Publications by authors named "Roel Quintens"

45 Publications

Hippocampal and cortical tissue-specific epigenetic clocks indicate an increased epigenetic age in a mouse model for Alzheimer's disease.

Aging (Albany NY) 2020 10 20;12(20):20817-20834. Epub 2020 Oct 20.

Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol 2400, Belgium.

Epigenetic clocks are based on age-associated changes in DNA methylation of CpG-sites, which can accurately measure chronological age in different species. Recently, several studies have indicated that the difference between chronological and epigenetic age, defined as the age acceleration, could reflect biological age indicating functional decline and age-associated diseases. In humans, an epigenetic clock associated Alzheimer's disease (AD) pathology with an acceleration of the epigenetic age. In this study, we developed and validated two mouse brain region-specific epigenetic clocks from the C57BL/6J hippocampus and cerebral cortex. Both clocks, which could successfully estimate chronological age, were further validated in a widely used mouse model for AD, the triple transgenic AD (3xTg-AD) mouse. We observed an epigenetic age acceleration indicating an increased biological age for the 3xTg-AD mice compared to non-pathological C57BL/6J mice, which was more pronounced in the cortex as compared to the hippocampus. Genomic region enrichment analysis revealed that age-dependent CpGs were enriched in genes related to developmental, aging-related, neuronal and neurodegenerative functions. Due to the limited access of human brain tissues, these epigenetic clocks specific for mouse cortex and hippocampus might be important in further unravelling the role of epigenetic mechanisms underlying AD pathology or brain aging in general.
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http://dx.doi.org/10.18632/aging.104056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655172PMC
October 2020

Establishing mechanisms affecting the individual response to ionizing radiation.

Int J Radiat Biol 2020 03 8;96(3):297-323. Epub 2020 Jan 8.

CEA, DRE-D3P, University of Paris-Saclay, France.

Humans are increasingly exposed to ionizing radiation (IR). Both low (<100 mGy) and high doses can cause stochastic effects, including cancer; whereas doses above 100 mGy are needed to promote tissue or cell damage. 10-15% of radiotherapy (RT) patients suffer adverse reactions, described as displaying radiosensitivity (RS). Sensitivity to IR's stochastic effects is termed radiosusceptibility (RSu). To optimize radiation protection we need to understand the range of individual variability and underlying mechanisms. We review the potential mechanisms contributing to RS/RSu focusing on RS following RT, the most tractable RS group. The IR-induced DNA damage response (DDR) has been well characterized. Patients with mutations in the DDR have been identified and display marked RS but they represent only a small percentage of the RT patients with adverse reactions. We review the impacting mechanisms and additional factors influencing RS/RSu. We discuss whether RS/RSu might be genetically determined. As a recommendation, we propose that a prospective study be established to assess RS following RT. The study should detail tumor site and encompass a well-defined grading system. Predictive assays should be independently validated. Detailed analysis of the inflammatory, stress and immune responses, mitochondrial function and life style factors should be included. Existing cohorts should also be optimally exploited.
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http://dx.doi.org/10.1080/09553002.2019.1704908DOI Listing
March 2020

Abnormal retinal pigment epithelium melanogenesis as a major determinant for radiation-induced congenital eye defects.

Reprod Toxicol 2020 01 6;91:59-73. Epub 2019 Nov 6.

Radiobiology Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre SCK-CEN, Boeretang 200, Mol 2400, Belgium. Electronic address:

Recent studies highlighted a link between ionizing radiation exposure during neurulation and birth defects such as microphthalmos and anophthalmos. Because the mechanisms underlying these defects remain largely unexplored, we irradiated pregnant C57BL/6J mice (1.0 Gy, X-rays) at embryonic day (E)7.5, followed by histological and gene/protein expression analyses at defined days. Irradiation impaired embryonic development at E9 and we observed a delayed pigmentation of the retinal pigment epithelium (RPE) at E11. In addition, a reduced RNA expression and protein abundance of critical eye-development genes (e.g. Pax6 and Lhx2) was observed. Furthermore, a decreased expression of Mitf, Tyr and Tyrp1 supported the radiation-induced perturbation in RPE pigmentation. Finally, via immunostainings for proliferation (Ki67) and mitosis (phosphorylated histone 3), a decreased mitotic index was observed in the E18 retina after exposure at E7.5. Overall, we propose a plausible etiological model for radiation-induced eye-size defects, with RPE melanogenesis as a major determining factor.
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http://dx.doi.org/10.1016/j.reprotox.2019.10.002DOI Listing
January 2020

Exposure to Ionizing Radiation Triggers Prolonged Changes in Circular RNA Abundance in the Embryonic Mouse Brain and Primary Neurons.

Cells 2019 07 26;8(8). Epub 2019 Jul 26.

Radiobiology Unit, Belgian Nuclear Research Centre, SCK·CEN, 2400 Mol, Belgium.

The exposure of mouse embryos in utero and primary cortical neurons to ionizing radiation results in the P53-dependent activation of a subset of genes that is highly induced during brain development and neuronal maturation, a feature that these genes reportedly share with circular RNAs (circRNAs). Interestingly, some of these genes are predicted to express circular transcripts. In this study, we validated the abundance of the circular transcript variants of four P53 target genes (, , and ). These circular variants were overall more stable than their linear counterparts. They were furthermore highly enriched in the brain and their transcript levels continuously increase during subsequent developmental stages (from embryonic day 12 until adulthood), while no further increase could be observed for linear mRNAs beyond post-natal day 30. Finally, whereas radiation-induced expression of P53 target mRNAs peaks early after exposure, several of the circRNAs showed prolonged induction in irradiated embryonic mouse brain, primary mouse cortical neurons, and mouse blood. Together, our results indicate that the circRNAs from these P53 target genes are induced in response to radiation and they corroborate the findings that circRNAs may represent biomarkers of brain age. We also propose that they may be superior to mRNA as long-term biomarkers for radiation exposure.
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http://dx.doi.org/10.3390/cells8080778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721538PMC
July 2019

Modulations of Neuroendocrine Stress Responses During Confinement in Antarctica and the Role of Hypobaric Hypoxia.

