiation environment is the dominance of high-energy charged particles (HZE or high LET radiation) emitted by the Sun and galactic sources, or trapped in the Van Allen radiation belts. These charged particles present a significant hazard to space flight crews, and accelerator-based experiments are underway to quantify the health risks due to unavoidable radiation exposure. There are three principal properties of charged particles that distinguish them from conventional radiation, i.e. gamma rays and x-rays. First, they have a defined range in matter rather than an exponential absorption profile. Second, they undergo nuclear reactions to produce secondary particles. Third, and most important, they deposit their energy along well-defined linear paths or tracks rather than diffuse fields. The structured energy deposition pattern interacts on multiple scales with the biological structures of DNA, cells and tissues to produce correlated patterns of damage that evade repair systems. Traditional concepts of dose and its associated normalization parameter, RBE (relative biological effectiveness), break down under experimental scrutiny, and probabilistic models of risk based on the number of particle traversals per cell may be more appropriate. Unique patterns of DNA damage, gene expression, mobilization of repair proteins, activation of cytokines and remodeling of cellular microenvironment are observed following exposure to high LET radiation. At low levels of exposure the communication of bioactive substances from irradiated to unirradiated "bystander" cells can amplify the damage and cause a significant deviation from linearity in dose vs. response relations. Under some circumstances, there is even a multigenerational delay in the expression of radiation-induced genetic damage (genomic instability) which is not strictly dose dependent. These issues and the experimental evidence derived from ground based experiments at particle accelerators are presented along with speculation about how modified inertial conditions might perturb homeostatic responses to radiation to further complicate risk assessment for space flight.

NASA Discipline Radiation Health↗
NASA NTRS2002

Shuttle radiation dose measurements in the International Space Station orbits

The International Space Station (ISS) is now a reality with the start of a permanent human presence on board. Radiation presents a serious risk to the health and safety of the astronauts, and there is a clear requirement for estimating their exposures prior to and after flights. Predictions of the dose rate at times other than solar minimum or solar maximum have not been possible, because there has been no method to calculate the trapped-particle spectrum at intermediate times. Over the last few years, a tissue-equivalent proportional counter (TEPC) has been flown at a fixed mid-deck location on board the Space Shuttle in 51.65 degrees inclination flights. These flights have provided data that cover the expected changes in the dose rates due to changes in altitude and changes in solar activity from the solar minimum to the solar maximum of the current 23rd solar cycle. Based on these data, a simple function of the solar deceleration potential has been derived that can be used to predict the galactic cosmic radiation (GCR) dose rates to within +/-10%. For altitudes to be covered by the ISS, the dose rate due to the trapped particles is found to be a power-law function, rho(-2/3), of the atmospheric density, rho. This relationship can be used to predict trapped dose rates inside these spacecraft to +/-10% throughout the solar cycle. Thus, given the shielding distribution for a location inside the Space Shuttle or inside an ISS module, this approach can be used to predict the combined GCR + trapped dose rate to better than +/-15% for quiet solar conditions.

NASA Discipline Radiation Health↗
NASA NTRS2003

Quantification of rat retinal growth and vascular population changes after single and split doses of proton irradiation: translational study using stereology methods

This study quantified architectural and population changes in the rat retinal vasculature after proton irradiation using stereology. A 100 MeV conformal proton beam delivered 8, 14, 20 and 28 Gy as single and split doses to the whole eye. The vascular networks were prepared from retinal digests. Stereological methods were used to obtain the area of the retina and unbiased estimates of microvessel/artery/vein endothelial, pericyte and smooth muscle population, and vessel length. The retinal area increased progressively in the unirradiated, age-matched controls and in the retinas irradiated with 8 and 14 Gy, indicating uniform progressive retinal growth. No growth occurred after 20 and 28 Gy. Regression analysis of total endothelial cell number in all vessels (arteries, veins and capillaries) after irradiation documented a progressive time- and dose-dependent cell loss occurring over 15 to 24 months. The difference from controls was significant (P<0.01) after 28 Gy given in single and split doses and after 20 Gy given as a split dose (P<0.05). Total vessel length in microvessel was significantly shortened at 20 and 28 Gy compared to that of controls (P<0.05). No evident dose recovery was observed in the endothelial populations after split doses. At 10 Gy, the rate of endothelial cell loss, a dose parameter used to characterize the time- and dose-dependent loss of the endothelial population, was doubled.

