Radioadaptive Response Research Articles

Radon induced hyperplasia: effective adaptation reducing the local doses in the bronchial epithelium

There is experimental and histological evidence that chronic irritation and cell death may cause hyperplasia in the exposed tissue. As the heterogeneous deposition of inhaled radon progeny results in high local doses at the peak of the bronchial bifurcations, it was proposed earlier that hyperplasia occurs in these deposition hot spots upon chronic radon exposure. The objective of the present study is to quantify how the induction of basal cell hyperplasia modulates the microdosimetric consequences of a given radon exposure. For this purpose, computational epithelium models were constructed with spherical cell nuclei of six different cell types based on histological data. Basal cell hyperplasia was modelled by epithelium models with additional basal cells and increased epithelium thickness. Microdosimetry for alpha-particles was performed by an own-developed Monte-Carlo code. Results show that the average tissue dose, and the average hit number and dose of basal cells decrease by the increase of the measure of hyperplasia. Hit and dose distribution reveal that the induction of hyperplasia may result in a basal cell pool which is shielded from alpha-radiation. It highlights that the exposure history affects the microdosimetric consequences of a present exposure, while the biological and health effects may also depend on previous exposures. The induction of hyperplasia can be considered as a radioadaptive response at the tissue level. Such an adaptation of the tissue challenges the validity of the application of the dose and dose rate effectiveness factor from a mechanistic point of view. As the location of radiosensitive target cells may change due to previous exposures, dosimetry models considering the tissue geometry characteristic of normal conditions may be inappropriate for dose estimation in case of protracted exposures. As internal exposures are frequently chronic, such changes in tissue geometry may be highly relevant for other incorporated radionuclides.

Non-induction of radioadaptive response in zebrafish embryos by neutrons.

In vivo neutron-induced radioadaptive response (RAR) was studied using zebrafish (Danio rerio) embryos. The Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Japan, was employed to provide 2-MeV neutrons. Neutron doses of 0.6, 1, 25, 50 and 100 mGy were chosen as priming doses. An X-ray dose of 2 Gy was chosen as the challenging dose. Zebrafish embryos were dechorionated at 4 h post fertilization (hpf), irradiated with a chosen neutron dose at 5 hpf and the X-ray dose at 10 hpf. The responses of embryos were assessed at 25 hpf through the number of apoptotic signals. None of the neutron doses studied could induce RAR. Non-induction of RAR in embryos having received 0.6- and 1-mGy neutron doses was attributed to neutron-induced hormesis, which maintained the number of damaged cells at below the threshold for RAR induction. On the other hand, non-induction of RAR in embryos having received 25-, 50- and 100-mGy neutron doses was explained by gamma-ray hormesis, which mitigated neutron-induced damages through triggering high-fidelity DNA repair and removal of aberrant cells through apoptosis. Separate experimental results were obtained to verify that high-energy photons could disable RAR. Specifically, 5- or 10-mGy X-rays disabled the RAR induced by a priming dose of 0.88 mGy of alpha particles delivered to 5-hpf zebrafish embryos against a challenging dose of 2 Gy of X-rays delivered to the embryos at 10 hpf.

Oxidative Stress, a Bridge that Links Radioadaptive Responses Induced by Ionizing Radiation to Those Induced by Non-Ionizing Radiation

The disturbance in the balance between production of reactive oxygen species (ROS) and antioxidant defense mechanisms may cause oxidative stress. Some environmental stimuli such as exposure to ionizing radiation or non-ionizing radiations (e.g. radiofrequency electromagnetic fields emitted from mobile phones and other wireless technologies) can severely disturb this balance. Substantial evidence now indicates that not only exposure to ionizing radiation can start oxidizing events which change the atomic structure by direct interactions of radiation with target macromolecules or via water radiolysis-induced products, non-ionizing radiations may trigger the same events. Radioadaptive response or radiation-induced adaptive response can be defined as the acquisition of radiation resistance against exposure to high levels of radiation in cultured cells or organisms that had been pre-exposed to a priming low dose radiation. The induction of adaptive responses by pre-exposure to ionizing and non-ionizing radiations is well documented by different researchers as well as our team. The induction of adaptive response by non-ionizing radiations, like ionizing radiations, requires a minimum level of damage to trigger this phenomenon. Therefore, ROS play a key role in producing the minimum level of damage that is required for triggering the induction of adaptive response. Current data support this hypothesis that there are similar patterns for induction of adaptive response by ionizing and non-ionizing radiations, and oxidative stress is a bridge that links radioadaptive responses induced by ionizing radiation to those induced by non-ionizing radiation.