Front Physiol 2018 26;9:1647. Epub 2018 Nov 26.

Laboratory of Translational Research "Stress and Immunity", Department of Anaesthesiology, University Hospital, LMU Munich, Munich, Germany.

The Antarctic continent is an environment of extreme conditions. Only few research stations exist that are occupied throughout the year. The German station Neumayer III and the French-Italian Concordia station are such research platforms and human outposts. The seasonal shifts of complete daylight (summer) to complete darkness (winter) as well as massive changes in outside temperatures (down to -80°C at Concordia) during winter result in complete confinement of the crews from the outside world. In addition, the crew at Concordia is subjected to hypobaric hypoxia of ∼650 hPa as the station is situated at high altitude (3,233 m). We studied three expedition crews at Neumayer III (sea level) ( = 16) and two at Concordia (high altitude) ( = 15) to determine the effects of hypobaric hypoxia on hormonal/metabolic stress parameters [endocannabinoids (ECs), catecholamines, and glucocorticoids] and evaluated the psychological stress over a period of 11 months including winter confinement. In the (sea level) crew, EC and -acylethanolamide (NAE) concentrations increased significantly already at the beginning of the deployment ( < 0.001) whereas catecholamines and cortisol remained unaffected. Over the year, ECs and NAEs stayed elevated and fluctuated before slowly decreasing till the end of the deployment. The classical stress hormones showed small increases in the last third of deployment. By contrast, at (high altitude), norepinephrine concentrations increased significantly at the beginning ( < 0.001) which was paralleled by low EC levels. Prior to the second half of deployment, norepinephrine declined constantly to end on a low plateau level, whereas then the EC concentrations increased significantly in this second period during the overwintering ( < 0.001). Psychometric data showed no significant changes in the crews at either station. These findings demonstrate that exposition of healthy humans to the physically challenging extreme environment of Antarctica (i) has a distinct modulating effect on stress responses. Additionally, (ii) acute high altitude/hypobaric hypoxia at the beginning seem to trigger catecholamine release that downregulates the EC response. These results (iii) are not associated with psychological stress.
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http://dx.doi.org/10.3389/fphys.2018.01647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276713PMC
November 2018

Gene expression-based biodosimetry for radiological incidents: assessment of dose and time after radiation exposure.

Int J Radiat Biol 2019 01 24;95(1):64-75. Epub 2018 Sep 24.

a Interdisciplinary Biosciences Group, Belgian Nuclear Research Centre, SCK•CEN, Mol , Belgium.

Purpose: In order to ensure efficient use of medical resources following a radiological incident, there is an urgent need for high-throughput time-efficient biodosimetry tools. In the present study, we tested the applicability of a gene expression signature for the prediction of exposure dose as well as the time elapsed since irradiation.

Materials And Methods: We used whole blood samples from seven healthy volunteers as reference samples (X-ray doses: 0, 25, 50, 100, 500, 1000, and 2000 mGy; time points: 8, 12, 24, 36 and 48 h) and samples from seven other individuals as 'blind samples' (20 samples in total).

Results: Gene expression values normalized to the reference gene without normalization to the unexposed controls were sufficient to predict doses with a correlation coefficient between the true and the predicted doses of 0.86. Importantly, we could also classify the samples according to the time since exposure with a correlation coefficient between the true and the predicted time point of 0.96. Because of the dynamic nature of radiation-induced gene expression, this feature will be of critical importance for adequate gene expression-based dose prediction in a real emergency situation. In addition, in this study we also compared different methodologies for RNA extraction available on the market and suggested the one most suitable for emergency situation which does not require on-spot availability of any specific reagents or equipment.

Conclusions: Our results represent an important advancement in the application of gene expression for biodosimetry purposes.
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http://dx.doi.org/10.1080/09553002.2018.1511926DOI Listing
January 2019

Immune sensitization during 1 year in the Antarctic high-altitude Concordia Environment.

Allergy 2019 01 20;74(1):64-77. Epub 2018 Nov 20.

Department of Anaesthesiology, Laboratory of Translational Research "Stress and Immunity" University Hospital, LMU Munich, Munich, Germany.

Background: Antarctica is a challenging environment for humans. It serves as a spaceflight ground analog, reflecting some conditions of long-duration exploration class space missions. The French-Italian Concordia station in interior Antarctica is a high-fidelity analog, located 1000 km from the coast, at an altitude of 3232 m. The aim of this field study was to characterize the extent, dynamics, and key mechanisms of the immune adaptation in humans overwintering at Concordia for 1 year.

Methods: This study assessed immune functions in fourteen crewmembers. Quantitative and phenotypic analyses from human blood were performed using onsite flow cytometry together with specific tests on receptor-dependent and receptor-independent functional innate and adaptive immune responses. Transcriptome analyses and quantitative identification of key response genes were assessed.

Results: Dynamic immune activation and a two-step escalation/activation pattern were observed. The early phase was characterized by moderately sensitized global immune responses, while after 3-4 months, immune responses were highly upregulated. The cytokine responses to an ex vivo stimulation were markedly raised above baseline levels. These functional observations were reflected at the gene transcriptional level in particular through the modulation of hypoxia-driven pathways.