NASA Discipline Radiation Health↗
NASA NTRS2002

Ascorbate, added after irradiation, reduces the mutant yield and alters the spectrum of CD59- mutations in A(L) cells irradiated with high LET carbon ions

It has been reported that X-ray induced HPRT- mutation in cultured human cells is prevented by ascorbate added after irradiation. Mutation extinction is attributed to neutralization by ascorbate, of radiation-induced long-lived radicals (LLR) with half-lives of several hours. We here show that post-irradiation treatment with ascorbate (5 mM added 30 min after radiation) reduces, but does not eliminate, the induction of CD59- mutants in human-hamster hybrid A(L) cells exposed to high-LET carbon ions (LET of 100 KeV/microm). RibCys, [2(R,S)-D-ribo-1',2',3',4'-Tetrahydroxybutyl]-thiazolidene-4(R)-ca riboxylic acid] (4 mM) gave a similar but lesser effect. The lethality of the carbon ions was not altered by these chemicals. Preliminary data are presented that ascorbate also alters the spectrum of CD59- mutations induced by the carbon beam, mainly by reducing the incidence of small mutations and mutants displaying transmissible genomic instability (TGI), while large mutations are unaffected. Our results suggest that LLR are important in initiating TGI.

NASA Discipline Radiation Health↗
NASA NTRS2002

Clustered DNA damages induced in human hematopoietic cells by low doses of ionizing radiation

Ionizing radiation induces clusters of DNA damages--oxidized bases, abasic sites and strand breaks--on opposing strands within a few helical turns. Such damages have been postulated to be difficult to repair, as are double strand breaks (one type of cluster). We have shown that low doses of low and high linear energy transfer (LET) radiation induce such damage clusters in human cells. In human cells, DSB are about 30% of the total of complex damages, and the levels of DSBs and oxidized pyrimidine clusters are similar. The dose responses for cluster induction in cells can be described by a linear relationship, implying that even low doses of ionizing radiation can produce clustered damages. Studies are in progress to determine whether clusters can be produced by mechanisms other than ionizing radiation, as well as the levels of various cluster types formed by low and high LET radiation.

NASA Discipline Radiation Health↗
NASA NTRS2002

Fluence-based and microdosimetric event-based methods for radiation protection in space

The National Council on Radiation Protection and Measurements (NCRP) has recently published a report (Report #137) that discusses various aspects of the concepts used in radiation protection and the difficulties in measuring the radiation environment in spacecraft for the estimation of radiation risk to space travelers. Two novel dosimetric methodologies, fluence-based and microdosimetric event-based methods, are discussed and evaluated, along with the more conventional quality factor/LET method. It was concluded that for the present, any reason to switch to a new methodology is not compelling. It is suggested that because of certain drawbacks in the presently-used conventional method, these alternative methodologies should be kept in mind. As new data become available and dosimetric techniques become more refined, the question should be revisited and that in the future, significant improvement might be realized. In addition, such concepts as equivalent dose and organ dose equivalent are discussed and various problems regarding the measurement/estimation of these quantities are presented.

NASA Discipline Radiation Health↗
NASA NTRS2003

An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells

Induction of checkpoint responses in G1, S, and G2 phases of the cell cycle after exposure of cells to ionizing radiation (IR) is essential for maintaining genomic integrity. Ataxia telangiectasia mutated (ATM) plays a key role in initiating this response in all three phases of the cell cycle. However, cells lacking functional ATM exhibit a prolonged G2 arrest after IR, suggesting regulation by an ATM-independent checkpoint response. The mechanism for this ataxia telangiectasia (AT)-independent G2-checkpoint response remains unknown. We report here that the G2 checkpoint in irradiated human AT cells derives from an overactivation of the ATR/CHK1 pathway. Chk1 small interfering RNA abolishes the IR-induced prolonged G2 checkpoint and radiosensitizes AT cells to killing. These results link the activation of ATR/CHK1 with the prolonged G2 arrest in AT cells and show that activation of this G2 checkpoint contributes to the survival of AT cells.

