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NASA NTRSDate not supplied

Comparison of Radiation-Induced Damage Between Livers From Control and Chimeric Mice

Assessment of human health risks associated with space radiation exposure is based largely on the knowledge gained from studies in which animals, mostly rodents, are exposed to high-LET radiation on the ground. It has been recognized that translation of animal results to meaningful implications for human disease can be challenging, particularly for certain risk categories such as the high-LET radiation effects in the central nervous system (CNS). Considering limitations in utilizing non-human primates and clinical studies in humans, chimeric animals can potentially bridge the knowledge gap between rodents and humans. In a chimeric animal, a specific organ or a cell type is replaced with respective human cells that are functional. In this pilot study, we used PXB mice whose livers contain >90% human cells. These mice were exposed to gamma rays to investigate DNA damage and transcriptomics changes in the chimeric livers. Results obtained from PXB mice were compared to non-engrafted control animals from the same background strain that were exposed to identical conditions. Staining of the liver tissues with H&E indicated that the human liver tissue in chimeric mice responded differently than the mouse liver tissue to gamma radiation on the cellular level, as evidenced by differences in inflammation and cellular damage seen on histopathology. The gene expression data collected from the liver samples will also be presented, which potentially offers an explanation for the differential responses.

Honglu Wu↗

NASA NTRSDate not supplied

Neurobiological Outcomes of Mice Exposed to Combined Spaceflight Stressors

As NASA plans for exploration beyond Low-Earth Orbit, it is imperative to understand how deep spaceflight stressors impact human physiology. Deep space exposes crew members to multiple NASA-defined risks, including altered gravity, ionizing radiation, and social isolation. While the effects of individual stressors have been studied, there are still gaps in our understanding of their combined effects. In this study, we utilized the simulated five-ion galactic cosmic radiation (GCR) and isolation to assess the combinatorial effects of space stressors on the central nervous system (CNS) in mice. Our study captures sexually dimorphic responses by quantifying CNS outcomes in crewage-matched male and female mice. We assessed CNS responses in mice exposed to four days of isolation, followed by three different dosage of acute radiation exposure (5 cGy, 15 cGy, and 50 cGy 5-ion GCRsim). Comprehensive hippocampal cytokine biomarker analyses were conducted in both males and females at two weeks post-irradiation (intermediate cohort) and 124 days post-irradiation (delayed cohort). Proteomics on hippocampal lysates were conducted in the delayed cohort. Our results provide evidence for sex-specific differentially regulated hippocampal cytokines and proteomic profiles. Immunohistochemical analysis of the mice brain from intermediate and delayed cohorts is currently underway for multiple protein markers, including microglial activation, astrocytes, and dopaminergic neuronal population, among others. This project closely aligns with NASA’s efforts to characterize sex-specific risks associated with deep space exploration. We anticipate the results from this project will aid in our understanding of spaceflight stressors to ensure crew health and performance.

spaceflight↗

NASA NTRS2001

Long-term insulin-like growth factor-I expression in skeletal muscles attenuates the enhanced in vitro proliferation ability of the resident satellite cells in transgenic mice

Insulin-like growth factor-I (IGF-I) overexpression for 1-month in mouse skeletal muscle increases satellite cell proliferation potential. However, it is unknown whether this beneficial enhancement by IGF-I expression would persist over a longer-term duration in aged mice. This is an important issue to address if a prolonged course of IGF-I is to be used clinically in muscle-wasting conditions where satellite cells may become limiting. Using the IGF-I transgenic (IGF-I Tg) mouse that selectively expresses the IGF-I transgene in striated muscles, we found that 18-months of continuous IGF-I overexpression led to a loss in the enhanced in vitro proliferative capacity of satellite cells from Tg skeletal muscles. Also 18-month-old IGF-I Tg satellite cells lost the enhanced BrdU incorporation, greater pRb and Akt phosphorylations, and decreased p27(Kip1) levels initially observed in cells from 1-month-old IGF-I Tg mice. The levels of those biochemical markers reverted to similar values seen in the 18-months WT littermates. These findings, therefore, suggest that there is no further beneficial effect on enhancing satellite cell proliferation ability with persistent long-term expression of IGF-I in skeletal muscles of these transgenic mice.