Conclusions: This study revealed unique insights into the extent, dynamics, and genetics of immune dysfunctions in humans exposed for 1 year to the Antarctic environment at the Concordia station. The scale of immune function was imbalanced toward a sensitizing of inflammatory pathways.
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http://dx.doi.org/10.1111/all.13545DOI Listing
January 2019

Differential Impact of Single-Dose Fe Ion and X-Ray Irradiation on Endothelial Cell Transcriptomic and Proteomic Responses.

Front Pharmacol 2017 22;8:570. Epub 2017 Sep 22.

Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN)Mol, Belgium.

Radiotherapy is an essential tool for cancer treatment. In order to spare normal tissues and to reduce the risk of normal tissue complications, particle therapy is a method of choice. Although a large part of healthy tissues can be spared due to improved depth dose characteristics, little is known about the biological and molecular mechanisms altered after particle irradiation in healthy tissues. Elucidation of these effects is also required in the context of long term space flights, as particle radiation is the main contributor to the radiation effects observed in space. Endothelial cells (EC), forming the inner layer of all vascular structures, are especially sensitive to irradiation and, if damaged, contribute to radiation-induced cardiovascular disease. Transcriptomics, proteomics and cytokine analyses were used to compare the response of ECs irradiated or not with a single 2 Gy dose of X-rays or Fe ions measured one and 7 days post-irradiation. To support the observed inflammatory effects, monocyte adhesion on ECs was also assessed. Experimental data indicate time- and radiation quality-dependent changes of the EC response to irradiation. The irradiation impact was more pronounced and longer lasting for Fe ions than for X-rays. Both radiation qualities decreased the expression of genes involved in cell-cell adhesion and enhanced the expression of proteins involved in caveolar mediated endocytosis signaling. Endothelial inflammation and adhesiveness were increased with X-rays, but decreased after Fe ion exposure. Fe ions induce pro-atherosclerotic processes in ECs that are different in nature and kinetics than those induced by X-rays, highlighting radiation quality-dependent differences which can be linked to the induction and progression of cardiovascular diseases (CVD). Our findings give a better understanding of the underlying processes triggered by particle irradiation in ECs, a crucial aspect for the development of protective measures for cancer patients undergoing particle therapy and for astronauts in space.
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http://dx.doi.org/10.3389/fphar.2017.00570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622284PMC
September 2017

Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose.

Front Pharmacol 2017 25;8:213. Epub 2017 Apr 25.

Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Institute for Environment, Health and SafetyMol, Belgium.

Epidemiological data suggests an excess risk of cardiovascular disease (CVD) at low doses (0.05 and 0.1 Gy) of ionizing radiation (IR). Furthermore, the underlying biological and molecular mechanisms of radiation-induced CVD are still unclear. Because damage to the endothelium could be critical in IR-related CVD, this study aimed to identify the effects of radiation on immortalized endothelial cells in the context of atherosclerosis. Microarrays and RT-qPCR were used to compare the response of endothelial cells irradiated with a single X-ray dose (0.05, 0.1, 0.5, 2 Gy) measured after various post-irradiation (repair) times (1 day, 7 days, 14 days). To consolidate and mechanistically support the endothelial cell response to X-ray exposure identified via microarray analysis, DNA repair signaling (γH2AX/TP53BP1-foci quantification), cell cycle progression (BrdU/7AAD flow cytometric analysis), cellular senescence (β-galactosidase assay with CPRG and IGFBP7 quantification) and pro-inflammatory status (IL6 and CCL2) was assessed. Microarray results indicated persistent changes in cell cycle progression and inflammation. Cells underwent G1 arrest in a dose-dependent manner after high doses (0.5 and 2 Gy), which was compensated by increased proliferation after 1 week and almost normalized after 2 weeks. However, at this point irradiated cells showed an increased β-Gal activity and IGFBP7 secretion, indicative of premature senescence. The production of pro-inflammatory cytokines IL6 and CCL2 was increased at early time points. IR induces pro-atherosclerotic processes in endothelial cells in a dose-dependent manner. These findings give an incentive for further research on the shape of the dose-response curve, as we show that even low doses of IR can induce premature endothelial senescence at later time points. Furthermore, our findings on the time- and dose-dependent response regarding differentially expressed genes, cell cycle progression, inflammation and senescence bring novel insights into the underlying molecular mechanisms of the endothelial response to X-ray radiation. This may in turn lead to the development of risk-reducing strategies to prevent IR-induced CVD, such as the use of cell cycle modulators and anti-inflammatory drugs as radioprotectors and/or radiation mitigators.
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http://dx.doi.org/10.3389/fphar.2017.00213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404649PMC
April 2017

Ionizing radiation biomarkers in epidemiological studies - An update.

Mutat Res 2017 Jan - Mar;771:59-84. Epub 2017 Jan 16.

Barcelona Institute of Global Health (ISGlobal), Centre for Research in Environmental Epidemiology, Radiation Programme, Barcelona Biomedical Research Park, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF) (MTD formerly), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. Electronic address:

Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased leukaemia and solid tumour risks following cumulative doses of <100mSv and dose rates of <10mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30-60mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles.
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http://dx.doi.org/10.1016/j.mrrev.2017.01.001DOI Listing
May 2017

Convergence and divergence between the transcriptional responses to Zika virus infection and prenatal irradiation.

Authors:
Roel Quintens

Cell Death Dis 2017 03 16;8(3):e2672. Epub 2017 Mar 16.

