Radiation-induced Perturbations Research Articles

Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure.

There are currently four radiation medical countermeasures that have been approved by the United States Food and Drug Administration to mitigate hematopoietic acute radiation syndrome, all of which are repurposed radiomitigators. The evaluation of additional candidate drugs that may also be helpful for use during a radiological/nuclear emergency is ongoing. A chlorobenzyl sulfone derivative (organosulfur compound) known as Ex-Rad, or ON01210, is one such candidate medical countermeasure, being a novel, small-molecule kinase inhibitor that has demonstrated efficacy in the murine model. In this study, nonhuman primates exposed to ionizing radiation were subsequently administered Ex-Rad as two treatment schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation) and the proteomic profiles of serum using a global molecular profiling approach were assessed. We observed that administration of Ex-Rad post-irradiation is capable of mitigating radiation-induced perturbations in protein abundance, particularly in restoring protein homeostasis, immune response, and mitigating hematopoietic damage, at least in part after acute exposure. Taken together, restoration of functionally significant pathway perturbations may serve to protect damage to vital organs and provide long-term survival benefits to the afflicted population.

The German Uranium Miners’ Biobank—A Biobank for OMICs Radiation Research

Systematic bio- and databanks are key prerequisites for modern radiation research to investigate radiation response mechanisms in the context of genetic, environmental and lifestyle-associated factors. This report presents the current status of the German Uranium Miners’ Biobank. In 2008, the bio- and databank was established at the Federal Office for Radiation Protection, and the sampling of biological materials from former uranium miners with and without lung cancer was initiated. For this purpose, various biological specimens, such as DNA and RNA, were isolated from blood samples as well as from formalin-fixed paraffin-embedded lung tissue. High-quality biomaterials suitable for OMICs research and the associated data on occupational radiation and dust exposure, and medical and lifestyle data from over 1000 individuals have been stored so far. Various experimental data, e.g., genome-wide SNPs, whole genome transcriptomic and miRNA data, as well as individual chromosomal aberration data from subgroups of biobank samples, are already available upon request for in-depth research on radiation-induced long-term effects, individual radiation susceptibility to lung cancer and radon-induced fingerprints in lung cancer. This biobank is the first systematic uranium miners´ biobank worldwide that is suitable for OMICs research on radiation-exposed workers. It offers the opportunity to link radiation-induced perturbations of biological pathways or processes and putative adverse outcome(s) by OMICs profiling at different biological organization levels.

Intestinal stem cells acquire premature senescence and senescence associated secretory phenotype concurrent with persistent DNA damage after heavy ion radiation in mice.

Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses risk to stem cells that are key to intestinal homeostasis. Currently, the molecular spectrum of heavy ion radiation-induced perturbations in intestinal stem cells (ISCs), that could trigger intestinal pathologies, remains largely unexplored. The Lgr5-EGFP-IRES-creERT mice were exposed to 50 cGy of iron radiation. Mice were euthanized 60 d after exposure and ISCs were sorted using fluorescence activated cell sorting. Reactive oxygen species (ROS) and mitochondrial superoxide were measured using fluorescent probes. Since DNA damage is linked to senescence and senescent cells acquire senescence-associated secretory phenotype (SASP), we stained ISCs for both senescence markers p16, p21, and p19 as well as SASP markers IL6, IL8, and VEGF. Due to potential positive effects of SASP on proliferation, we also stained for PCNA. Data show increased ROS and ongoing DNA damage, by staining for γH2AX, and 53BP1, along with accumulation of senescence markers. Results also showed increased SASP markers in senescent cells. Collectively, our data suggest that heavy-ion-induced chronic stress and ongoing DNA damage is promoting SASP in a fraction of the ISCs, which has implications for gastrointestinal function, inflammation, and carcinogenesis in astronauts and patients.

BIOINFORMATIC ANALYSIS OF DOSE- AND TIME-DEPENDENT miRNome RESPONSES.

The advent of new 'omics' techniques determined a massive boost in the measurement of the whole spectra of molecules within cells, favoring promising new radiobiological studies at low doses. The main aim of this work was to assess the radiation-induced perturbations of miRNA profiles and their temporal dynamics. Human Umbilical Vein Endothelial Cells were irradiated with low doses of γ-rays. At different time points post-irradiation, cells were harvested and miRNAs isolated. A full mapping of the miRNA sequences via Next-Generation-Sequencing analysis was performed followed by bioinformatic analyses. Pathway enrichment analyses on the differentially expressed miRNAs focused both on the averaged effects of different doses over the 24-h experiment and on the altered temporal dynamics of the miRNA profiles. These complementary analyses provided a picture of the dose- and time-dependent miRNAs responses, allowing to better explore the candidate biomarkers linked to radiation exposures and their corresponding pathways and functions.