Radioadaptive Response for Reproductive Cell Death Demonstrated in In Vivo Tissue Model of Caenorhabditis elegans.

Reproductive cell death (RCD) occurs after one or more cell divisions resulting from an insult such as radiation exposure or other treatments with carcinogens or mutagens. The radioadaptive response for RCD is usually investigated by in vitro or in vivo clonogenic assay. To date, this has not been demonstrated in the vulval tissue in Caenorhabditis elegans ( C. elegans ), which is a well established in vivo model for radiation-induced RCD. In this study to determine whether radioadaptive response occurs in the vulval tissue model of C. elegans , early larval worms were gamma irradiated with lower adaptive doses, followed by higher challenge doses. The ratio of protruding vulva was used to assess the RCD of vulval cells. The results of this study showed that the radioadaptive response for RCD in this vulval tissue model could be well induced by dose combinations of 5 + 75 Gy and 5 + 100 Gy at the time point of 14-16 h in worm development. In addition, the time course analysis indicated that radioresistance in vulval cells developed within 1.75 h after an adaptive dose and persisted for only a short period of time (2-4 h). DNA damage checkpoint and non-homologous end joining were involved in the radioadaptive response, exhibiting induction of protruding vulva in worms deficient in these two pathways similar to their controls. Interestingly, the DNA damage checkpoint was not active in the somatic vulval cells, and it was therefore suggested that the DNA damage checkpoint might mediate the radioadaptive response in a cell nonautonomous manner. Here, we show evidence of the occurrence of a radioadaptive response for RCD in the vulval tissue model of C. elegans . This finding provides a potential opportunity to gain further insight into the underlying mechanisms of the radioadaptive response for RCD, in view of the abundant genetic resources of C. elegans .

Role of heme Oxygenase-1 in low dose Radioadaptive response

Radioadaptive response (RAR) is an important phenomenon induced by low dose radiation. However, the molecular mechanism of RAR is obscure. In this study, we focused on the possible role of heme oxygenase 1 (HO-1) in RAR. Consistent with previous studies, priming dose of X-ray radiation (1–10cGy) induced significant RAR in normal human skin fibroblasts (AG 1522 cells). Transcription and translation of HO-1 was up-regulated more than two fold by a priming dose of radiation (5cGy). Zinc protoporphyrin Ⅸ, a specific competitive inhibitor of HO-1, efficiently inhibited RAR whereas hemin, an inducer of HO-1, could mimic priming dose of X-rays to induce RAR. Knocking down of HO-1 by transfection of HO-1 siRNA significantly attenuated RAR. Furthermore, the expression of HO-1 gene was modulated by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which translocated from cytoplasm to nucleus after priming dose radiation and enhance the antioxidant level of cells.

Involvement of MAPK signalling in radioadaptive response in BALB/c mice exposed to low dose ionizing radiation

To investigate low dose ionizing radiation (LDIR)-induced adaptive response in lymphocytes of BALB/c mice and to elucidate related molecular mechanisms. Mice were exposed to a priming dose (PD) of 0.1 Gy and challenge dose (CD) of 2 Gy ionizing radiation. Proliferation response to mitogen concanavalin A was assessed using 3H thymidine incorporation and carboxyfluoresceinsuccinamidylester (CFSE) dye dilution. Early activation markers were assessed by flow cytometry, cytokines by ELISA, DNA damage by comet assay and mitogen activated protein kinase (MAPK) signaling by Western blotting. Radioadaptive response was observed in lymphocytes of mice exposed to PD prior to CD of ionizing radiation in terms of DNA damage, early activation markers CD69, CD71, cytokines IL-2, IFN-γ as well as proliferation. This effect was transient and observed 24 h after CD and not after 0 h or 72 h. Hyper activation of MAPK signaling pathways in lymphocytes from LDIR-exposed mice and abrogation by ERK and p38 inhibitors suggests the involvement of MAPK signaling in radioadaptive response. Our study demonstrates that LDIR-induced transient adaptive response was due to hyper activation of MAPK signaling. Our findings contribute towards the understanding of LDIR-induced adaptive response.