Radiobiology Unit, Institute of Environment, Health and Safety, Belgian Nuclear Research Centre, Mol, Belgium.

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http://dx.doi.org/10.1038/cddis.2017.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386517PMC
March 2017

Investigation of the influence of calibration practices on cytogenetic laboratory performance for dose estimation.

Int J Radiat Biol 2017 01 13;93(1):118-126. Epub 2016 Oct 13.

a Institut de Radioprotection et de Sûreté Nucléaire (IRSN) , Fontenay-aux-roses, France.

Purpose: In the frame of the QA program of RENEB, an inter-laboratory comparison (ILC) of calibration sources used in biological dosimetry was achieved to investigate the influence of calibration practices and protocols on the results of the dose estimation performance as a first step to harmonization and standardization of dosimetry and irradiation practices in the European biological dosimetry network.

Materials And Methods: Delivered doses by irradiation facilities used by RENEB partners were determined with EPR/alanine dosimetry system. Dosimeters were irradiated in the same conditions as blood samples. A short survey was also performed to collect the information needed for the data analysis and evaluate the diversity of practices.

Results: For most of partners the deviation of delivered dose from the targeted dose remains below 10%. Deviations larger than 10% were observed for five facilities out of 21. Origins of the largest discrepancies were identified. Correction actions were evaluated as satisfactory. The re-evaluation of some ILC results for the fluorescence in situ hybridization (FISH) and premature chromosome condensation (PCC) assays has been performed leading to an improvement of the overall performances.

Conclusions: This work has shown the importance of dosimetry in radiobiology studies and the needs of harmonization, standardization in irradiation and dosimetry practices and educational training for biologists using ionizing radiation.
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http://dx.doi.org/10.1080/09553002.2016.1213455DOI Listing
January 2017

RENEB - Running the European Network of biological dosimetry and physical retrospective dosimetry.

Int J Radiat Biol 2017 01 6;93(1):2-14. Epub 2016 Oct 6.

ag Stockholm University, Centre for Radiation Protection Research , Stockholm , Sweden.

Purpose: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios.

Results: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015.

Conclusions: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects.
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http://dx.doi.org/10.1080/09553002.2016.1230239DOI Listing
January 2017

Comparable dose estimates of blinded whole blood samples are obtained independently of culture conditions and analytical approaches. Second RENEB gene expression study.

Int J Radiat Biol 2017 01 14;93(1):87-98. Epub 2016 Sep 14.

a Cancer Mechanisms and Biomarkers Group, Radiation Effects Department , Centre for Radiation, Chemical and Environmental Hazards, Public Health England , Chilton , UK.

Purpose: This collaboration of five established European gene expression labs investigated the potential impact of culture conditions on the transcriptional response of peripheral blood to radiation exposure.

Materials And Methods: Blood from one healthy donor was exposed ex vivo to a Cobalt 60 source to produce a calibration curve in addition to four unknown doses. After exposure, the blood samples were either diluted with RPMI medium or left untouched. After 24-h incubation at 37 °C the diluted blood samples were lysed, while the undiluted samples were mixed with the preservative RNALater and all samples were shipped frozen to the participating labs. Samples were processed by each lab using microarray (one lab) and QRT-PCR (four labs).

Results: We show that although culture conditions affect the total amount of RNA recovered (p < .0001) and its integrity (p < .0001), it does not significantly affect dose estimates (except for the true dose at 1.1 Gy). Most importantly, the different analysis approaches provide comparable mean absolute difference of estimated doses relative to the true doses (p = .9) and number of out of range (>0.5 Gy) measurements (p = .6).

Conclusion: This study confirms the robustness of gene expression as a method for biological dosimetry.
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http://dx.doi.org/10.1080/09553002.2016.1227105DOI Listing
January 2017

Integration of new biological and physical retrospective dosimetry methods into EU emergency response plans - joint RENEB and EURADOS inter-laboratory comparisons.

Int J Radiat Biol 2017 01 20;93(1):99-109. Epub 2016 Jul 20.

ai Helmholtz Zentrum München (HMGU) , Neuherberg , Germany.

Purpose: RENEB, 'Realising the European Network of Biodosimetry and Physical Retrospective Dosimetry,' is a network for research and emergency response mutual assistance in biodosimetry within the EU. Within this extremely active network, a number of new dosimetry methods have recently been proposed or developed. There is a requirement to test and/or validate these candidate techniques and inter-comparison exercises are a well-established method for such validation.

Materials And Methods: The authors present details of inter-comparisons of four such new methods: dicentric chromosome analysis including telomere and centromere staining; the gene expression assay carried out in whole blood; Raman spectroscopy on blood lymphocytes, and detection of radiation-induced thermoluminescent signals in glass screens taken from mobile phones.

Results: In general the results show good agreement between the laboratories and methods within the expected levels of uncertainty, and thus demonstrate that there is a lot of potential for each of the candidate techniques.

Conclusions: Further work is required before the new methods can be included within the suite of reliable dosimetry methods for use by RENEB partners and others in routine and emergency response scenarios.
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http://dx.doi.org/10.1080/09553002.2016.1206233DOI Listing
January 2017

Current Evidence for Developmental, Structural, and Functional Brain Defects following Prenatal Radiation Exposure.

Neural Plast 2016 12;2016:1243527. Epub 2016 Jun 12.

Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.