Non-NASA Center↗

NASA NTRS2004

Effects of heavy ions on visual function and electrophysiology of rodents: the ALTEA-MICE project

ALTEA-MICE will supplement the ALTEA project on astronauts and provide information on the functional visual impairment possibly induced by heavy ions during prolonged operations in microgravity. Goals of ALTEA-MICE are: (1) to investigate the effects of heavy ions on the visual system of normal and mutant mice with retinal defects; (2) to define reliable experimental conditions for space research; and (3) to develop animal models to study the physiological consequences of space travels on humans. Remotely controlled mouse setup, applied electrophysiological recording methods, remote particle monitoring, and experimental procedures were developed and tested. The project has proved feasible under laboratory-controlled conditions comparable in important aspects to those of astronauts' exposure to particle in space. Experiments are performed at the Brookhaven National Laboratories [BNL] (Upton, NY, USA) and the Gesellschaft fur Schwerionenforschung mbH [GSI]/Biophysik (Darmstadt, FRG) to identify possible electrophysiological changes and/or activation of protective mechanisms in response to pulsed radiation. Offline data analyses are in progress and observations are still anecdotal. Electrophysiological changes after pulsed radiation are within the limits of spontaneous variability under anesthesia, with only indirect evidence of possible retinal/cortical responses. Immunostaining showed changes (e.g. increased expression of FGF2 protein in the outer nuclear layer) suggesting a retinal stress reaction to high-energy particles of potential relevance in space. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

NASA Center JSC↗

NASA NTRS2002

Dynamics of cell proliferation in the adult dentate gyrus of two inbred strains of mice

The output potential of proliferating populations in either the developing or the adult nervous system is critically dependent on the length of the cell cycle (T(c)) and the size of the proliferating population. We developed a new approach for analyzing the cell cycle, the 'Saturate and Survive Method' (SSM), that also reveals the dynamic behaviors in the proliferative population and estimates of the size of the proliferating population. We used this method to analyze the proliferating population of the adult dentate gyrus in 60 day old mice of two inbred strains, C57BL/6J and BALB/cByJ. The results show that the number of cells labeled by exposure to BUdR changes dramatically with time as a function of the number of proliferating cells in the population, the length of the S-phase, cell division, the length of the cell cycle, dilution of the S-phase label, and cell death. The major difference between C57BL/6J and BALB/cByJ mice is the size of the proliferating population, which differs by a factor of two; the lengths of the cell cycle and the S-phase and the probability that a newly produced cell will die within the first 10 days do not differ in these two strains. This indicates that genetic regulation of the size of the proliferating population is independent of the genetic regulation of cell death among those newly produced cells. The dynamic changes in the number of labeled cells as revealed by the SSM protocol also indicate that neither single nor repeated daily injections of BUdR accurately measure 'proliferation.'.

Non-NASA Center↗

NASA NTRS2001

Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene

Female BALB/c mice are unusually radiosensitive and more susceptible than C57BL/6 and other tested inbred mice to ionizing radiation (IR)-induced mammary tumors. This breast cancer susceptibility is correlated with elevated susceptibility for mammary cell transformation and genomic instability following irradiation. In this study, we report the identification of two BALB/c strain-specific polymorphisms in the coding region of Prkdc, the gene encoding the DNA-dependent protein kinase catalytic subunit, which is known to be involved in DNA double-stranded break repair and post-IR signal transduction. First, we identified an A --> G transition at base 11530 resulting in a Met --> Val conversion at codon 3844 (M3844V) in the phosphatidylinositol 3-kinase domain upstream of the scid mutation (Y4046X). Second, we identified a C --> T transition at base 6418 resulting in an Arg --> Cys conversion at codon 2140 (R2140C) downstream of the putative leucine zipper domain. This unique PrkdcBALB variant gene is shown to be associated with decreased DNA-dependent protein kinase catalytic subunit activity and with increased susceptibility to IR-induced genomic instability in primary mammary epithelial cells. The data provide the first evidence that naturally arising allelic variation in a mouse DNA damage response gene may associate with IR response and breast cancer risk.