Information value of the test with radioadaptive response upon functional evaluation of pilots

Information value of the radioadaptive response test was assessed during functional evaluation of pilots in the course of adaptation to flight factors. The functional evaluation was performed at the system level using cardiorespiratory parameters (spirometry and arterial cardiography), at the cellular level using individual sensitivity to ionizing radiation (a radioadaptive response (RAR) test on lymphocytes of peripheral blood), and at the molecular level using the direction of metabolic shifts (laser correlation spectroscopy of biological liquids). Changes in molecular composition of the blood serum and cardiorespiratory functions were compared depending on individual radiosensitivity of pilots with different flight hours. The incidence and strength of RAR in lymphocytes decreased with an increase in flight hours. In light scattering spectra, the input of particles with small hydrodynamic radii (smaller than 11 nm) decreased and that of large particles (larger than 200 nm) increased. The total power of the heart rate variability (HRV) spectrum decreased, whereas the value of stress index increased. Breathing test through a mask raised peripheral systolic and diastolic blood pressure in pilots without RAR. Moreover, it reduced the total spectrum of variability of systolic pressure and input of very low frequencies. In the group of pilots with RAR, the relative input of low frequencies into HRV increased and that of high frequencies decreased, the blood pressure not being altered. Decreased input of small particles and increased input of large particles in light scattering, when compared to the baseline values, were found only in pilots with RAR, which suggests shifts in the metabolism and humoral immunity. It could be hypothesized that the level of individual radiosensitivity reflects the general resistance of the body to negative factors of the environment.

Low-Dose Gamma Radiation Does Not Induce an Adaptive Response for Micronucleus Induction in Mouse Splenocytes.

Low-dose ionizing radiation is known to induce radioadaptive responses in cells in vitro as well as in mice in vivo. Low-dose radiation decreases the incidence and increases latency for spontaneous and radiation-induced tumors in mice, potentially as a result of enhanced cellular DNA repair efficiency or a reduction in genomic instability. In this study, the cytokinesis-block micronucleus (CBMN) assay was used to examine dose response and potential radioadaptive response for cytogenetic damage and cell survival in C57BL/6 and BALB/c spleen cells exposed in vitro or in vivo to low-dose 60Co gamma radiation. The effects of genetic background, radiation dose and dose rate, sampling time and cell cycle were investigated with respect to dose response and radioadaptive response. In C57BL/6 mice, a linear-quadratic dose-response relationship for the induction of micronuclei (MN) was observed for doses between 100 mGy and 2 Gy. BALB/c mice exhibited increased radiosensitivity for MN induction compared to C57BL/6 mice. A 20 mGy dose had no effect on MN frequencies in splenocytes of either mouse strain, however, increased spleen weight and a reduced number of dead cells were noted in the C57BL/6 strain only. Multiple experimental parameters were investigated in radioadaptive response studies, including dose and dose rate of the priming dose (20 mGy at 0.5 mGy/min and 100 mGy at 10 mGy/min), time interval (4 and 24 h) between priming and challenge doses, cell cycle stage (resting or proliferating) at exposure and kinetics after the challenge dose. Radioadaptive responses were not observed for MN induction for either mouse strain under any of the experimental conditions investigated. In contrast, a synergistic response for radiation-induced micronuclei in C57BL/6 spleen was detected after in vivo 20 mGy irradiation. This increase in the percentage of cells with cytogenetic damage was associated with a reduction in the number of nonviable spleen cells, suggesting that low-dose irradiation led to a reduction in the turnover of damaged cells within the spleen of C57BL/6 mice. Overall, these results indicate that long-term protective effects against tumor latency and other beneficial health outcomes observed after low-dose irradiation are not mediated by a reduction of the proportion of cells harboring radiation-induced cytogenetic damage.