Ionizing radiation is omnipresent. We are continuously exposed to natural (e.g., radon and cosmic) and man-made radiation sources, including those from industry but especially from the medical sector. The increasing use of medical radiation modalities, in particular those employing low-dose radiation such as CT scans, raises concerns regarding the effects of cumulative exposure doses and the inappropriate utilization of these imaging techniques. One of the major goals in the radioprotection field is to better understand the potential health risk posed to the unborn child after radiation exposure to the pregnant mother, of which the first convincing evidence came from epidemiological studies on in utero exposed atomic bomb survivors. In the following years, animal models have proven to be an essential tool to further characterize brain developmental defects and consequent functional deficits. However, the identification of a possible dose threshold is far from complete and a sound link between early defects and persistent anomalies has not yet been established. This review provides an overview of the current knowledge on brain developmental and persistent defects resulting from in utero radiation exposure and addresses the many questions that still remain to be answered.
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http://dx.doi.org/10.1155/2016/1243527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921147PMC
October 2017

Combined Exposure to Simulated Microgravity and Acute or Chronic Radiation Reduces Neuronal Network Integrity and Survival.

PLoS One 2016 20;11(5):e0155260. Epub 2016 May 20.

Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, Mol, Belgium.

During orbital or interplanetary space flights, astronauts are exposed to cosmic radiations and microgravity. However, most earth-based studies on the potential health risks of space conditions have investigated the effects of these two conditions separately. This study aimed at assessing the combined effect of radiation exposure and microgravity on neuronal morphology and survival in vitro. In particular, we investigated the effects of simulated microgravity after acute (X-rays) or during chronic (Californium-252) exposure to ionizing radiation using mouse mature neuron cultures. Acute exposure to low (0.1 Gy) doses of X-rays caused a delay in neurite outgrowth and a reduction in soma size, while only the high dose impaired neuronal survival. Of interest, the strongest effect on neuronal morphology and survival was evident in cells exposed to microgravity and in particular in cells exposed to both microgravity and radiation. Removal of neurons from simulated microgravity for a period of 24 h was not sufficient to recover neurite length, whereas the soma size showed a clear re-adaptation to normal ground conditions. Genome-wide gene expression analysis confirmed a modulation of genes involved in neurite extension, cell survival and synaptic communication, suggesting that these changes might be responsible for the observed morphological effects. In general, the observed synergistic changes in neuronal network integrity and cell survival induced by simulated space conditions might help to better evaluate the astronaut's health risks and underline the importance of investigating the central nervous system and long-term cognition during and after a space flight.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874625PMC
July 2017

Persistent Impact of In utero Irradiation on Mouse Brain Structure and Function Characterized by MR Imaging and Behavioral Analysis.

Front Behav Neurosci 2016 4;10:83. Epub 2016 May 4.

Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN) Mol, Belgium.

Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8-15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI). We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration, and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum, and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests.
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http://dx.doi.org/10.3389/fnbeh.2016.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854899PMC
May 2016

Brain Radiation Information Data Exchange (BRIDE): integration of experimental data from low-dose ionising radiation research for pathway discovery.

BMC Bioinformatics 2016 May 11;17(1):212. Epub 2016 May 11.

Department of Genetics, Development & Molecular Biology, School of Biology, Aristotle University of Thessalonica, 54124, Thessalonica, Greece.

Background: The underlying molecular processes representing stress responses to low-dose ionising radiation (LDIR) in mammals are just beginning to be understood. In particular, LDIR effects on the brain and their possible association with neurodegenerative disease are currently being explored using omics technologies.

Results: We describe a light-weight approach for the storage, analysis and distribution of relevant LDIR omics datasets. The data integration platform, called BRIDE, contains information from the literature as well as experimental information from transcriptomics and proteomics studies. It deploys a hybrid, distributed solution using both local storage and cloud technology.

Conclusions: BRIDE can act as a knowledge broker for LDIR researchers, to facilitate molecular research on the systems biology of LDIR response in mammals. Its flexible design can capture a range of experimental information for genomics, epigenomics, transcriptomics, and proteomics. The data collection is available at: .
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http://dx.doi.org/10.1186/s12859-016-1068-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865096PMC
May 2016

Higher Initial DNA Damage and Persistent Cell Cycle Arrest after Carbon Ion Irradiation Compared to X-irradiation in Prostate and Colon Cancer Cells.

Front Oncol 2016 13;6:87. Epub 2016 Apr 13.

Expert Group for Molecular and Cellular Biology, Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Institute for Environment, Health and Safety , Mol , Belgium.

The use of charged-particle beams, such as carbon ions, is becoming a more and more attractive treatment option for cancer therapy. Given the precise absorbed dose-localization and an increased biological effectiveness, this form of therapy is much more advantageous compared to conventional radiotherapy, and is currently being used for treatment of specific cancer types. The high ballistic accuracy of particle beams deposits the maximal dose to the tumor, while damage to the surrounding healthy tissue is limited. In order to better understand the underlying mechanisms responsible for the increased biological effectiveness, we investigated the DNA damage and repair kinetics and cell cycle progression in two p53 mutant cell lines, more specifically a prostate (PC3) and colon (Caco-2) cancer cell line, after exposure to different radiation qualities. Cells were irradiated with various absorbed doses (0, 0.5, and 2 Gy) of accelerated (13)C-ions at the Grand Accélérateur National d'Ions Lourds facility (Caen, France) or with X-rays (0, 0.1, 0.5, 1, 2, and 5 Gy). Microscopic analysis of DNA double-strand breaks showed dose-dependent increases in γ-H2AX foci numbers and foci occupancy after exposure to both types of irradiation, in both cell lines. However, 24 h after exposure, residual damage was more pronounced after lower doses of carbon ion irradiation compared to X-irradiation. Flow cytometric analysis showed that carbon ion irradiation induced a permanent G2/M arrest in PC3 cells at lower doses (2 Gy) compared to X-rays (5 Gy), while in Caco-2 cells the G2/M arrest was transient after irradiation with X-rays (2 and 5 Gy) but persistent after exposure to carbon ions (2 Gy).
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http://dx.doi.org/10.3389/fonc.2016.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830044PMC
May 2016

Radiation-induced alternative transcription and splicing events and their applicability to practical biodosimetry.