Non-NASA Center↗

NASA NTRS1998

Effects of 2-deoxy-D-glucose administration on immune parameters in mice

Physical exercise and diet alterations have been shown to affect immune parameters. Similar effects are also induced by the administration of the non-metabolizable glucose analog, 2-deoxy-D-glucose (2-DG). The current study was designed to characterize the effects of glucoprivation induced by 2-DG administration on leukocyte subset distribution and function. BDF1 mice (n = 8 per group) were injected intraperitoneally one or three times with 0, 500, 750, 1000 or 1500 mg/kg of 2-DG. Two hours after the last injection of 2-DG, immunological parameters were analyzed. A dose-dependent increase in plasma glucose concentrations of mice injected once with up to 1500 mg/kg of 2-DG was observed (p < 0.001). After either one or three injections of up to 1500 mg/kg of 2-DG, corticosterone levels, leukocyte counts in the spleen, and CD3+ cells in the thymus increased. In vitro proliferation of partially purified lymphocytes from the spleen in the presence of both concanavalin-A and lipopolysaccharide decreased in a dose dependent manner (p < 0.05). In addition, after three injections, the proportion of both thymocytes and splenocytes bearing alphabeta-TCR increased as the concentration of 2-DG increased (p < 0.01). These results demonstrate that 2-DG administration induced dose-dependent changes in both thymus and spleen cell distribution and function.

NASA Discipline Regulatory Physiology↗

NASA NTRS1975

A study of the effects on mice of smoke and gases from controlled fires in simulated aircraft cabins

Male Swiss albino mice were exposed to the pyrolysis products of two fire-retardant materials, a chlorinated aromatic polyamide and a copolymer of vinylidine fluoride and hexafluoropropene. Comparison tests were made with cotton and a 50/50 cotton-polyester composite. In addition, tests were conducted under the presence of CO, and mice were injected intraperitoneally or intramuscularly with aqueous solutions containing dissolved effluents from the pyrolysis of cotton or of chlorinated aromatic polyamide. Results indicate that unique thermodecomposition products of the polymeric materials are more toxic to mice than are other products from cotton under similar controlled conditions.

Moreci, A. P.↗

NASA NTRS1975

Preflight studies on tolerance of pocket mice to oxygen and heat. II - Effects on lungs

An electron microscope examination was carried out on the lungs of 11 pocket mice (Perognathus longimembris) that breathed oxygen at 10 psi or 12 psi partial pressure over a period of 7 d, at the end of which time they were decompressed to sea-level O2 pressure, either suddenly or in 30, 60, or 90 min. Vesiculation was noted in the endothelium of the alveolar-capillary wall in most of the animals and, occasionally, blebbing. Some mitochrondria were swollen in a few of the animals. Alveolar exudate was, in general, sparse. Compared with the lungs of other rodents, the lungs of pocket mice appeared relatively resistant to the toxic effects of oxygen. This conclusion needs, however, to be tempered by the fact that 5% N2 was used in the tests reported here. Nonetheless, the results suggest that the oxygen pressures anticipated on the flight of Apollo XVII should be well tolerated by the pocket mice.

Harrison, G. A.↗

NASA NTRS1976

A technique for extracting blood samples from mice in fire toxicity tests

The extraction of adequate blood samples from moribund and dead mice has been a problem because of the small quantity of blood in each animal and the short time available between the animals' death and coagulation of the blood. These difficulties are particularly critical in fire toxicity tests because removal of the test animals while observing proper safety precautions for personnel is time-consuming. Techniques for extracting blood samples from mice were evaluated, and a technique was developed to obtain up to 0.8 ml of blood from a single mouse after death. The technique involves rapid exposure and cutting of the posterior vena cava and accumulation of blood in the peritoneal space. Blood samples of 0.5 ml or more from individual mice have been consistently obtained as much as 16 minutes after apparent death. Results of carboxyhemoglobin analyses of blood appeared reproducible and consistent with carbon monoxide concentrations in the exposure chamber.

