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At least 37 records · Page 2

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↗

Differential Saccade-Pursuit Coordination Under Sleep Loss and Low-Dose Alcohol

Introduction: Ocular tracking of a moving object requires tight coordination between smooth pursuit and saccadic eye movements. Normally, pursuit drives gaze velocity to closely match target velocity, with residual position offsets corrected by catch-up saccades. However, how/if common stressors affect this coordination is largely unknown. This study seeks to elucidate the effects of acute and chronic sleep loss, and low-dose alcohol, on saccade-pursuit coordination, as well as that of caffeine. Methods: We used an ocular tracking paradigm to assess three metrics of tracking (pursuit gain, saccade rate, saccade amplitude) and to compute “ground lost” (from reductions in steady-state pursuit gain) and “ground recouped” (from increases in steady-state saccade rate and/or amplitude). We emphasize that these are measures of relative changes in positional offsets, and not absolute offset from the fovea. Results: Under low-dose alcohol and acute sleep loss, ground lost was similarly large. However, under the former, it was nearly completely recouped by saccades, whereas under the latter, compensation was at best partial. Under chronic sleep restriction and acute sleep loss with a caffeine countermeasure, the pursuit deficit was dramatically smaller, yet saccadic behavior remained altered from baseline. In particular, saccadic rate remained significantly elevated, despite the fact that ground lost was minimal. Discussion: This constellation of findings demonstrates differential impacts on saccade-pursuit coordination with low-dose alcohol impacting only pursuit, likely through extrastriate cortical pathways, while acute sleep loss not only disrupts pursuit but also undermines saccadic compensation, likely through midbrain/brainstem pathways. Furthermore, while chronic sleep loss and caffeine-mitigated acute sleep loss show little residual pursuit deficit, consistent with uncompromised cortical visual processing, they nonetheless show an elevated saccade rate, suggesting residual midbrain and/or brainstem impacts.

smooth pursuit↗

Quantitative assessment of the cataractogenic potential of very low doses of neutrons

We report on the prevalence and relative biological effectiveness (RBE) for various stages of lens opacification in rats induced by very low doses (2 to 250 mGy) of medium-energy (440 keV) neutrons, compared to those for X rays. Neutron doses were delivered either in a single fraction or in four separate fractions and the irradiated animals were followed for over 100 weeks. At the highest observed dose (250 mGy) and at early observation times, there was evidence of an inverse dose-rate effect; i.e., a fractionated exposure was more potent than a single exposure. Neutron RBEs relative to X rays were estimated using a non-parametric technique. The results were only weakly dependent on time postirradiation. At 30 weeks, for example, 80% confidence intervals for the RBE of acutely delivered neutrons relative to X rays were 8-16 at 250 mGy, 10-20 at 50 mGy, 50-100 at 10 mGy and 250-500 at 2 mGy. The results are consistent with the estimated neutron RBEs in Japanese A-bomb survivors, though broad confidence bounds are present in the Japanese results. Our findings are also consistent with data reported earlier for cataractogenesis induced by heavy ions in rats, mice, and rabbits. We conclude from these results that, at very low doses (<10 mGy), the RBE for neutron-induced cataractogenesis is considerably larger than the RBE of 20 commonly used, and use of a significantly larger value for calculating equivalent dose would be prudent.

NASA Discipline Radiation Health↗

The Effects of ELDRS at Ultra-Low Dose Rates

We present results on the effects on ELDRS at dose rates of 10, 5, 1, and 0.5 mrad(Si)/s for a variety of radiation hardened and commercial devices. We observed low dose rate enhancement below 10 mrad(Si)/s in several different parts. The magnitudes of the dose rate effects vary. The TL750L, a commercial voltage regulator, showed dose rate dependence in the functional failures, with initial failures occurring after 10 krad(Si) for the parts irradiated at 0.5 mrad(Si)/s. The RH1021 showed an increase in low dose rate enhancement by 2x at 5 mrad(Si)/s relative to 8 mrad(Si)/s and high dose rate, and parametric failure after 100 krad(Si). Additionally the ELDRS-free devices, such as the LM158 and LM117, showed evidence of dose rate sensitivity in parametric degradations. Several other parts also displayed dose rate enhancement, with relatively lower degradations up to approx.15 to 20 krad(Si). The magnitudes of the dose rate enhancement will likely increase in significance at higher total dose levels.