Investigation of radiation-induced multilayered signalling response of the inflammatory pathway.

Ionising radiation exposure of cells might induce the perturbation of cell functions and, in particular, the activation or inhibition of several important pathways. This perturbation can cause the deregulation of both intra- and extra-cellular signalling cascades (such as the inflammatory pathway) and alter not only the behaviour of directly exposed cells but also the neighbouring non-irradiated ones, through the so-called bystander effect. The aim of the present work was to investigate the complex nonlinear interactions between the inflammatory pathway and other strictly interlaced signalling pathways, such as Erk1/2 and Akt/PKB, focusing on the radiation-induced perturbation of such pathways in the dose range of 0-2 Gy. The results show how radiation affects these interconnected pathways and how confounding factors, such as the change of culture medium, can hide radiation-induced perturbations.

Radiation hardness of the storage phosphor europium doped potassium chloride for radiation therapy dosimetry

An important property of a reusable dosimeter is its radiation hardness, that is, its ability to retain its dosimetric merits after irradiation. The radiation hardness of europium doped potassium chloride (KC1:Eu2+), a storage phosphor material recently proposed for radiation therapy dosimetry, is examined in this study. Pellet-style KCl:Eu2+ dosimeters, 6 mm in diameter, and 1 mm thick, were fabricated in-house for this study. The pellets were exposed by a 6 MV photon beam or in a high dose rate 137Cs irradiator. Macroscopic properties, such as radiation sensitivity, dose response linearity, and signal stability, were studied with a laboratory photostimulated luminescence (PSL) readout system. Since phosphor performance is related to the state of the storage centers and the activator, Eu2+, in the host lattice, spectroscopic and temporal measurements were carried out in order to explore radiation-induced changes at the microscopic level. KCl:Eu2+ dosimeters retained approximately 90% of their initial signal strength after a 5000 Gy dose history. Dose response was initially supralinear over the dose range of 100-700 cGy but became linear after 60 Gy. Linearity did not change significantly in the 0-5000 Gy dose history spanned in this study. Annealing high dose history chips resulted in a return of supralinearity and a recovery of sensitivity. There were no significant changes in the PSL stimulation spectra, PSL emission spectra, photoluminescence spectra, or luminescence lifetime, indicating that the PSL signal process remains intact after irradiation but at a reduced efficiency due to reparable radiation-induced perturbations in the crystal lattice. Systematic studies of KCl:Eu2+ material are important for understanding how the material can be optimized for radiation therapy dosimetry purposes. The data presented here indicate that KCl:Eu2+ exhibits strong radiation hardness and lends support for further investigations of this novel material.

Impurity hot atoms in irradiated metals with different nuclear history

General relationships in the effect of the nuclear history on the forms of stabilization of impurity hot atoms and on the diffusion mobility and specific features of the physicochemical behavior of radioactive micro-impurities in the course of annealing of radiation-induced perturbations and of structural transformations of irradiated metals were elucidated. The forms of stabilization of impurity hot atoms in metals after irradiation and in the course of annealing of radiation-induced perturbations and of structural transformations, were determined by emission Mossbauer spectroscopy. It was shown that the positions occupied by impurity atoms in irradiated metals are determined by the nuclear history and crystallographic features of these metals. Studies of how impurity hot atoms formed by nuclear transformations migrate in the course of annealing of the irradiated metals show that the rate of migration of radioactive micro-impurities is determined by the extent of the radiation damage of the targets and by the possible position of the impurity hot or daughter atom in the crystal lattice of the irradiated metal. The transport mechanism accounting for the anomalous behavior of impurities is suggested. Anomalies (accelerated diffusion in the bulk and in surface layers of irradiated metals and emanation into the gas phase) in the physicochemical behavior of impurity atoms in the course of structural transformations of irradiated metals were revealed. These anomalies depend on the nuclear and mechanical history of the samples and on the conditions of their annealing. The interrelation between the nuclear history, crystallographic position of impurity hot atoms, their physicochemical characteristics, and structural changes occurring in metals in the course of irradiation, annealing of radiation-induced perturbations, and structural transformations was demonstrated by X-ray phase analysis and various kinds of Mossbauer spectroscopy. For metals having several allotropic modifications (Mn, Fe, Sn), the effect of stabilization of high- and low-temperature structural phases at room temperature upon irradiation was discovered.