Radiation protection and secondary cancer prevention using biological radioprotectors in radiotherapy

Radiotherapy is the feasible treatment approach for many malignant diseases and cancers. New radiotherapy techniques such as ion therapy, stereotactic radiosurgery and intensity modulated radiation therapy deliver higher low dose radiation to large volume of normal tissues and are in debating as more secondary cancers inducers. A secondary cancer after radiotherapy is an important issue that reduces treatment efficiency and should be decreased. Radioprotective compounds are of importance in clinical radiation therapy for saving normal tissues. In the present study, we are so interest to introduce, suggest and review the application of biological radioprotectors in radiotherapy. We propose probiotics, prebiotics, gas, vitamin and nanoparticle producing microorganisms as new biological systems based radioprotectors to protect normal tissues. Also, we reviewed the main biological pathways, molecules and also radioadaptive response that act as radioprotectors. In this review we tried to address the secondary cancer induction by radiotherapy and also main biological radiation protection approaches, although there is a wealth of data in this subject.

Studies of adaptive response and mutation induction in MCF-10A cells following exposure to chronic or acute ionizing radiation

A phenomenon in which exposure to a low adapting dose of radiation makes cells more resistant to the effects of a subsequent high dose exposure is termed radio-adaptive response. Adaptive response could hypothetically reduce the risk of late adverse effects of chronic or acute radiation exposures in humans. Understanding the underlying mechanisms of such responses is of relevance for radiation protection as well as for the clinical applications of radiation in medicine. However, due to the variability of responses depending on the model system and radiation condition, there is a need to further study under what conditions adaptive response can be induced. In this study, we analyzed if there is a dose rate dependence for the adapting dose, assuming that the adapting dose induces DNA response/repair pathways that are dose rate dependent. MCF-10A cells were exposed to a 50mGy adapting dose administered acutely (0.40Gy/min) or chronically (1.4mGy/h or 4.1mGy/h) and then irradiated by high acute challenging doses. The endpoints of study include clonogenic cell survival and mutation frequency at X-linked hprt locus. In another series of experiment, cells were exposed to 100mGy and 1Gy at different dose rates (acutely and chronically) and then the mutation frequencies were studied. Adaptive response was absent at the level of clonogenic survival. The mutation frequencies were significantly decreased in the cells pre-exposed to 50mGy at 1.4mGy/h followed by 1Gy acute exposure as challenging dose. Importantly, at single dose exposures (1 Gy or 100mGy), no differences at the level of mutation were found comparing different dose rates.

Radio-adaptive response of base excision repair genes and proteins in human peripheral blood mononuclear cells exposed to gamma radiation.

Radio-adaptive response is a mechanism whereby a low-dose exposure (priming dose) induces resistance to a higher dose (challenging dose) thus significantly reducing its detrimental effects. Radiation-induced DNA damage gets repaired through various DNA repair pathways in human cells depending upon the type of lesion. The base excision repair (BER) pathway repairs radiation-induced base damage, abasic sites and single-strand breaks in cellular DNA. In the present study, an attempt has been made to investigate the involvement of BER genes and proteins in the radio-adaptive response in human resting peripheral blood mononuclear cells (PBMC). Venous blood samples were collected from 20 randomly selected healthy male individuals with written informed consent. PBMC were isolated and irradiated at a priming dose of 0.1 Gy followed 4h later with a challenging dose of 2.0 Gy (primed cells). Quantitation of DNA damage was done using the alkaline comet assay immediately and expression profile of BER genes and proteins were studied 30 min after the challenging dose using real-time quantitative polymerase chain reaction and western blot, respectively. The overall result showed significant (P ≤ 0.05) reduction of DNA damage in terms of percentage of DNA in tail (%T) with a priming dose of 0.1 Gy followed by a challenging dose of 2.0 Gy after 4 h. Twelve individuals showed significant (P ≤ 0.05) reduction in %T whereas eight individuals showed marginal reduction in DNA damage that was not statistically significant. However, at the transcriptional level, BER genes such as APE1, FEN1 and LIGASE1 showed significant (P ≤ 0.05) up-regulation in both groups. Significant (P ≤ 0.05) up-regulation was also observed at the protein level for OGG1, APE1, MBD4, FEN1 and LIGASE1 in primed cells. Up-regulation of some BER genes and proteins such as APE1, FEN1 and LIGASE1 in primed cells of resting PBMC is suggestive of active involvement of the BER pathway in radio-adaptive response.