Sci Rep 2016 Jan 14;6:19251. Epub 2016 Jan 14.

Radiobiology Unit, Belgian Nuclear Research Centre, SCK•CEN, Mol, Belgium.

Accurate assessment of the individual exposure dose based on easily accessible samples (e.g. blood) immediately following a radiological accident is crucial. We aimed at developing a robust transcription-based signature for biodosimetry from human peripheral blood mononuclear cells irradiated with different doses of X-rays (0.1 and 1.0 Gy) at a dose rate of 0.26 Gy/min. Genome-wide radiation-induced changes in mRNA expression were evaluated at both gene and exon level. Using exon-specific qRT-PCR, we confirmed that several biomarker genes are alternatively spliced or transcribed after irradiation and that different exons of these genes exhibit significantly different levels of induction. Moreover, a significant number of radiation-responsive genes were found to be genomic neighbors. Using three different classification models we found that gene and exon signatures performed equally well on dose prediction, as long as more than 10 features are included. Together, our results highlight the necessity of evaluating gene expression at the level of single exons for radiation biodosimetry in particular and transcriptional biomarker research in general. This approach is especially advisable for practical gene expression-based biodosimetry, for which primer- or probe-based techniques would be the method of choice.
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http://dx.doi.org/10.1038/srep19251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725928PMC
January 2016

A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis.

J Neurodev Disord 2015 9;7(1). Epub 2015 Jan 9.

Radiobiology Unit, Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, 2400 Mol, Belgium.

Background: In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive.

Methods: Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry.

Results: Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age.

Conclusions: Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field.
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http://dx.doi.org/10.1186/1866-1955-7-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448911PMC
June 2015

Identification of novel radiation-induced p53-dependent transcripts extensively regulated during mouse brain development.

Biol Open 2015 Feb 13;4(3):331-44. Epub 2015 Feb 13.

Radiobiology Unit, Belgian Nuclear Research Centre, SCK•CEN, B-2400 Mol, Belgium.

Ionizing radiation is a potent activator of the tumor suppressor gene p53, which itself regulates the transcription of genes involved in canonical pathways such as the cell cycle, DNA repair and apoptosis as well as other biological processes like metabolism, autophagy, differentiation and development. In this study, we performed a meta-analysis on gene expression data from different in vivo and in vitro experiments to identify a signature of early radiation-responsive genes which were predicted to be predominantly regulated by p53. Moreover, we found that several genes expressed different transcript isoforms after irradiation in a p53-dependent manner. Among this gene signature, we identified novel p53 targets, some of which have not yet been functionally characterized. Surprisingly, in contrast to genes from the canonical p53-regulated pathways, our gene signature was found to be highly enriched during embryonic and post-natal brain development and during in vitro neuronal differentiation. Furthermore, we could show that for a number of genes, radiation-responsive transcript variants were upregulated during development and differentiation, while radiation non-responsive variants were not. This suggests that radiation exposure of the developing brain and immature cortical neurons results in the p53-mediated activation of a neuronal differentiation program. Overall, our results further increase the knowledge of the radiation-induced p53 network of the embryonic brain and provide more evidence concerning the importance of p53 and its transcriptional targets during mouse brain development.
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http://dx.doi.org/10.1242/bio.20149969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359739PMC
February 2015

Dose- and time-dependent gene expression alterations in prostate and colon cancer cells after in vitro exposure to carbon ion and X-irradiation.

J Radiat Res 2015 Jan 4;56(1):11-21. Epub 2014 Sep 4.

Radiobiology Unit, Expert Group for Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, Boeretang 200, 2400 Mol, Belgium Department of Molecular Biotechnology, Ghent University, Coupure links 653, Ghent, Belgium

Hadrontherapy is an advanced form of radiotherapy that uses beams of charged particles (such as protons and carbon ions). Compared with conventional radiotherapy, the main advantages of carbon ion therapy are the precise absorbed dose localization, along with an increased relative biological effectiveness (RBE). This high ballistic accuracy of particle beams deposits the maximal dose to the tumor, while damage to the surrounding healthy tissue is limited. Currently, hadrontherapy is being used for the treatment of specific types of cancer. Previous in vitro studies have shown that, under certain circumstances, exposure to charged particles may inhibit cell motility and migration. In the present study, we investigated the expression of four motility-related genes in prostate (PC3) and colon (Caco-2) cancer cell lines after exposure to different radiation types. Cells were irradiated with various absorbed doses (0, 0.5 and 2 Gy) of accelerated (13)C-ions at the GANIL facility (Caen, France) or with X-rays. Clonogenic assays were performed to determine the RBE. RT-qPCR analysis showed dose- and time-dependent changes in the expression of CCDC88A, FN1, MYH9 and ROCK1 in both cell lines. However, whereas in PC3 cells the response to carbon ion irradiation was enhanced compared with X-irradiation, the effect was the opposite in Caco-2 cells, indicating cell-type-specific responses to the different radiation types.
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http://dx.doi.org/10.1093/jrr/rru070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572596PMC
January 2015

Modulation of gene expression in endothelial cells in response to high LET nickel ion irradiation.