Irradiation-Induced Electron Tunnelling and Small-Polaron Hopping in Single-Crystalline YIG

In electron (e - )-irradiated (>10 23 e - m -2 ) single crystalline yttrium-ion Garnet (YIG), after moderate annealing, low-temperature (T < 125 K) magnetic after-effect (MAE) spectra are observed which are of striking similarity to the well investigated spectra occurring in magnetite (Fe 3 O 4 ) below the Verwey transition (T V 125 K). Our analysis shows that this similarity is the result of corresponding relaxation mechanisms in both systems, i.e. electron tunnelling and small-polaron hopping. Deeper insights into these mechanisms are obtained from a thorough inspection of these spectra and their physical preconditions in the two, a-priori, completely different ferrimagnetic systems: (i) semiconductor, transformed into a quasi-insulating state due to long-range ionic ordering at low-temperatures (Fe 3 O 4 ) and (ii) insulator, brought into a state of low resistivity due to radiation-induced perturbations of the charge equilibrium (YIG).

Effect of vindesine sulfate on the radiation-induced alterations in mouse spermatogenesis: a flow cytometric evaluation

The effect of 0.05 mg/kg body weight of vindesine sulfate was studied on the radiation-induced changes in mouse spermatogenesis at 1, 2, 7, 14, 21, 28, 35 and 70 days post-irradiation. Vindesine administration before exposure to 0, 0.5, 1, 2 and 3 Gy γ-irradiation resulted in an increase in the radiation-induced perturbations of mouse spermatogenesis at various post-exposure time periods studied. A significant reduction in testicular weight was observed in both DDW+irradiated and VDS+irradiated groups at various post-irradiation time periods, depending on the exposure dose. Vindesine pretreatment resulted in an enhanced killing of spermatogonial cells at day 2 post-exposure at all the exposure doses, except 3 Gy when compared to DDW+irradiated controls. Consequently, the tetraploid (4C) population declined significantly by day 14 post-irradiation followed by a severe depletion in round spermatids (1C) by day 21 post-irradiation. The dose–response relationship for 4C and 1C populations was linear-quadratic at days 14 and 21, respectively. A significant elevation was observed in HC population from days 1 to 21 depending on the exposure dose. The germ cell ratios, viz. 4C:2C, 4C:S-phase, 1C:2C and 1C:4C, showed a significant decline in the VDS+irradiated group when compared to the DDW+irradiated group at various time periods, depending on the exposure dose.

Effect of low doses of gamma-radiation on the steady-state spermatogenesis of mouse: a flow-cytometric study

Radiation-induced perturbations in the steady-state spermatogenesis of mouse exposed to 0.05 to 2 Gy of 60Co gamma-radiation were studied at 7 to 70 days post-irradiation flow cytometrically. Five quantifiable populations viz: elongated spermatids (HC), round spermatids (1C), spermatogonia and other diploid cells (2C), spermatogonial cells synthesizing DNA (S-phase) and primary spermatocytes (4C) were identified in the sham-irradiated controls. Exposure of mice to different doses of radiation resulted in a significant decline in the total germ-cell transformation ratio (1C:2C) at 21 and 28 days post-irradiation as compared to the control group, except for the animals exposed to 0.05 Gy. The 1C:2C ratio is sub-divided into two components viz. 4C:2C and 1C:4C. The 4C:2C ratio decreased significantly on day 14 post-irradiation, except for 0.05 Gy where it was non-significant. Consequently, meiotic transformation (1C:4C) showed a significant increase on day 14 post-irradiation compared to the sham-irradiated control barring 0.05 Gy where the difference between the two groups was non-significant. The ratio of HC:1C (cell transformation during spermiogenesis) increased significantly at day 21 post-irradiation 0.2 to 2 Gy and between day 7 and 14 for 0.05 Gy as compared to the control group. It appears that a dose as low as 0.05 Gy radiation was able to cause the perturbations in the steady-state spermatogenesis of mouse and normalcy was not restored even up to 70 days post-irradiation at all exposure doses.

Radiation-induced orientation of atmospheric aerosols

A theoretical model is presented for computing the radiation-induced orientation of nonspherical particles in the atmosphere. This process is examined as a possible remote-sensing technique for determining size and shape characteristics of atmospheric aerosols. The theoretical model is applied to cirrus particles modeled as prolate dielectric spheroids. The radiation-induced perturbations in the average tip angle of the spheroids and in the backscattered depolarization ratio are computed for an assumed radiation flux of 5 mJ/cm2 for three different wavelengths. The computed perturbations are found to be approximately 30–40 dB down from the corresponding unperturbed values and appear marginally detectable by ground-based lidars.