Gene profiling characteristics of radioadaptive response in AG01522 normal human fibroblasts.

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose.

Radio-adaptive response of peripheral blood lymphocytes following bystander effects induced by preirradiated CHO-K1 cells using the micronucleus assay

Background: Radio-adapve response and bystander effects are known phenomena occurring in cells following exposure to ionizing radiaon (IR). In this study we examined possible radio-adaptaon of lymphocytes following bystander effects induced by CHO-K1 cells. Materials and Methods: Whole blood and CHO-K1 cells were cultured in RPMI-1640 complete medium. Cells were separately irradiated with various doses of gamma rays. A co-culture was set to examine the bystander ef fects induced by CHO-K1 cells on lymphocytes exposed later to a challenge dose of 4 Gy. Treated cells were exposed to cytochalasin-B to arrest cells in cytokinesis stage. Micronucleus (MN) as end point was scored in binucleate cells a2er staining in Giemsa. Results: The frequency of MN increased significantly with increasing dose of radiaon both in lymphocytes and CHO-K1 cells (p 0.05). Co-culture of the non-irradiated lymphocytes with pre-irradiated CHO-K1 cells significantly reduced the mean frequency of MN in lymphocytes irradiated with a dose of 4Gy (p<0.001). Conclusion: Results showed that bystander effects induced by gamma- irradiated CHO-K1 cells led to inducon of radio-adapve response in lymphocytes. The mechanism by which radio-adapve response is induced following bystander effect is not clearly known, however cellular signaling and genome instability induced in cells indirectly might be considered as possible triggering events for radio-adapve response.

Effect of chronic low dose natural radiation in human peripheral blood mononuclear cells: Evaluation of DNA damage and repair using the alkaline comet assay

This study investigates whether peripheral blood mononuclear cells (PBMCs) from inhabitants of Kerala in southwest India, exposed to chronic low dose natural radiation in vivo (>1mSvyear−1), respond with a radioadaptive response to a challenging dose of gamma radiation. Toward this goal, PBMCs isolated from 77 subjects from high-level natural radiation areas (HLNRA) and 37 subjects from a nearby normal level natural radiation area (NLNRA) were challenged with 2Gy and 4Gy gamma radiation. Subjects from HLNRA were classified based on the mean annual effective dose received, into low dose group (LDG) and high dose group (HDG) with mean annual effective doses of 2.69mSv (N=43, range 1.07mSvyear−1 to 5.55mSvyear−1) and 9.62mSv (N=34, range 6.07mSvyear−1 to17.41mSvyear−1), respectively. DNA strand breaks and repair kinetics (at 7min, 15min and 30min after 4Gy) were evaluated using the alkaline single cell gel electrophoresis (comet) assay. Initial levels of DNA strand breaks observed after either a 2Gy or a 4Gy challenging dose were significantly lower in subjects of the HDG from HLNRA compared to subjects of NLNRA (2Gy, P=0.01; 4Gy, P=0.02) and LDG (2Gy P=0.01; 4Gy, P=0.05). Subjects of HDG from HLNRA showed enhanced rejoining of DNA strand breaks (HDG/NLNRA, P=0.06) during the early stage of repair (within 7min). However at later times a similar rate of rejoining of strand breaks was observed across the groups (HDG, LDG and NLNRA). Preliminary results from our study suggest in vivo chronic low-level natural radiation provides an initial exposure that allows an adaptation to a subsequent higher radiation exposure, perhaps through improving DNA repair via an unknown mechanism. Therefore, further investigations would be necessary in this population to understand the biological and health effects of chronic low-level natural radiation exposures.

NFκB and Survivin-Mediated Radio-Adaptive Response.