Bucci, T. J.↗

NASA NTRS1987

Enhancement of viral pathogenesis in mice maintained in an antiorthostatic suspension model - Coordination with effects on interferon production

Both rodents and men returning from spaceflight have exhibited alterations in immune responses and, in particular, interferon production. This work utilizes a model for antiorthostatic (20-deg head-down tilt), hypokinetic, hypodynamic suspension of mice that simulates some aspects of weightlessness. Female Swiss/Webster mice that are normally resistant to infection with the D variant of encephalomyocarditis virus showed a marked increase in susceptibility to infection when suspended. This correlated with a drop in interferom production. Control, orthostatically suspended mice (no tilt) showed no increase in susceptibility to the virus.

Gould, C. L.↗

NASA NTRS2001

NASA Rodent Foodbar: Long Term Effects in Swiss Webster Mice

Swiss Webster male and female mice (150 of each) were fed NASA Rodent Foodbar for more than 110 days to test the diet's nutritional adequacy for use in future long-term studies aboard the International Space Station. Mice were grouped three to a cage (one cage = one sample) and cages were assigned to either Foodbar or Purina Chow #5001 (control) diet groups. Body weights, food intake, and water intake were obtained throughout the study. There were no significant differences in body weights between male Foodbar fed and Chow fed males (p=0.58), and at 15 weeks into the female mouse study there appear to be no significant body weight differences. Both male and female Foodbar fed groups consumed more food and less water than their Chow controls, both factors thought to be attributable to the high moisture content of the Foodbars (26% versus 10% for Chow). All differences in gross food and water consumption had p-values of less than 0.01. When food and water intake were adjusted for the moisture content in the food, both male and female Foodbar fed animals consumed less food, but still had a lower water intake rate than their controls. (p is less than 0.01). Preliminary analysis on blood samples from male and female halfway point dissections suggests differences in glucose and fat metabolism. In both male and female Foodbar fed animals, blood glucose values were significantly lower (p is less than 0.01) but there were no significant differences in cholesterol levels (p=0.51). In Foodbar fed females, triglycerides were significantly higher (p is less than 0.01). These data suggest that Foodbars allow for normal growth in Swiss Webster mice, but affect some blood chemistry parameters.

Santiago, D. L.↗

NASA NTRS2000

Pulmonary Toxicity of Simulated Lunar and Martian Dusts Intratracheally Instilled into Mice

The National Aeronautics and Space Administration (NASA) is contemplating sending humans to Mars and to the Moon for further exploration. Equipment designated for these extraterrestrial bases will require testing in simulated Martian or lunar environments. The properties of Hawaiian and San Francisco Mountain volcanic ashes make them suitable to be used in these test environments as Martian and lunar dust simulants, respectively. The present toxicity study was conducted to address NASA's concern about the health risk of dust exposures in the test facilities. In addition, the results obtained on these simulants can be used to design a toxicity study of actual moon dust and Martian dust, which will probably be available in a few years. Respirable portions of lunar soil simulant (LSS) and Martian soil simulant (MSS) were separated from their respective raw materials. These soil simulants, together- with fine titanium dioxide (negative control for fibrogenesis in mice), and crystalline silica (positive control) were each intratracheally instilled in saline to groups of 4 male mice (C57BL/6J, 2-3 months old) at 0.1 mg/mouse (LD) or lmg/mouse (HD). The lungs were harvested 7 or 90 days after the single dust treatment for histopathological examination. Lungs of the LSS-LD groups on either the 7- or 90-day study showed no evidence of inflammation, edema, or fibrosis. Clumps of particles and an increased number of macrophages, visible in the lungs examined after 7 days, were absent after 90 days. The LSS-HD-7d group showed mild to moderate alveolitis with neutrophilic and lymphocytic infiltration, and mild perivascular and peribronchiolar inflammation. The LSS-HD-90d group showed signs of chronic inflammation: septal thickening, mild perivascular and peribronchiolar inflammation, mild alveolitis and some fibrosis. Foci of particle-laden macrophages (PLMs) were still visible. Lungs of the MSS-LD-7d group revealed mild focal intraalveolar inflammation with neutrophilic and lymphocytic infiltration, and mild perivascular and peribronchiolar inflammation. The MSS-LD-90d group showed PLMs and scattered foci of mild fibrosis. The MSS-HD-7d group showed large foci of PLMs, intraalveolar debris, mild to moderate focal alveolitis, and mild to moderate perivascular and peribronchiolar inflammation. The MSS-HD-90d group showed focal chronic mild to moderate alveolitis and fibrosis. To mimic the oxidative and reactive properties of Martian surface dust in the test animals, groups of 4 mice were exposed to ozone (0.5 ppm for 3 hours) prior to instillation of the MSS. Lung lesions in the MSS groups were more severe with the ozone pretreatment. The O3-MSS-HD-90d group had wide spread intraalveolar debris, focal moderate alveolitis and fibrosis. The results for the titanium dioxide and quartz controls were consistent with the known pulmonary toxicity of these compounds. The overall severity of toxic injury to the lungs was TiO2<LSS<MSS<MSS+O3<quartz. In general, the toxic responses increased with the increase of dust burden in the lung. Except for TiO2, the increased duration of dust presence in the lung from 7 to 90 days transformed the acute inflammatory response to a chronic inflammatory lesion.