NASA Discipline Radiation Health↗
NASA NTRS2003

Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium

Cyclooxygenase-2 (COX-2) is emerging as an important cancer biomarker and is now an experimental target for solid tumor treatment.However, no study has exclusively focused on COX-2 expression in early lesions such as ductal carcinoma in situ (DCIS). We examined COX-2 expression by immunohistochemistry in 46 cases of women undergoing surgical resection for DCIS. We found that COX-2 expression was detected in 85% of all DCIS specimens, with increased COX-2 staining correlating with higher nuclear grade. Strikingly, COX-2 staining intensity in the normal adjacent epithelium was stronger than in the DCIS lesion itself. Our observations demonstrate that COX-2 is up-regulated in the normal adjacent epithelium and supports the hypothesis that the surrounding epithelial tissue is part of the disease process in DCIS.

NASA Discipline Radiation Health↗
NASA NTRS2003

An algorithm for neurite outgrowth reconstruction

We present a numerical method which provides the ability to analyze digitized microscope images of retinal explants and quantify neurite outgrowth. Few parameters are required as input and limited user interaction is necessary to process an entire experiment of images. This eliminates fatigue related errors and user-related bias common to manual analysis. The method does not rely on stained images and handles images of variable quality. The algorithm is used to determine time and dose dependent, in vitro, neurotoxic effects of 1 GeV per nucleon iron particles in retinal explants. No neurotoxic effects are detected until 72 h after exposure; at 72 h, significant reductions of neurite outgrowth occurred at doses higher than 10 cGy.

NASA Program Biomedical Research and Countermeasur↗
NASA NTRS2003

Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia

Cultures of human mammary epithelial cells (HMECs) contain a subpopulation of variant cells with the capacity to propagate beyond an in vitro proliferation barrier. These variant HMECs, which contain hypermethylated and silenced p16(INK4a) (p16) promoters, eventually accumulate multiple chromosomal changes, many of which are similar to those detected in premalignant and malignant lesions of breast cancer. To determine the origin of these variant HMECs in culture, we used Luria-Delbruck fluctuation analysis and found that variant HMECs exist within the population before the proliferation barrier, thereby raising the possibility that variant HMECs exist in vivo before cultivation. To test this hypothesis, we examined mammary tissue from normal women for evidence of p16 promoter hypermethylation. Here we show that epithelial cells with methylation of p16 promoter sequences occur in focal patches of histologically normal mammary tissue of a substantial fraction of healthy, cancer-free women.

NASA Discipline Radiation Health↗
NASA NTRS2003

Long-term effects of low-dose proton radiation on immunity in mice: shielded vs. unshielded

BACKGROUND: Outside the protection of the terrestrial environment, astronauts on any long-term missions will unavoidably be exposed to fields of charged particle radiation dominated by protons. These fields and their biological risks are modified in complex ways by the presence of protective shielding. METHODS: To examine the long-term effects of space-like proton exposures on immune status, we treated female C57BL/6 mice with 3 or 4 Gy of 250 MeV monoenergetic protons or the complex space-like radiation field produced after 250 MeV protons are transported through 15 g x cm(-2) aluminum shielding. The animals were euthanized 122 d post-irradiation and lymphocyte phenotypes, hematological parameters, and lymphocyte blastogenesis were characterized. RESULTS: There were significant dose-dependent decreases in macrophage, CD3+/CD8+ T, NK, platelet, and red blood cell populations, as well as low hematocrit and hemoglobin levels. In contrast, dose-dependent increases in spontaneous, but not mitogen-induced, blastogenesis were noted. The differences in dose composition between pristine and shielded proton fields did not lead to significant effects in most measures, but did result in significant changes in monocyte and macrophage populations and spontaneous blastogenesis in the spleen. CONCLUSIONS: The data indicate that whole body exposure to proton radiation at doses of the order of large solar particle events or clinical treatment fractions may have long-term effects on immune system status.