A survivin-mediated radio-adaptive response was induced in SA-NH murine sarcoma cells following activation of nuclear transcription factor κB (NFκB) by very low doses of ionizing radiation of 5, 20 or 100 mGy. SA-NH cells and a clone stably transfected with a plasmid containing a mutated IκBα gene that prevents the activation of NFκB (SA-NH+mIκBα1) were used to investigate the role of NFκB activation in the development and expression of the survivin-mediated radio-adaptive response. Tumor cells were exposed to very low doses of radiation 30 min prior to or at times ranging from 30 min to 6 h after the first of two 2 Gy doses separated by 24 h under in vitro conditions. Evidence of very low dose radiation induced a radio-adaptive response only in SA-NH but not SA-NH+mIκBα1 cells was shown by both an increase in SA-NH cell survival of 20-40% using a standard colony forming assay and reduced apoptosis frequencies of 20-40% as determined by the TUNEL assay. Changes in survivin protein levels as a function of irradiation conditions were monitored by Western blot. A 100 mGy exposure 30 min prior to a 2 Gy dose resulted in an elevation in total survivin protein 24 h later in SA-NH but not SA-NH+mIκBα1 cells. Transfection of cells with survivin siRNA inhibited elevation of survivin protein by very low dose radiation and the subsequent radio-adaptive response in SA-NH cells. These data suggest that the survivin-mediated radio-adaptive response is dependent upon the ability of cells to activate NFκB.

CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection

Mammalian cells are able to sense environmental oxidative and genotoxic conditions such as the environmental low-dose ionizing radiation (LDIR) present naturally on the earth’s surface. The stressed cells then can induce a so-called radioadaptive response with an enhanced cellular homeostasis and repair capacity against subsequent similar genotoxic conditions such as a high dose radiation. Manganese superoxide dismutase (MnSOD), a primary mitochondrial antioxidant in mammals, has long been known to play a crucial role in radioadaptive protection by detoxifying O2•− generated by mitochondrial oxidative phosphorylation. In contrast to the well-studied mechanisms of SOD2 gene regulation, the mechanisms underlying posttranslational regulation of MnSOD for radioprotection remain to be defined. Herein, we demonstrate that cyclin D1/cyclin-dependent kinase 4 (CDK4) serves as the messenger to deliver the stress signal to mitochondria to boost mitochondrial homeostasis in human skin keratinocytes under LDIR-adaptive radioprotection. Cyclin D1/CDK4 relocates to mitochondria at the same time as MnSOD enzymatic activation peaks without significant changes in total MnSOD protein level. The mitochondrial-localized CDK4 directly phosphorylates MnSOD at serine-106 (S106), causing enhanced MnSOD enzymatic activity and mitochondrial respiration. Expression of mitochondria-targeted dominant negative CDK4 or the MnSOD-S106 mutant reverses LDIR-induced mitochondrial enhancement and adaptive protection. The CDK4-mediated MnSOD activation and mitochondrial metabolism boost are also detected in skin tissues of mice receiving in vivo whole-body LDIR. These results demonstrate a unique CDK4-mediated mitochondrial communication that allows cells to sense environmental genotoxic stress and boost mitochondrial homeostasis by enhancing phosphorylation and activation of MnSOD.

Flight Factors Influence on Human Lymphocyte Radioadaptive Response and Gamma-Interferon Production

Interferon-γ (IFN-γ) is a pleiotropic cytokine with antiproliferative and immunomodulatory activities that are crucial for the regulation of immune responses. We examined a group of military pilots. The examinees were divided into 3 subgroups: ground personnel (9 persons, control group), 17 pilots with 1000 h flight time. No differences in IFN-α serum content after induction by NDV virus were detected. The quality of reparation is in many respects genetically determined; therefore, we used peripheral blood lymphocytes from pilots for in vitro detection of a radioadaptive response (RAR), which was evaluated by the number of chromosome aberrations. The adaptive response was observed in 7 individuals of the control group (78%), in 10 pilots who had 1000 flight hours (33%). The examined individuals were divided into 2 groups depending on the presence of RAR, and IFN-γ production after radiation was measured. It was shown that at doses 0.05 Gy or 0.5 Gy no differences between groups were detected. Exposure with these doses sequentially in 48 h interval resulted to differently directed changes: lymphocytes of individuals with RAR produced more IFN-γ than before while cells of persons without RAR made it less. The quality of adaptive mechanists evaluated by RAR may be useful for estimation of individual sensitivity to radiation during radiotherapy in oncology and in prediction of professional risk.

