The effect of ionizing radiation on genetic transcription - Aspects of the mechanism.
Genetic transcription as affected by ionizing radiation and hydrogen peroxide
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Genetic transcription as affected by ionizing radiation and hydrogen peroxide
The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.
A long-standing dogma in the radiation sciences is that energy from radiation must be deposited in the cell nucleus to elicit a biological effect. A number of non-targeted, delayed effects of ionizing radiation have been described that challenge this dogma and pose new challenges to evaluating potential hazards associated with radiation exposure. These effects include induced genomic instability and non-targeted bystander effects. The in vitro evidence for non-targeted effects in radiation biology will be reviewed, but the question as to how one extrapolates from these in vitro observations to the risk of radiation-induced adverse health effects such as cancer remains open.
One of the main health risks in human deep space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neurodegeneration and neuroinflammation associated with cognitive and behavioral dysfunction. The extent of CNS damage is partially mediated by the blood-brain barrier (BBB), which regulates the interaction between CNS and systemic responses to stressors in the rest of the body. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, neuroinflammation and oxidative stress. However, studies on BBB and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we developed a high throughput 3D human neurovascular system model, based on commercially available Mimetas OrganoPlates seeded by primary human cells, to investigate the neurovascular responses to simulated deep space radiation. Using this system, we have demonstrated that 600MeV/n 56Fe irradiation leads to cellular damage and increased blood-brain barrier permeability via dysfunction of brain cells called astrocytes, which appear to be the weakest link and therefore a highly suitable countermeasure target to reduce the impact of space radiation on the blood-brain barrier. We anticipate that our results form merely the first step in ongoing development of organ models, including their adaptation for personalized risk assessment, high throughput approaches to countermeasure screening and validation, and eventual payload adaptation.
The Total Ozone Mapping Spectrometer (TOMS) will fly on several different spacecraft, each having an orbit which is approximately polar and 800-980 km in altitude. A description is given of the computer-based tools used for characterizing the spacecraft interactions with the ionizing radiation environment in orbit and the susceptibility requirements for ionizing radiation compatibility. The peak flux from the model was used to derive the expected radiation-induced noise in the South Atlantic Anomaly for the new TOMS instruments intended to fly on Advanced Earth Observatory System and Earth Probe.
The normal working and living areas of the astronauts are designed to provide an acceptable level of protection against the hazards of ionizing radiation of the space environment. Still there are occasions when they must don a spacesuit designed mainly for environmental control and mobility and leave the confines of their better-protected domain. This is especially true for deep space exploration. The impact of spacesuit construction on the exposure of critical astronaut organs will be examined in the ionizing radiation environments of free space, the lunar surface and the Martian surface. The computerized anatomical male model is used to evaluate astronaut self-shielding factors and to determine space radiation exposures to critical radiosensitive human organs.
Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have demonstrated that genes with upregulated expression induced by IR may play important roles in DNA damage sensing, cell cycle checkpoint and chromosomal repair, the relationship between the regulation of gene expression by IR and its impact on cytogenetic responses to ionizing radiation has not been systematically studied. In our present study, the expression of 25 genes selected based on their transcriptional changes in response to IR or from their known DNA repair roles were individually knocked down by siRNA transfection in human fibroblast cells. Chromosome aberrations (CA) and micronuclei (MN) formation were measured as the cytogenetic endpoints. Our results showed that the yield of MN and/or CA formation were significantly increased by suppressed expression of 5 genes that included Ku70 in the DSB repair pathway; XPA in the NER pathway; RPA1 in the MMR pathway; RAD17 and RBBP8 in cell cycle control. Knocked-down expression of 4 genes including MRE11A, RAD51 in the DSB pathway, and SESN1 and SUMO1 showed significant inhibition of cell cycle progression, possibly because of severe impairment of DNA damage repair. Furthermore, loss of XPA, p21 and MLH1 expression resulted in both enhanced cell cycle progression and significantly higher yield of cytogenetic damage, indicating the involvement of these gene products in both cell cycle control and DNA damage repair. Of these 11 genes that affected the cytogenetic response, 9 were up-regulated in the cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulating the biological consequences after IR. Failure to express these IR-responsive genes, such as by gene mutation, could seriously change the outcome of the post IR scenario and lead to carcinogenesis.