Int J Mol Med 2014 Oct 11;34(4):1124-32. Epub 2014 Aug 11.

Laboratory of Radiobiology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK‑CEN), Mol, Belgium.

Ionizing radiation can elicit harmful effects on the cardiovascular system at high doses. Endothelial cells are critical targets in radiation-induced cardiovascular damage. Astronauts performing a long-term deep space mission are exposed to consistently higher fluences of ionizing radiation that may accumulate to reach high effective doses. In addition, cosmic radiation contains high linear energy transfer (LET) radiation that is known to produce high values of relative biological effectiveness (RBE). The aim of this study was to broaden the understanding of the molecular response to high LET radiation by investigating the changes in gene expression in endothelial cells. For this purpose, a human endothelial cell line (EA.hy926) was irradiated with accelerated nickel ions (Ni) (LET, 183 keV/µm) at doses of 0.5, 2 and 5 Gy. DNA damage was measured 2 and 24 h following irradiation by γ-H2AX foci detection by fluorescence microscopy and gene expression changes were measured by microarrays at 8 and 24 h following irradiation. We found that exposure to accelerated nickel particles induced a persistent DNA damage response up to 24 h after treatment. This was accompanied by a downregulation in the expression of a multitude of genes involved in the regulation of the cell cycle and an upregulation in the expression of genes involved in cell cycle checkpoints. In addition, genes involved in DNA damage response, oxidative stress, apoptosis and cell-cell signaling (cytokines) were found to be upregulated. An in silico analysis of the involved genes suggested that the transcription factors, E2F and nuclear factor (NF)-κB, may be involved in these cellular responses.
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http://dx.doi.org/10.3892/ijmm.2014.1893DOI Listing
October 2014

Early adaption to the antarctic environment at dome C: consequences on stress-sensitive innate immune functions.

High Alt Med Biol 2014 Sep 6;15(3):341-8. Epub 2014 Aug 6.

1 Department of Anaesthesiology, Klinikum Großhadern, University of Munich , Research Group Stress and Immunity, Munich, Germany .

Unlabelled: Abstract Feuerecker, Matthias, Brian Crucian, Alex P. Salam, Ales Rybka, Ines Kaufmann, Marjan Moreels, Roel Quintens, Gustav Schelling, Manfred Thiel, Sarah Baatout, Clarence Sams, and Alexander Choukèr. Early adaption in the Antarctic environment at Dome C: Consequences on stress-sensitive innate immune functions. High Alt Med Biol 15:341-348, 2014.-Purpose/Aims: Medical reports of Antarctic expeditions indicate that health is affected under these extreme conditions. The present study at CONCORDIA-Station (Dome C, 3233 m) seeks to investigate the early consequences of confinement and hypobaric hypoxia on the human organism.

Methods: Nine healthy male participants were included in this study. Data collection occurred before traveling to Antarctica (baseline), and at 1 week and 1 month upon arrival. Investigated parameters included basic physiological variables, psychological stress tests, cell blood count, stress hormones, and markers of innate immune functions in resting and stimulated immune cells. By testing for the hydrogen peroxide (H2O2) production of stimulated polymorphonuclear leukocytes (PMNs), the effects of the hypoxia-adenosine-sensitive immune modulatory pathways were examined.

Results: As compared to baseline data, reduced oxygen saturation, hemoconcentration, and an increase of secreted catecholamines was observed, whereas no psychological stress was seen. Upon stimulation, the activity of PMNs and L-selectin shedding was mitigated after 1 week. Endogenous adenosine concentration was elevated during the early phase. In summary, living conditions at high altitude influence the innate immune system's response. After 1 month, some of the early effects on the human organism were restored.

Conclusion: As this early adaptation is not related to psychological stress, the changes observed are likely to be induced by environmental stressors, especially hypoxia. As hypoxia is triggering ATP-catabolism, leading to elevated endogenous adenosine concentrations, this and the increased catecholamine concentration might contribute to the early, but reversible downregulation of innate immune functions. This indicates the slope of innate immune adaptation to hypoxia.
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http://dx.doi.org/10.1089/ham.2013.1128DOI Listing
September 2014

Chronic exposure to simulated space conditions predominantly affects cytoskeleton remodeling and oxidative stress response in mouse fetal fibroblasts.

Int J Mol Med 2014 Aug 22;34(2):606-15. Epub 2014 May 22.

Radiobiology Unit, Expert Group of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK-CEN), Mol, Belgium.

Microgravity and cosmic rays as found in space are difficult to recreate on earth. However, ground-based models exist to simulate space flight experiments. In the present study, an experimental model was utilized to monitor gene expression changes in fetal skin fibroblasts of murine origin. Cells were continuously subjected for 65 h to a low dose (55 mSv) of ionizing radiation (IR), comprising a mixture of high‑linear energy transfer (LET) neutrons and low-LET gamma-rays, and/or simulated microgravity using the random positioning machine (RPM), after which microarrays were performed. The data were analyzed both by gene set enrichment analysis (GSEA) and single gene analysis (SGA). Simulated microgravity affected fetal murine fibroblasts by inducing oxidative stress responsive genes. Three of these genes are targets of the nuclear factor‑erythroid 2 p45-related factor 2 (Nrf2), which may play a role in the cell response to simulated microgravity. In addition, simulated gravity decreased the expression of genes involved in cytoskeleton remodeling, which may have been caused by the downregulation of the serum response factor (SRF), possibly through the Rho signaling pathway. Similarly, chronic exposure to low-dose IR caused the downregulation of genes involved in cytoskeleton remodeling, as well as in cell cycle regulation and DNA damage response pathways. Many of the genes or gene sets that were altered in the individual treatments (RPM or IR) were not altered in the combined treatment (RPM and IR), indicating a complex interaction between RPM and IR.
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http://dx.doi.org/10.3892/ijmm.2014.1785DOI Listing
August 2014

Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation.