Radio-adaptive Response: An Implication for the Biological Consequences of Low Dose-rate Exposure to X-Ray

RADIATION induced adaptive response is described as the reduced damaging effect of a challenging radiation dose when induced by a previous low priming dose. To verify the radio-adaptive response that can be induced by occupationally (

Low-dose γ-irradiation induces dual radio-adaptive responses depending on the post-irradiation time by altering microRNA expression profiles in normal human dermal fibroblasts

Exposure to high-dose ionizing radiation, including γ-radiation, induces severe skin disorders. However, the biological consequences and molecular mechanisms responsible for the response of human skin to low-dose γ-radiation (LDR) are largely unknown. In the present study, we demonstrate that LDR (0.1 Gy) induces distinct cellular responses in normal human dermal fibroblasts (NHDFs) depending on the post-irradiation time point. A MTT-based cell viability assay and propidium iodide staining-based cell cycle assay revealed that the viability and proportion of the cells in the G2/M phase were differed at 6 and 24 h post-irradiation. Reverse transcription quantitative PCR (RT-qPCR) revealed that LDR significantly upregulated the mRNA expression of collagen type I alpha 1 (COL1A1), but downregulated the mRNA expression of matrix metalloproteinase 1 (MMP1) at 24 h post-irradiation. MicroRNA (miRNA) microarray analysis further demonstrated that LDR induced changes in the expression profiles of specific miRNAs and that some of the deregulated miRNAs were specific to either the early or late radio-adaptive response. Our results suggest that LDR generates dual radio-adaptive responses depending on the post-irradiation time by altering specific miRNA expression profiles in NHDFs.

Abstract 861: Survivin-mediated adaptive response: a risk factor for IGRT

Abstract Exposure of cells to very low doses of ionizing radiation can induce an enhanced resistance or adaptive response to a subsequent larger radiation dose as demonstrated by an increase in cell survival. Expression of a radio-adaptive response has been attributed to pro-survival signaling processes induced by very low radiation doses in the range of 5 to 100 mGy. The radiation-induced adaptive response is gaining considerable attention due in part to the expanding use of imaging technologies such as computerized axial tomography and portal imaging to monitor tumor response and positioning during multi-dose standard radiation therapy protocols. The focus of this study was to investigate whether this process could occur when the very small imaging radiation dose was administered prior to or following the administration of the first of two typically used radiation therapy level doses. SA-NH mouse sarcoma cells and SA-NH cells stably transfected with mutated IκBα (SA-NH+mIκBα1) to inhibit the activation of NFκB were grown to confluence in vitro or as tumors in the right hind leg of C3H mice. Percentage of cell survival, apoptosis frequencies and survivin protein levels were determined as a function of radiation conditions and transfection of cells with survivin siRNA. A significant radio-adaptive response was observed in cells exposed to 5 mGy - 100 mGy 15 min to 6 h prior to or after irradiation with the first of two 2 Gy therapeutic radiation doses and was associated with a concomitant reduction in apoptosis frequencies and a rapid elevation in survivin protein levels. The very low dose radiation-induced elevation in survivin levels, the reduction in apoptosis frequencies and enhanced cell survival were not observed in SA-NH+mIκBα1 cells or SA-NH cells transfected with survivin siRNA. We have identified a very low radiation dose-induced survivin-mediated adaptive response that could compromise therapeutic outcomes associated with the increased usage of imaging procedures in radiation therapy. This work was supported by NIH/NCI grant R01 CA132998 and DOE Low Dose Program/Project Grant DE-SC0001271 (D.J.G.) Citation Format: David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Gayle E. Woloschak, Jian Jian Li, Ralph R. Weichselbaum. Survivin-mediated adaptive response: a risk factor for IGRT. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2014-861