Radiation-induced perturbations in CO and Xe sidelight in the CO-He-Xe laser

Laser oscillation in a sealed-off room-temperature CO-He-Xe laser was observed to perturb CO and Xe sidelight intensities in the laser discharge. Bands of the CO fourth-positive group (A 1 Pi to X 1 Sigma +) with v'=1-5 and 7 were enhanced during laser oscillation, while those with v'=6 and 8 exhibited no change in intensity. Bandheads of the CO third-positive group (b 3 Sigma +, v'=0, 1 to a 3 Pi r) were either enhanced or inhibited during laser oscillation depending on the discharge conditions; tail intensities of the third-positive bands, however, were always inhibited. Near-infrared Xe lines were enhanced (by up to 190%) during lasing. The excitation routes for the CO bands and the Xe lines have been identified, and the effects of laser oscillation on those routes are explained in terms of altered rates during lasing of electron-impact processes and collision-induced energy transfers.

Radiation-induced perturbations in C2 and CH sidelight in the CO-He-Xe laser

Visible C2 and CH sidelight emission in a CO-He-Xe laser discharge exhibits intensity fluctuations of typically 30-40% when laser oscillation is chopped on and off. Chemical reactions in the discharge plasma are shown to play the major role in the perturbations of the C2 Swan and high-pressure bands and the CH 4300 AA bands. The dissociation of CO is shown to take place in the reaction of CO (a 3 Pi r) metastables and ground-state CO, and via the reaction of two vibrationally excited ground-state CO molecules, rather than via direct electron impact.

Effect of gamma radiation on enzymatic activity and sulphydryl groups of human erythrocyte membrane.

The effect of ionizing radiation on human erythrocyte ghost membranes was studied by following changes in membrane -SH groups and activities of four membrane bound enzymes: Na+K+Mg2+ ATP-ase, Mg2+Ca2+ ATP-ase, Na+K+ATP-ase, and AChE. Irradiation up to 100 Gy gamma X-rays produced a significant decrease in the activity of ATP-ase and an increase in AChE activity. At higher radiation doses a marked decrease in the activities of all the enzymes was observed. A correlation between radiation-induced perturbations in enzyme activities and changes in membrane -SH groups was found.

The Influence of Silicon Surface Defects on MOS Radiation-Sensitivity

The relationships of the electrical properties of irradiated MOS structures to processed-induced surface defects have been investigated. It has been found that the radiation-induced perturbations in oxide space-charge and interface states relate directly to the density of oxidation-induced stacking faults and edge dislocations. The density of such surface defects depends on both the structural properties of the starting silicon and the fabrication procedures. Oxidation-induced stacking faults are strongly related to the oxidation conditions, such as temperature, time, and ambiance. High-frequency CV, quasi-static CV, and ac conductance techniques were used to determine the interface state densities and flat-band voltage distributions. It has been found that, in addition to interface states, exposure to ionizing radiation causes gross non-uniformities in trapped positive space-charge. Using secondary ion mass spectrometry (SIMS) on an MOS sample possessing a high density of stacking faults, it has been shown that positive charge-species drift to the SiO2/Si interface and form clusters in a random fashion similar to that of the defects delineated by differential etching. Based on the known relationship of surface generation lifetime on surface defects pre-irradiation lifetime has been demonstrated as an effective electrical parameter for the prediction of the total-dose radiation sensitivity of MOS devices.

Radiation-induced perturbations in metal-insulator-semiconductor structures : H. L. Hughes. Proc. IEEE Reliab. Phys. Symp., Las Vegas, U.S.A., 31 March–2 April (1971)

Radiation-induced perturbations in metal-insulator-semiconductor structures : H. L. Hughes. Proc. IEEE Reliab. Phys. Symp., Las Vegas, U.S.A., 31 March–2 April (1971)

Radiation-Induced Perturbations of the Electrical Properties of the Silicon-Silicon Dioxide Interface

Interface-state densities and MOS transistor characteristics dependent upon such states have been studied as a function of radiation dose and type. Special MOS devices possessing doped silicon-dioxide layers as well as undoped control devices have been utilized. Infrared absorption measurements were performed on silicon-dioxide samples before and after exposure to radiation, as well as for doped and undoped samples. A model based on structural modifications of the silicon-dioxide-films is proposed for the build-up of interface-states resulting from exposure to radiation. It has been found that with the proper doping of the silicon-dioxide films, the build-up of such states can be reduced. Using such doped gate-dielectrics, planar semiconductor devices much less sensitive to radiation have been fabricated.