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Both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. Much of this is unavoidable, e.g., natural background radiation, but as the use of radiation increases, so does the potential health risk and the public's concerns. This perspective reflects the authors' view of current issues in low dose radiation biology research, highlights some of the controversies therein, and suggests areas of future research to address both issues in low dose radiation research and the controversies. This is a critical time for the radiation sciences and the implications of future research will have a significant impact on radiation protection, medicine, national security, research and industry. The views expressed here are the authors' own and do not represent any institution, organization or funding body.
Human exposure to high-energy protons occurs in space flight scenarios or, where necessary, during radiotherapy for cancer or benign conditions. However, few studies have assessed the mutagenic effectiveness of high-energy protons, which may contribute to cancer risk. Mutations cause cancer and most cancer-associated mutations occur at autosomal loci. This study addresses the cytotoxic and mutagenic effects of 1 GeV protons in mouse kidney epithelium. Mutant fractions were measured for an endogenous autosomal locus (Aprt) that detects all types of mutagenic events. Results for kidneys irradiated in vivo are compared with the results for kidney cells from the same strain exposed in vitro. The results demonstrate dose-dependent cell killing in vitro and for cells explanted 3–4 months postirradiation in vivo. Incubation in vivo for longer periods (8–9 months) further attenuates proton-induced cell killing. Protons are mutagenic to cells in vitro and for in vivo irradiated kidneys. The dose-response for Aprt mutation is curvilinear after in vitro or in vivo exposure, bending upward at the higher doses. While the absolute mutant fractions are higher in vivo, the fold-increase over background is similar for both in vitro and in situ exposures. Results are also presented for a limited study on the effect of dose fractionation on the induction of Aprt mutations in kidney epithelial cells. Dose-fractionation reduces the fraction of proton-induced Aprt mutants in vitro and in vivo and also results in less cell killing. Taken together, the mutation burden in the epithelium is slightly reduced by dose-fractionation. Autosomal mutations accumulated during clinical exposure to high-energy protons may contribute to the risk of treatment-associated neoplasms, thereby highlighting the need for rigorous treatment planning to reduce the dose to normal tissues. For low dose exposures that occur during most space flight scenarios, the mutagenic effects of protons appear to be modest.
Proton exposure induces mutations and cancer, which are presumably linked. Because protons are abundant in the space environment and significant uncertainties exist for the effects of space travel on human health, the purpose of this study was to identify the types of mutations induced by exposure of mammalian cells to 4–5 Gy of 1 GeV protons. We used an assay that selects for mutations affecting the chromosome 8-encoded Aprt locus in mouse kidney cells and selected mutants after proton exposure both in vivo and in cell culture. A loss of heterozygosity (LOH) assay for DNA preparations from the in vivo-derived kidney mutants revealed that protons readily induced large mutational events. Fluorescent in situ hybridization painting for chromosome 8 showed that >70% of proton-induced LOH patterns resembling mitotic recombination were in fact the result of nonreciprocal chromosome translocations, thereby demonstrating an important role for DNA double-strand breaks in proton mutagenesis. Large interstitial deletions, which also require the formation and resolution of double-strand breaks, were significantly induced in the cell culture environment (14% of all mutants), but to a lesser extend in vivo (2% of all mutants) suggesting that the resolution of proton-induced double-strand breaks can differ between the intact tissue and cell culture microenvironments. In total, the results demonstrate that double-strand break formation is a primary determinant for proton mutagenesis in epithelial cell types and suggest that resultant LOH for significant genomic regions play a critical role in proton-induced cancers.