Lam, Chiu-Wing↗

NASA NTRS2007

Payload Processing for Mice Drawer System

Experimental payloads flown to the International Space Station provide us with valuable research conducted in a microgravity environment not attainable on earth. The Mice Drawer System is an experiment designed by Thales Alenia Space Italia to study the effects of microgravity on mice. It is designed to fly to orbit on the Space Shuttle Utilization Logistics Flight 2 in October 2008, remain onboard the International Space Station for approximately 100 days and then return to earth on a following Shuttle flight. The experiment apparatus will be housed inside a Double Payload Carrier. An engineering model of the Double Payload Carrier was sent to Kennedy Space Center for a fit check inside both Shuttles, and the rack that it will be installed in aboard the International Space Station. The Double Payload Carrier showed a good fit quality inside each vehicle, and Thales Alenia Space Italia will now construct the actual flight model and continue to prepare the Mice Drawer System experiment for launch.

Brown, Judy↗

NASA NTRS2017

Behavioral Adaptations of Female Mice on the International Space Station

Adult female mice were sent to the International Space Station (ISS) as part of an early life science mission utilizing NASA's Rodent Habitat. Its primary purpose was to provide further insight into the influence of a microgravity environment on various aspects of mammalian physiology and well-being as part of an ongoing program of research aimed ultimately at understanding and ameliorating the deleterious influences of space on the human body. The present study took advantage of video collected from fixed, in-flight cameras within the habitat itself, to assess behavioral adaptations observed among in-flight mice aboard the ISS and differences in behavior with respect to a control group on the ground. Data collection consisted of several behavioral measures recorded by a trained observer with the assistance of interactive behavior analysis software. Specific behavioral measures included frequencies of conspecific interactionsociability, time spent feeding and conducting hygienic behavior, and relative durations of thigmotactic behavior, which is commonly used as an index of anxiety. Data were used to test tentative hypotheses that such behaviors differ significantly across mice under microgravity versus 1g conditions, and the assumption that the novel experience of microgravity itself may represent an initially anxiogenic stimulus which an animal will eventually acclimate to, perhaps through habituation.

Behavior in space↗

NASA NTRS2017

Behavioral Adaptations of Female Mice on the International Space Station

rodent behavior↗

NASA NTRS2018

Variability in Galactic Cosmic Radiation- Induced DNA Damage Response in Inbred Mice Is Modulated by Genetics