NASA Discipline Radiation Health↗
NASA NTRS2003

Bayesian estimation of dose thresholds

An example is described of Bayesian estimation of radiation absorbed dose thresholds (subsequently simply referred to as dose thresholds) using a specific parametric model applied to a data set on mice exposed to 60Co gamma rays and fission neutrons. A Weibull based relative risk model with a dose threshold parameter was used to analyse, as an example, lung cancer mortality and determine the posterior density for the threshold dose after single exposures to 60Co gamma rays or fission neutrons from the JANUS reactor at Argonne National Laboratory. The data consisted of survival, censoring times and cause of death information for male B6CF1 unexposed and exposed mice. The 60Co gamma whole-body doses for the two exposed groups were 0.86 and 1.37 Gy. The neutron whole-body doses were 0.19 and 0.38 Gy. Marginal posterior densities for the dose thresholds for neutron and gamma radiation were calculated with numerical integration and found to have quite different shapes. The density of the threshold for 60Co is unimodal with a mode at about 0.50 Gy. The threshold density for fission neutrons declines monotonically from a maximum value at zero with increasing doses. The posterior densities for all other parameters were similar for the two radiation types.

NASA Discipline Radiation Health↗
NASA NTRS2002

Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation

Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.

NASA Discipline Radiation Health↗
NASA NTRS2002

Characteristics of genomic instability in clones of TK6 human lymphoblasts surviving exposure to 56Fe ions

Genomic instability in the human lymphoblast cell line TK6 was studied in clones surviving 36 generations after exposure to accelerated 56Fe ions. Clones were assayed for 20 characteristics, including chromosome aberrations, plating efficiency, apoptosis, cell cycle distribution, response to a second irradiation, and mutant frequency at two loci. The primary effect of the 56Fe-ion exposure on the surviving clones was a significant increase in the frequency of unstable chromosome aberrations compared to the very low spontaneous frequency, along with an increase in the phenotypic complexity of the unstable clones. The radiation-induced increase in the frequency of unstable chromosome aberrations was much greater than that observed previously in clones of the related cell line, WTK1, which in comparison to the TK6 cell line expresses an increased radiation resistance, a mutant TP53 protein, and an increased frequency of spontaneous unstable chromosome aberrations. The characteristics of the unstable clones of the two cell lines also differed. Most of the TK6 clones surviving exposure to 56Fe ions showed unstable cytogenetic abnormalities, while the phenotype of the WTK1 clones was more diverse. The results underscore the importance of genotype in the characteristics of instability after radiation exposure.

NASA Discipline Radiation Health↗
NASA NTRS2002

Opportunities for nutritional amelioration of radiation-induced cellular damage

The closed environment and limited evasive capabilities inherent in space flight cause astronauts to be exposed to many potential harmful agents (chemical contaminants in the environment and cosmic radiation exposure). Current power systems used to achieve space flight are prohibitively expensive for supporting the weight requirements to fully shield astronauts from cosmic radiation. Therefore, radiation poses a major, currently unresolvable risk for astronauts, especially for long-duration space flights. The major detrimental radiation effects that are of primary concern for long-duration space flights are damage to the lens of the eye, damage to the immune system, damage to the central nervous system, and cancer. In addition to the direct damage to biological molecules in cells, radiation exposure induces oxidative damage. Many natural antioxidants, whether consumed before or after radiation exposure, are able to confer some level of radioprotection. In addition to achieving beneficial effects from long-known antioxidants such as vitamins E and C and folic acid, some protection is conferred by several recently discovered antioxidant molecules, such as flavonoids, epigallocatechin, and other polyphenols. Somewhat counterintuitive is the protection provided by diets containing elevated levels of omega-3 polyunsaturated fatty acids, considering they are thought to be prone to peroxidation. Even with the information we have at our disposal, it will be difficult to predict the types of dietary modifications that can best reduce the risk of radiation exposure to astronauts, those living on Earth, or those enduring diagnostic or therapeutic radiation exposure. Much more work must be done in humans, whether on Earth or, preferably, in space, before we are able to make concrete recommendations.