This article presents a biochemical kinetic model for the non-homologous end joining (NHEJ) of DNA double-strand break (DSB) repair pathway. The model is part of a theoretical framework to encompass all cellular DSB repair pathways. The NHEJ model was developed by taking into consideration the biological characteristics of the repair processes in the absence of homologous recombination (HR), the major alternative pathway for DSB repair. The model considers fast and slow components of the repair kinetics resulting in a set of differential equations that were solved numerically. In the absence of available published data for reaction rate constants for the repair proteins involved in NHEJ, we propose reaction rate constants for the solution of the equations. We assume as a first approximation that the reaction rate constants are applicable to mammalian cells under same conditions. The model was tested by comparing measured and simulated DSB repair kinetics obtained with HR-deficient cell lines irradiated by X rays in the dose range of 20–80 Gy. Measured data for initial protein recruitment to a DSB were used to independently estimate rate constants for Ku70/Ku80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We show here based on the model of DSB repair described in this article, application of the model in the accompanying article (Taleei et al., Radiat. Res. 179, 540–548, 2013) and by simulation of repair times for each individual DSB produced by individual tracks of electrons, that the complexity of damage may explain the slow kinetics of DNA DSB repair.
We investigated the kinetics of simple and complex types of double-strand breaks (DSB) using our newly proposed mechanistic mathematical model for NHEJ DSB repair. For this purpose the simulated initial spectrum of DNA DSB, induced in an atomistic canonical model of B-DNA by low-energy single electron tracks, 100 eV to 4.55 keV, and the electrons generated by ultrasoft X rays (CK, AlK and TiK), were subjected to NHEJ repair processes. The activity elapsed time of sequentially independent steps of repair performed by proteins involved in NHEJ repair process were calculated for separate DSB. The repair kinetics of DSBs were computed and compared with published data on repair kinetics obtained by pulsed-field gel electrophoresis method. The comparison shows good agreement for V79-4 cells irradiated with ultrasoft X rays. The average times for the repair of simple and complex DSB confirm that double-strand break complexity is a potential explanation for the slow component of DSB repair observed in V79-4 cells irradiated by ultrasoft X rays.
Cognitive impairment precipitated by irradiation of normal brain tissue is commonly associated with radiation therapy for treatment of brain cancer, and typically manifests more than 6 months after radiation exposure. The risks of cognitive impairment are of particular concern for an increasing number of long-term cancer survivors. There is presently no effective means of preventing or mitigating this debilitating condition. Neuroinflammation mediated by activated microglial cytokines has been implicated in the pathogenesis of radiation-induced cognitive impairment in animal models, including the disruption of neurogenesis and activity-induced gene expression in the hippocampus. These pathologies evolve rapidly and are associated with relatively subtle cognitive impairment at 2 months postirradiation. However, recent reports suggest that more profound cognitive impairment develops at later post-irradiation time points, perhaps reflecting a gradual loss of responsiveness within the hippocampus by the disruption of neurogenesis. We hypothesized that inhibiting neuroinflammation using MW01-2-151SRM (MW-151), a selective inhibitor of proinflammatory cytokine production, might mitigate these deleterious radiation effects by preserving/restoring hippocampal neurogenesis. MW-151 therapy was initiated 24 h after 10 Gy whole-brain irradiation (WBI) administered as a single fraction and maintained for 28 days thereafter. Proinflammatory activated microglia in the dentate gyrus were assayed at 2 and 9 months post-WBI. Cell proliferation and neurogenesis in the dentate gyrus were assayed at 2 months post-WBI, whereas novel object recognition and long-term potentiation were assayed at 6 and 9 months post-WBI, respectively. MW-151 mitigated radiation-induced neuroinflammation at both early and late time points post-WBI, selectively mitigated the deleterious effects of irradiation on hippocampal neurogenesis, and potently mitigated radiation-induced deficits of novel object recognition consolidation and of long-term potentiation induction and maintenance. Our results suggest that transient administration of MW-151 is sufficient to partially preserve/restore neurogenesis within the subgranular zone and to maintain the functional integrity of the dentate gyrus long after MW-151 therapy withdrawal.