The effects of ionizing radiation on three different charge coupled imagers have been investigated. Device performance was evaluated as a function of total gamma ray dose. The principal failure mechanisms have been identified for each particular device structure. The clock and bias voltages required for high total dose operation of the devices are presented.
The ionizing radiation measurements flown on the Long Duration Exposure Facility (LDEF) were contained in 15 experiments which utilized passive detectors to pursue objectives in astrophysics and to measure the radiation environment and dosimetric quantities. The spacecraft structure became sufficiently radioactive to permit additional important studies. The induced activity allows extensive radiation mapping in the structure, and independent comparison with experiment dosimetric techniques, and significant studies of secondary effects. The long exposure time, attitude stability, and number and types of measurements produced a unique and critical set of data for low Earth orbit that will not be duplicated for more than a decade. The data allow an unprecedented test, and improvement if required, of models of the radiation environment and the radiation transport methods that are used to calculate the internal radiation and its effects in spacecraft. Results of measurements in the experiments, as well as from radioactivity in the structure, have clearly shown effects from the directional properties of the radiation environment, and progress was made in the dosimetric mapping of LDEF. These measurements have already influenced some Space Station Freedom design requirements. Preliminary results from experiments, reported at this symposium and in earlier papers, show that the 5.8 years exposure considerably enhanced the scientific return of the radiation measurements. The early results give confidence that the experiments will make significant advances in the knowledge of ultra heavy cosmic rays, anomalous cosmic rays, and heavy ions trapped in the radiation belts. Unexpected phenomena were observed, which require explanation. These include stopping iron group ions between the energy ranges anticipated for anomalous and galactic cosmic rays in the LDEF orbit. A surprising concentration of the Be-7 nuclide was discovered on the 'front' surface of LDEF, apparently transported up from the stratosphere with exceptional efficiency.
A new Atmospheric Ionizing Radiation (AIR) model is currently being developed for use in radiation dose evaluation in epidemiological studies targeted to atmospheric flight personnel such as civilian airlines crewmembers. The model will allow computing values for biologically relevant parameters, e.g. dose equivalent and effective dose, for individual flights from 1945. Each flight is described by its actual three dimensional flight profile, i.e. geographic coordinates and altitudes varying with time. Solar modulated primary particles are filtered with a new analytical fully angular dependent geomagnetic cut off rigidity model, as a function of latitude, longitude, arrival direction, altitude and time. The particle transport results have been obtained with a technique based on the three-dimensional Monte Carlo transport code FLUKA, with a special procedure to deal with HZE particles. Particle fluxes are transformed into dose-related quantities and then integrated all along the flight path to obtain the overall flight dose. Preliminary validations of the particle transport technique using data from the AIR Project ER-2 flight campaign of measurements are encouraging. Future efforts will deal with modeling of the effects of the aircraft structure as well as inclusion of solar particle events. Published by Elsevier Ltd on behalf of COSPAR.
Energy dissipation characteristics in tissue for ionizing radiation in space
The Diffuse Infrared Background Experiment (DIRBE) is one of three experiments to be carried aboard the Cosmic Background Explorer (COBE) satellite scheduled to be launched by NASA on a Delta rocket in 1989. The DIRBE is a cryogenic absolute photometer operating in a liquid helium dewar at 1.5 K. Photometric stability is a principal requirement for achieving the scientific objectives of this experiment. The Infrared Astronomy Satellite (IRAS), launched in 1983, which used detectors similar to those in DIRBE, revealed substantial changes in detector responsivity following exposure to ionizing radiation encountered on passage through the South Atlantic Anomaly (SAA). Since the COBE will use the same 900 Km sun-synchronous orbit as IRAS, ionizing radiation-induced performance changes in the detectors were a major concern. Here, ionizing radiation tests carried out on all the DIRBE photodetectors are reported. Responsivity changes following exposure to gamma rays, protons, and alpha particle are discussed. The detector performance was monitored following a simulated entire mission life dose. In addition, the response of the detectors to individual particle interactions was measured. The InSb photovoltaic detectors and the Blocked Impurity Band (BIB) detectors revealed no significant change in responsivity following radiation exposure. The Ge:Ga detectors show large effects which were greatly reduced by proper thermal annealing.