Chen, Dakai↗

Integrating Large Scale Data Sets to Develop Predictive Hypotheses of Low-Dose Radiation-Induced Health Effects

Over one hundred years of radiation biology research has revealed much about the DNA damages induced by the deposition of energy from exposure to ionizing radiation and the subsequent cellular responses. However, there are still significant gaps in our understanding of how these might lead to detrimental health effects, particularly at low doses (100 mGy (milligray)). Recent advances in high throughput omics technologies enable interrogation of induced radiation effects at the genomic, proteomic and metabolomic levels. These include changes in gene expression, protein modifications, e.g., phosphorylation, acetylation, and methylation, and metabolic changes. We will discuss the integration of data obtained from multiple omics platforms to understand radiation dose, and dose rate effects in a complex human tissue model as a function of time. We will use as an example our results on the low dose responses in a 3D human skin model.

ionizing radiation↗

Low-Dose Caffeine Administration During Acute Sleep Deprivation Eliminates Visual Motion Processing Impairment, but Does Not Improve Saccadic Rate

Oculomotor tracking performance changes according to time awake. A constant routine (CR) study demonstrated that increasing time awake 1) reduces the precision of visual motion processing, 2) decreases steady-state closed-loop pursuit performance and 3) decreases peak saccadic velocity. We aimed to determine the contribution of homeostatic sleep pressure on these oculometric changes by administering low-dose caffeine over one night of sleep deprivation. Participants completed two weeks of at-home 8.5 hours sleep per day, followed by an approximately 24-hour laboratory CR in semi-recumbent posture under less than 4 lux of light. The visual tracking task was performed every two hours after waking and hourly overnight. Low-dose caffeine of 0.3 milligrams per kilogram was administered hourly during the biological night. Nine participants (5F) completed the study. Caffeine dosing: 1) prevented the impairment of visual motion processing, 2) reduced by approximately half the impairment of closed-loop pursuit performance (gain, minus 0.47 percent per hour, significance of slope change: p (probability) less than 0.006; proportion smooth, minus 0.35 percent per hour, p less than 0.005), and 3) had an insignificant (p less than 0.39) effect on the impairment of saccadic peak velocity (slope, minus 1.13 percent per hour; intercept, minus 0.62 percent per hour). These results suggest that visual motion processing and some proportion of closed-loop pursuit performance are impaired due to homeostatic mechanisms during sleep deprivation.

Sleep↗

Neuro-behavioral Consequences of Low Dose Radiation Social Isolation and Sex Differences in the Longevity MCAT Mouse Model

The physiological responses to spaceflight elicit wide-ranging consequences and resemble aspects of aging on Earth. Previous studies have shown that oxidative damage via reactive oxygen species (ROS), contributes to aging-related pathologies. Our study uses 1-year old C57BL/6NJ male and female mice (astronaut-relevant age) that underwent exposure to 0.5 gray of gamma radiation together with social isolation and were euthanized 12 weeks after. We used the longevity MCAT mouse model in which human catalase is overexpressed in the mitochondria, for ROS quenching. We aimed to determine whether in older mice quenching ROS, will mitigate the neuro-behavioral consequences of low dose ionizing radiation and/or social isolation and whether the outcomes will differ in males and females. We have performed five mission relevant behavioral tests which focused on performance, memory, physical stance, and stress. We have detected both sex and radiation effects; the older females look physically better are faster and perform better almost in all behavioral tests compared to their male counterparts. On the other hand, they are more sensitive to low dose radiation in many cases, in some cases this effect was indeed mitigated in the MCAT mice, pointing out to the importance of ROS in response to radiation stress and social isolation. We have measured plasma (7- and 90-days post radiation), cytokines, corticosterone and hippocampal cytokine and microglial activation at the end of the experiment. We saw significant changes in the plasma markers due to radiation, sex, and genotype in both short and long post radiation period and detected long term sex and radiation effects in the brain. Our focus is now on applying advanced statistical modeling to corelate the behavioral tests with our recent molecular findings to look for specific biomarkers that could predict behavioral deficits.