Dicentric chromosome analysis remains the most widely used method in biodosimetry. It has a lower detection limit of about 0.1 Gy, and allows one to distinguish between whole- and partial-body exposures. A drawback of the dicentric analysis is that it is a time consuming method and maybe difficult to implement in a mass casualty event. To try to increase the analysis capacity, automatic dicentric scoring (ADS) using image analysis software is being incorporated in several laboratories. Here we present the results obtained in an emergency exercise simulating 50 victims. The ability to distinguish different radiations scenarios is evaluated. To simulate whole-body exposures peripheral blood samples were irradiated at doses between 0–4.7 Gy, and to simulate partial-body exposures irradiated and nonirradiated blood were mixed in different proportions. With the data obtained from the first slide analyzed (with about 300–400 cells), 32 of 34 simulated whole-body exposures were correctly classified according to radiation exposure levels. For simulated partial-body irradiations, it was possible to detect them as partial exposures at the end of the first slide analyzed but only at the highest doses. In all cases the classification was updated every time the analysis of one additional slide was finished. The comparison between our present results and those reported in the literature for manual scoring shows that for triage purposes the ADS based on 300–400 cells is similar in efficiency to classifying the cases based on manual scoring of 50 cells. However, if one accounts for the associated uncertainties and the time needed for ADS, we suggest that ADS triage scoring should be based on about 1,000 cells. For final dose estimations the number of cells to score will depend on the initial estimated dose, and on the information contributed from physical dose-reconstruction or clinical symptoms. At doses higher than 1 Gy, we propose analysis of 1,500 and for lower doses or suspected partial-body exposures, the number of cells to score should be 3,000.
Gamma radiation is used for several therapeutic indications such as cancers and autoimmune diseases. Low-dose whole-body γ irradiation has been shown to activate immune responses in several ways, however, the effect and mechanism of irradiation on allergic asthma remains poorly understood. This study investigated whether or not irradiation exacerbates allergic asthma responses and its potential mechanism. C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) to induce asthma. The mice received whole-body irradiation once daily for 3 consecutive days with a dose of 0.667 Gy using 137Cs γ rays 24 h before every OVA challenge. Repeated low-dose irradiation reduced OVA-specific IgE levels, the number of inflammatory cells including mast cells, goblet cell hyperplasia, collagen deposition, airway hyperresponsiveness, expression of inflammatory cytokines, CCL2/CCR2, as well as nuclear factor kappa B (NF-κB) and activator protein-1 activities. All of these factors were increased in BAL cells and lung tissue of OVA-challenged mice. Irradiation increased the number of Treg cells, expression of interleukin (IL)-10, IL-2 and IL-35 in BAL cells and lung tissue. Irradiation also increased Treg cell-expressed Foxp3 and IL-10 by NF-κB and RUNX1 in OVA-challenged mice. Furthermore, while Treg cell-expressing OX40 and IL-10 were enhanced in lung tissue or act-bone marrow-derived mast cells (BMMCs) with Treg cells, but BMMCs-expressing OX40L and TGF-β were decreased. The data suggest that irradiation enhances Foxp3- and IL-10-producing Treg cells, which reduce OVA-induced allergic airway inflammation and tissue remodeling through the down-regulation of migration by the CCL2/CCR2 axis and activation of mast cells via OX40/OX40L in lung tissue of OVA-challenged mice.
Local radiotherapy is the major therapeutic approach to control inoperable cervical cancer. In this study, we analyzed the local immune microenvironment of cervical cancer before and after clinical radiation therapy to investigate whether tumor response due to immunomodulation. A total of 59 patients with pathologically diagnosed cervical cancers classified according to the International Federation of Obstetrics and Gynecology (FIGO) criteria were recruited. The patients were treated according to their disease status with standard radiation regimens. For each patient, tumor biopsies were conducted before, during and after radiation treatment with the doses of 0, 10, 20 and 30 Gy, respectively. All of the tumor samples were then grouped according to the doses delivered and tumor infiltrating lymphocytes with the biomarkers of CD8, CD4, FOXP3 and OX40 were measured by in situ immunohistochemistry. We found that before radiation treatment both CD8 T cell and CD4 T cell infiltrates were more present in the tumor stroma than in the tumor nests, while OX40 and FOXP3 T cell infiltrates were present at similar levels in both the tumor nests and stroma. After radiation treatment, the levels of CD8 T cells and CD4 T cells in the tumor nests and stroma were decreased compared with the levels before irradiation. However, OX40 T cells and FOXP3 T cells did not show any difference before and after irradiation, which indicates that the FOXP3 T cells were more resistant to ionizing radiation than were the cytotoxic effector T cells and demonstrates a dynamic rebalance of infiltrating lymphocytes in the tumor milieu occurs after radiotherapy. This suggest that local antitumor immunity could be compromised due to decreased cytotoxic effector cells and the relatively stable status of FOXP3 T cells after irradiation. Therefore, regulation of these FOXP3 T cells may be a potentially effective approach to enhance the efficacy of cancer radiation therapy.