Int J Radiat Biol 2014 Jul;90(7):560-74

Radiobiology Unit, Belgian Nuclear Research Centre, SCK•CEN , Mol , Belgium.

Purpose: Ionizing radiation has been recognized to increase the risk of cardiovascular diseases (CVD). However, there is no consensus concerning the dose-risk relationship for low radiation doses and a mechanistic understanding of low dose effects is needed.

Material And Methods: Previously, human umbilical vein endothelial cells (HUVEC) were exposed to chronic low dose rate radiation (1.4 and 4.1 mGy/h) during one, three and six weeks which resulted in premature senescence in cells exposed to 4.1 mGy/h. To gain more insight into the underlying signaling pathways, we analyzed gene expression changes in these cells using microarray technology. The obtained data were analyzed in a dual approach, combining single gene expression analysis and Gene Set Enrichment Analysis.

Results: An early stress response was observed after one week of exposure to 4.1 mGy/h which was replaced by a more inflammation-related expression profile after three weeks and onwards. This early stress response may trigger the radiation-induced premature senescence previously observed in HUVEC irradiated with 4.1 mGy/h. A dedicated analysis pointed to the involvement of insulin-like growth factor binding protein 5 (IGFBP5) signaling in radiation-induced premature senescence.

Conclusion: Our findings motivate further research on the shape of the dose-response and the dose rate effect for radiation-induced vascular senescence.
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http://dx.doi.org/10.3109/09553002.2014.905724DOI Listing
July 2014

Carbon ion irradiation of the human prostate cancer cell line PC3: a whole genome microarray study.

Int J Oncol 2014 Apr 3;44(4):1056-72. Epub 2014 Feb 3.

Radiobiology Unit, Molecular and Cellular Biology, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium.

Hadrontherapy is a form of external radiation therapy, which uses beams of charged particles such as carbon ions. Compared to conventional radiotherapy with photons, the main advantage of carbon ion therapy is the precise dose localization along with an increased biological effectiveness. The first results obtained from prostate cancer patients treated with carbon ion therapy showed good local tumor control and survival rates. In view of this advanced treatment modality we investigated the effects of irradiation with different beam qualities on gene expression changes in the PC3 prostate adenocarcinoma cell line. For this purpose, PC3 cells were irradiated with various doses (0.0, 0.5 and 2.0 Gy) of carbon ions (LET=33.7 keV/µm) at the beam of the Grand Accélérateur National d'Ions Lourds (Caen, France). Comparative experiments with X-rays were performed at the Belgian Nuclear Research Centre. Genome-wide gene expression was analyzed using microarrays. Our results show a downregulation in many genes involved in cell cycle and cell organization processes after 2.0 Gy irradiation. This effect was more pronounced after carbon ion irradiation compared with X-rays. Furthermore, we found a significant downregulation of many genes related to cell motility. Several of these changes were confirmed using qPCR. In addition, recurrence-free survival analysis of prostate cancer patients based on one of these motility genes (FN1) revealed that patients with low expression levels had a prolonged recurrence-free survival time, indicating that this gene may be a potential prognostic biomarker for prostate cancer. Understanding how different radiation qualities affect the cellular behavior of prostate cancer cells is important to improve the clinical outcome of cancer radiation therapy.
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http://dx.doi.org/10.3892/ijo.2014.2287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977812PMC
April 2014

Morphological and physiological changes in mature in vitro neuronal networks towards exposure to short-, middle- or long-term simulated microgravity.

PLoS One 2013 16;8(9):e73857. Epub 2013 Sep 16.

Radiobiology Unit, Molecular and Cellular Biology expert group, Belgian Nuclear Research Centre, SCK•CEN, Mol, Belgium ; Laboratory of Biochemistry and Molecular Cytology, Department of Molecular Biotechnology, Ghent University, Ghent, Belgium.

One of the objectives of the current international space programmes is to investigate the possible effects of the space environment on the crew health. The aim of this work was to assess the particular effects of simulated microgravity on mature primary neuronal networks and specially their plasticity and connectivity. For this purpose, primary mouse neurons were first grown for 10 days as a dense network before being placed in the Random Positioning Machine (RPM), simulating microgravity. These cultures were then used to investigate the impact of short- (1 h), middle- (24 h) and long-term (10 days) exposure to microgravity at the level of neurite network density, cell morphology and motility as well as cytoskeleton properties in established two-dimensional mature neuronal networks. Image processing analysis of dense neuronal networks exposed to simulated microgravity and their subsequent recovery under ground conditions revealed different neuronal responses depending on the duration period of exposure. After short- and middle-term exposures to simulated microgravity, changes in neurite network, neuron morphology and viability were observed with significant alterations followed by fast recovery processes. Long exposure to simulated microgravity revealed a high adaptation of single neurons to the new gravity conditions as well as a partial adaptation of neuronal networks. This latter was concomitant to an increase of apoptosis. However, neurons and neuronal networks exposed for long-term to simulated microgravity required longer recovery time to re-adapt to the ground gravity. In conclusion, a clear modulation in neuronal plasticity was evidenced through morphological and physiological changes in primary neuronal cultures during and after simulated microgravity exposure. These changes were dependent on the duration of exposure to microgravity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073857PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774774PMC
May 2014