radiation↗

A Dedicated, Long Duration Balloon Mission from Antarctica to Measure the Effects of Low Dose Galactic Cosmic Radiation on Biology

Antarctic long duration balloon missions flown by NASA’s Science Mission Directorate (SMD)can be used as a surrogate for the deep space radiation environment, reducing the need to launch orbital experiments to assess the impact of galactic cosmic radiation (GCR) on biology. To date, over fifty NASA balloon missions flown from Antarctica have carried scientific payloads from Astrophysics (APD) and Heliophysics (HPD)in SMD. Only two life science experiments have been flown from Antarctica, and both were ride-along (piggyback) opportunities, limiting the sophistication and types of model organisms that can be incorporated into studies. Herein, we argue for establishing a large, dedicated Antarctic balloon mission for the Biological and Physical Sciences (BPS) Division in SMD to be launched in 2029/2030, with an “omnibus” gondola carrying dozens of independent Space Biology payloads that would receive a sustained exposure to low dose rate GCRs for 30+ days. Our unprecedented, protracted radiation experiment cannot be done using ground-based simulation facilities or in space; it can only be achieved through an Antarctic balloon mission dedicated to BPS Division payloads. By providing more access to radiation research platforms through existing NASA SMD access to Antarctic balloon flight opportunities, the Space Biology community will be better positioned to address unknowns associated with low dose rate GCR exposures in long duration spaceflight.

David J Smith↗

The Effects of ELDRS at Ultra-Low Dose Rates

We present results of ultra-low dose-rate irradiations on a variety of commercial and radiation hardened bipolar circuits. We observed enhanced degradations at dose rates lower than 10 mrad(Si)/s in some devices.

Chen, Dakai↗

Solar Variability and the Near-Earth Environment: Mining Enhanced Low Dose Rate Sensitivity Data From the Microelectronics and Photonics Test Bed Space Experiment

This effort is a detailed analysis of existing microelectronics and photonics test bed satellite data from one experiment, the bipolar test board, looking to improve our understanding of the enhanced low dose rate sensitivity (ELDRS) phenomenon. Over the past several years, extensive total dose irradiations of bipolar devices have demonstrated that many of these devices exhibited ELDRS. In sensitive bipolar transistors, ELDRS produced enhanced degradation of base current, resulting in enhanced gain degradation at dose rates <0.1 rd(Si)/s compared to similar transistors irradiated at dose rates >1 rd(Si)/s. This Technical Publication provides updated information about the test devices, the in-flight experiment, and both flight-and ground-based observations. Flight data are presented for the past 5 yr of the mission. These data are compared to ground-based data taken on devices from the same date code lots. Information about temperature fluctuations, power shutdowns, and other variables encountered during the space flight are documented.

Turflinger, T.↗

M-BAND Analysis of Chromosome Aberration In Human Epithelial Cells exposed to Gamma-ray and Secondary Neutrons of Low Dose Rate

High-energy secondary neutrons, produced by the interaction of galactic cosmic rays with the atmosphere, spacecraft structure and planetary surfaces, contribute to a significant fraction to the dose equivalent in crew members and passengers during commercial aviation travel, and astronauts in space missions. The Los Alamos Nuclear Science Center (LANSCE) neutron facility's "30L" beam line is known to generate neutrons that simulate the secondary neutron spectrum of the Earth's atmosphere at high altitude. The neutron spectrum is also similar to that measured onboard spacecraft like the MIR and the International Space Station (ISS). To evaluate the biological damage, we exposed human epithelial cells in vitro to the LANSCE neutron beams at an entrance dose rate of 2.5 cGy/hr or gamma-ray at 1.7cGy/hr, and assessed the induction of chromosome aberrations that were identified with mBAND. With this technique, individually painted chromosomal bands on one chromosome allowed the identification of inter-chromosomal aberrations (translocation to unpainted chromosomes) and intra-chromosomal aberrations (inversions and deletions within a single painted chromosome). Compared to our previous results for gamma-rays and 600 MeV/nucleon Fe ions of high dose rate, the neutron data showed a higher frequency of chromosome aberrations. However, detailed analysis of the inversion type revealed that all of the three radiation types in the study induced a low incidence of simple inversions. The low dose rate gamma-rays induced a lower frequency of chromosome aberrations than high dose rate gamma-rays, but the inversion spectrum was similar for the same cytotoxic effect. The distribution of damage sites on chromosome 3 for different radiation types will also be discussed.