Relatively little is known about early irradiation effects on hippocampal function in wild-type mice. In this study, the effects of 56Fe irradiation on hippocampal function were assessed starting 2 weeks after whole-body irradiation. Compared to sham irradiation, radiation impaired novel object recognition in female and male C57BL/6J wild-type mice. There were no effects of irradiation on contextual fear conditioning or spatial memory retention in the water maze. It is possible that oxidative damage might contribute to radiation-induced cognitive changes. Therefore, hippocampal and cortical levels of 3-nitrotyrosine (3NT) and lipid peroxidation, measures of oxidative damage were assessed. There were no effects of irradiation on these measures of oxidative damage. As 56Fe irradiation can increase reactive oxygen species (ROS) levels, which may contribute to the impairments in novel object recognition, the effects of the antioxidant alpha-lipoic acid (ALA) on cognition following sham irradiation and irradiation were also assessed. ALA did not prevent radiation-induced impairments in novel object recognition and impaired spatial memory retention of sham-irradiated and irradiated mice in the probe trial after the first day of hidden platform training in the water maze. Thus, the novel object recognition test is particularly sensitive to detect early cognitive effects of 56Fe irradiation through a mechanism unlikely involving ROS or oxidative damage.
The U.S. National Cancer Institute, in collaboration with the Belarusian Ministry of Health, is conducting a study of thyroid cancer and other thyroid diseases in a cohort of about 12,000 persons who were exposed to fallout from the Chernobyl accident in April 1986. The study subjects were 18 years old or younger at the time of exposure and resided in Belarus in the most contaminated areas of the Gomel and Mogilev Oblasts, as well as in the city of Minsk. All cohort members had at least one direct thyroid measurement made in April–June 1986. Individual data on residential history, consumption of milk, milk products and leafy vegetables as well as administration of stable iodine were collected for all cohort members by means of personal interviews conducted between 1996 and 2007. Based on the estimated 131I activities in the thyroids, which were derived from the direct thyroid measurements, and on the responses to the questionnaires, individual thyroid doses from intakes of 131I were reconstructed for all cohort members. In addition, radiation doses to the thyroid were estimated for the following minor exposure pathways: (a) intake of short-lived 132I, 133I and 132Te by inhalation and ingestion; (b) external irradiation from radionuclides deposited on the ground; and (c) ingestion intake of 134Cs and 137Cs. Intake of 131I was the major pathway for thyroid exposure; its mean contribution to the thyroid dose was 92%. The thyroid doses from 131I intakes varied from 0.5 mGy to almost 33 Gy; the mean was estimated to be 0.58 Gy, while the median was 0.23 Gy. The reconstructed doses are being used to evaluate the risk of thyroid cancer and other thyroid diseases in the cohort.
Medulloblastomas in Patched heterozygous mice (Ptc1 /– mice) are induced with high probability by ionizing radiation applied in the immediate post-natal period. A mathematical model is described here that accommodates the dependence of the medulloblastoma incidence on dose, age at exposure and age. The model assumes that the first step in the development of the cancer is already present in all cells of the patched mouse due to germ-line inactivation of one allele of the patched tumor suppressor gene. The subsequent rate-limiting step is dependent linearly on dose at least up to 3 Gy. The observed strong decrease in carcinogenic effect of radiation between exposure on day 1 and day 10 is described by a physiological elimination of target cells during post-natal maturation of the brain. A single malignant cell develops into a tumor following a gamma-distribution with mean of about 160 days. The multiplicity of medulloblastomas is predicted.
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