Review↗
NASA NTRS2002

Relative biological effectiveness of light ions in human tumoural cell lines: role of protein p53

Protons and alpha particles of high linear energy transfer (LET) have shown an increased relative biological effectiveness (RBE) with respect to X/gamma rays for several cellular and molecular endpoints in different in vitro cell systems. To contribute to understanding the biochemical mechanisms involved in the increased effectiveness of high LET radiation, an extensive study has been designed. The present work reports the preliminary result of this study on two human tumoural cell lines, DLD1 and HCT116, (with different p53 status), which indicate that for these cell lines, p53 does not appear to take a part in the response to radiation induced DNA damage, suggesting an alternative p53-independent pathway and a cell biochemical mechanism dependent on the cell type.

NASA Center JSC↗
NASA NTRS2002

Bystander effects in radiation-induced genomic instability

Exposure of GM10115 hamster-human hybrid cells to X-rays can result in the induction of chromosomal instability in the progeny of surviving cells. This instability manifests as the dynamic production of novel sub-populations of cells with unique cytogenetic rearrangements involving the "marker" human chromosome. We have used the comet assay to investigate whether there was an elevated level of endogenous DNA breaks in chromosomally unstable clones that could provide a source for the chromosomal rearrangements and thus account for the persistent instability observed. Our results indicate no significant difference in comet tail measurement between non-irradiated and radiation-induced chromosomally unstable clones. Using two-color fluorescence in situ hybridization we also investigated whether recombinational events involving the interstitial telomere repeat-like sequences in GM10115 cells were involved at frequencies higher than random processes would otherwise predict. Nine of 11 clones demonstrated a significantly higher than expected involvement of these interstitial telomere repeat-like sequences at the recombination junction between the human and hamster chromosomes. Since elevated levels of endogenous breaks were not detected in unstable clones we propose that epigenetic or bystander effects (BSEs) lead to the activation of recombinational pathways that perpetuate the unstable phenotype. Specifically, we expand upon the hypothesis that radiation induces conditions and/or factors that stimulate the production of reactive oxygen species (ROS). These reactive intermediates then contribute to a chronic pro-oxidant environment that cycles over multiple generations, promoting chromosomal recombination and other phenotypes associated with genomic instability.

NASA Discipline Radiation Health↗
NASA NTRS2002

Antimutagenicity of WR-1065 in L5178Y cells exposed to accelerated (56)Fe ions

The ability of the aminothiol WR-1065 [N-(2-mercaptoethyl)-1,3-diaminopropane] to protect L5178Y (LY) cells against the cytotoxic and mutagenic effects of exposure to accelerated (56)Fe ions (1.08 GeV/nucleon) was determined. It was found that while WR-1065 reduced the mutagenicity in both cell lines when it was present during the irradiation, the addition of WR-1065 after the exposure had no effect on the mutagenicity of the radiation in either cell line. No marked protection against the cytotoxic effects of exposure to (56)Fe ions was provided by WR-1065 when added either during or after irradiation in either cell line. We reported previously that WR-1065 protected the LY-S1 and LY-SR1 cell lines against both the cytotoxicity and mutagenicity of X radiation when present during exposure, but that its protection when administered after exposure was limited to the mutagenic effects in the radiation-hypersensitive cell line, LY-S1. The results indicate that the mechanisms involved differ in the protection against cytotoxic compared to mutagenic effects and in the protection against damage caused by accelerated (56)Fe ions compared to X radiation.

NASA Discipline Radiation Health↗