Hada, M.↗

Mice Exposed to Combined Chronic Low-Dose Irradiation and Modeled Microgravity Develop Long-Term Neurological Sequelae

Spaceflight poses many challenges for humans. Ground-based analogs typically focus on single parameters of spaceflight and their associated acute effects. This study assesses the long-term transcriptional effects following single and combination spaceflight analog conditions using the mouse model, simulated microgravity via hindlimb unloading (HLU) and/or low-dose irradiation (LDR) for 21-days, followed by 4 months of readaptation. Changes in gene expression and epigenetic modifications in whole brain samples during readaptation were analyzed by DESeq2 and reduced representation bisulfite sequencing (RRBS). The results showed minimal gene expression alterations at 4-months within single treatment conditions of HLU and LDR. Following combined HLU+LDR, gene ontology and methylation analyses showed multiple altered pathways involved in neurogenesis and neuroplasticity, regulation of neuropeptides and cellular signaling. In brief, neurological readaptation following combined chronic LDR and HLU is a dynamic process that impacts brain structure and function and may lead to late onset neurological sequelae

Overbey, Eliah G.↗

Multi-Omics Analysis of Mouse Retina Following Low Dose Radiation and/or Hindlimb Unloading

Rodent models have been used as analogs for studying the effects of spaceflight. NASA’s GeneLab provides access to omics datasets generated from spaceflight and ground-based experiments allowing for additional retrospective analysis. We used GeneLab’s GLDS-203, a dataset generated by researchers at Loma Linda University to study the impact of prolonged unloading and/or low-dose radiation on mouse retina. The purpose of this study was to understand the effect of gamma radiation and/or hindlimb unloading on mice retinas through a multi-omics analysis. In the experiment that generated the omics data, mice were irradiated with gamma-ray and/or subjected to hindlimb unloading for 21 days and multi-omics analysis was performed at 7 days, 1 month, or 4 months post exposure. In the current study, for each of the three timepoints, we compared epigenomic profiles for retinas from exposed mice against timepoint-matched controls. We identified a total of 5,271 differentially methylated loci (DML) and 321 differentially methylated regions (DMR; using a sliding window and step size of 500 bp) with methylation difference > 10% and q-value < 0.05 (sliding linear model corrected p-value) across the nine exposure groups. Highest correlation in methylation difference was seen for significant DMLs (q-value < 0.05) across different conditions at same post exposure timepoint (Figure 1).The location of DMLs and DMRs were characterized with respect to CpG islands and shores, putative promoters, gene body, and intergenic regions (Table 1). We analyzed RNA-seq counts and performed gene set enrichment analysis using differential expression results from comparing each exposure group to its timepoint-matched control group. Significant pathways (adjusted p-value <0.05) enriched in all three microgravity-only groups were related to morphogenesis of a branching epithelium, skeletal muscle cell differentiation, and response to fibroblast growth factor. Common processes across all timepoints in the radiation-only groups were retina homeostasis, synaptic vesicle exocytosis-endocytosis, and chemotaxis. In the combination groups, regulation of trans-synaptic signaling, and Rho protein signal transduction were enriched at all three timepoints. Processes related to purine nucleotide metabolism were enriched in all nine exposure groups, with activation at 1 month, and suppression at 7 days and 4 months. A total of 14 genes contained at least one DML and were differentially expressed at adjusted p-value < 0.05, including genes implicated in cataract development (Sipa1l3, Crybb3) and those involved in cytoskeletal organization (Plec, Flnb, Eef1a1). This analysis is part of a larger effort to understand the molecular mechanisms following spaceflight exposures that can help translate effects observed in animal models to human impacts.

Prachi Kothiyal↗