In radiation biology, the ability to predict cancer risk associated with exposure to low doses of high-LET (Linear Energy Transfer) ionizing radiation remains a challenge. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer and ignore individual sensitivity. We have hypothesized that DNA repair capacity is the primary factor differentiating peoples radiation sensitivity. We previously showed in immortalized human cell lines that characterizing the dose and time dependence of p53-binding protein 1 (53BP1) foci formation in the nucleus following X-rays exposure is sufficient to predict DNA repair response to any other LET in the same cell line. We now tested this hypothesis across a population of mice with different genetic background. Fibroblast cells were extracted and cultivated from 76 individual mice from 15 different strains and exposed to HZE (high (H) atomic number (Z) and energy (E) galactic cosmic ray particles) particles and X-rays. Individual radiation sensitivities were investigated by high throughput measurement of DNA repair kinetics that evaluated 53bp1 foci numbers as a surrogate for DNA double-strand breaks at various times post-irradiation. Instead of just counting foci which can be hard to distinguish for high-LET or high doses, we also took into account the track structure of high-LET particles to compute the remaining number of unrepaired tracks as a function of time post-irradiation. As expected, the percentage of unrepaired track over a 48 hours follow-up period increased with LET. In addition, repair rate was modulated by genetics, with animals from the same strain showing small variance while large rate differences were observed between strains. Radiation strain sensitivity ranking was estimated based on repair rates from exposure to each LET evaluated in this work, and ranking for high-LET correlated better with ranking from high dose of X-ray, not low dose. At the in-vivo level, drops in T-cells and B-cells number measured 24 hours after 0.1 Gy (Gray) X-ray exposure, correlated with slower DNA repair kinetic in fibroblast cells of the same strains of mice. At the genomic level, mouse genome wide association (GWA) analysis identified seven significant genetic loci on chromosomes 2, 3, 7, 10, 11, 13 and 19 with different significance depending on the LET. Interestingly, for the two highest LET, a common locus on Chromosome 10 was identified with high enrichment for DNA repair associated genes.Overall, this work suggests that repair kinetics of primary skin fibroblasts is a good surrogate marker for in-vivo radiation sensitivities in other tissues and that this response is modulated by genetics. Our study also confirms that DNA repair kinetics following high doses of X-ray can be used to predict radiation sensitivity to high-LET.

High-LET Radiation↗

NASA NTRS2019

DNA Damage Response to Low and High-LET in a Large Cohort of Mice and Humans and Latest Advancement in NASA Space Omics

This presentation will first focus on a thorough evaluation of the DNA damage response to both low and high-LET in a cohort of 76 mice primary skin fibroblast derived from 15 different strains or in human blood mononuclear cells derived from 550 healthy donors. In both the human and mice work, we have hypothesized that DNA repair capacity can be used as a marker to evaluate and differentiate individual radiation sensitivity. More specifically, this work is based on the concept that the combined time-dose dependence of radiation-induced foci (RIF) of p53-binding protein 1 (53BP1) following low-LET exposure contains sufficient information to infer sensitivity to any other LET. This work is one of the most extensive studies on the kinetics and possible genetic underpinnings of radiation-induced DNA damage and repair. Results on humans are still preliminary as we are still in the process of collecting and isolating primary blood mononuclear cells from 500 to 800 healthy subjects of European descent, 18-75 years of age, 50/50 male/female distribution. We have analyzed 53BP1+ RIF formation as well as oxidative stress and cell death in primary cells from 192 subjects in response to the same HZE particles as used in mice: 600 MeV/n Fe, 350 MeV/n Ar and 350 MeV/n Si, 1.1 and 3 particles/100m2, 4 and 24 hours after irradiation. The second part of the talk will focus on describing GeneLab: The NASA Systems Biology Platform for Space Omics Repository, Analysis and Visualization. NASA GeneLab is an open-access repository for omics datasets generated by biological experiments conducted in space or experiments relevant to spaceflight (e.g. simulated cosmic radiation, simulated microgravity, bed rest studies). Started as a repository designed to archive precious omics from space experiments, GeneLab has expanded its scope to maximize the intelligibility of the raw data (e.g. RNAseq, microarray, WGBS, metagenome), particularly for users with limited bioinformatics knowledge. As such GeneLab is now providing processed data derived from the raw data covering a large spectrum of omics (genome, epigenome, transcriptome, epitranscriptome, proteome, metabolome), to help users explore important questions: Which genes or proteins are expressed differently in space for various living organisms? What are the consequences arising from these changes? What specifics DNA mutations or epigenetic changes happen in space? What species or genetic features lead to better adaption to such a unique environment? In this presentation, we will report on the current and future objectives for GeneLab, and review recent published studies relating molecular changes observed in various animal models and tissue with microgravity, radiation, circadian rhythm, hydration and carbon dioxide conditions.

DNA repair kinetics↗