Future long duration missions outside the protection of the Earth's magnetosphere, or unshielded exposures to solar particle events, achieves total doses capable of causing cancellous bone loss. Cancellous bone loss caused by ionizing radiation occurs quite rapidly in rodents: Initially, radiation increases the number and activity of bone-resorbing osteoclasts, followed by decrease in bone forming osteoblast cells. Here we report that Dried Plum (DP) diet completely prevented cancellous bone loss caused by ionizing radiation (Figure 1). DP attenuated marrow expression of genes related to bone resorption (Figure 2), and protected the bone marrow-derived pre-osteoblasts ex vivo from total body irradiation (Figure 3). DP is known to inhibit resorption in models of aging and ovariectomy-induced osteopenia; this is the first report that dietary DP is radioprotective.
The SuperSonic Transport (SST) development program within the US was based at the Langley Research Center as was the Apollo radiation testing facility (Space Radiation Effects Laboratory) with associated radiation research groups. It was natural for the issues of the SST to be first recognized by this unique combination of research programs. With a re-examination of the technologies for commercial supersonic flight and the possible development of a High Speed Civil Transport (HSCT), the remaining issues of the SST required resolution. It was the progress of SST radiation exposure research program founded by T. Foelsche at the Langley Research Center and the identified remaining issues after that project over twenty-five years ago which became the launch point of the current atmospheric ionizing radiation (AIR) research project. Added emphasis to the need for reassessment of atmospheric radiation resulted from the major lowering of the recommended occupational exposure limits, the inclusion of aircrew as radiation workers, and the recognition of civil aircrew as a major source of occupational exposures. Furthermore, the work of Ferenc Hajnal of the Environmental Measurements Laboratory brought greater focus to the uncertainties in the neutron flux at high altitudes. A re-examination of the issues involved was committed at the Langley Research Center and by the National Council on Radiation Protection (NCRP). As a result of the NCRP review, a new flight package was assembled and flown during solar minimum at which time the galactic cosmic radiation is at a maximum (June 1997). The present workshop is the initial analysis of the new data from that flight. The present paper is an overview of the status of knowledge of atmospheric ionizing radiations. We will re-examine the exposures of the world population and examine the context of aircrew exposures with implications for the results of the present research. A condensed version of this report was given at the 1998 Annual Meeting of the NCRP with proceedings published in the journal of Health Physics.
Spectral features arising from the fluorescence caused by solar ionizing radiation examined by mode atmospheres, solar flux, and absorption cross section methods
DNA enzymatic breakdown in Escherichia coli as function of ionizing radiation and temperature
Monograph on ionizing radiation effects on molecular biology of Escherichia coli, discussing cellular damage, DNA degradation and synthesis, incorporating radioactivity, mutations, etc
Oxidative damages by ionizing radiation are the source of radiation-induced carcinogenesis, damage to the central nervous system, lowering of the immune response, as well as other radiation-induced damages to human health. Monte Carlo track simulations and kinetic modeling of radiation damages to the DNA employ available molecular and cellular data to simulate the biological effect of high and low LET radiation io the DNA. While the simulations predict single and double strand breaks and base damages, so far all complex lesions are the result of stochastic coincidence from independent processes. Tandem double lesions have not yet been taken into account. Unlike the standard double lesions that are produced by two separate attacks by charged particles or radicals, tandem double lesions are produced by one single attack. The standard double lesions dominate at the high dosage regime. On the other hand, tandem double lesions do not depend on stochastic coincidences and become important at the low dosage regime of particular interest to NASA. Tandem double lesions by hydroxyl radical attack of guanine in isolated DNA have been reported at a dosage of radiation as low as 10 Gy. The formation of two tandem base lesions was found to be linear with the applied doses, a characteristic of tandem lesions. However, tandem double lesions from attack by a charged particle have not been reported.