Publications by authors named "Mohammed Abderrafi Benotmane"

17 Publications

  • Page 1 of 1

Radiation-induced cardiovascular disease: an overlooked role for DNA methylation?

Epigenetics 2021 Jan 31:1-22. Epub 2021 Jan 31.

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

Radiotherapy in cancer treatment involves the use of ionizing radiation for cancer cell killing. Although radiotherapy has shown significant improvements on cancer recurrence and mortality, several radiation-induced adverse effects have been documented. Of these adverse effects, radiation-induced cardiovascular disease (CVD) is particularly prominent among patients receiving mediastinal radiotherapy, such as breast cancer and Hodgkin's lymphoma patients. A number of mechanisms of radiation-induced CVD pathogenesis have been proposed such as endothelial inflammatory activation, premature endothelial senescence, increased ROS and mitochondrial dysfunction. However, current research seems to point to a so-far unexamined and potentially novel involvement of epigenetics in radiation-induced CVD pathogenesis. Firstly, epigenetic mechanisms have been implicated in CVD pathophysiology. In addition, several studies have shown that ionizing radiation can cause epigenetic modifications, especially DNA methylation alterations. As a result, this review aims to provide a summary of the current literature linking DNA methylation to radiation-induced CVD and thereby explore DNA methylation as a possible contributor to radiation-induced CVD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15592294.2021.1873628DOI Listing
January 2021

Folic Acid Fortification Prevents Morphological and Behavioral Consequences of X-Ray Exposure During Neurulation.

Front Behav Neurosci 2020 8;14:609660. Epub 2021 Jan 8.

Radiobiology Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (Studiecentrum voor Kernenergie; Centre d'étude de l'énergie nucléaire), Mol, Belgium.

Previous studies suggested a causal link between pre-natal exposure to ionizing radiation and birth defects such as microphthalmos and exencephaly. In mice, these defects arise primarily after high-dose X-irradiation during early neurulation. However, the impact of sublethal (low) X-ray doses during this early developmental time window on adult behavior and morphology of central nervous system structures is not known. In addition, the efficacy of folic acid (FA) in preventing radiation-induced birth defects and persistent radiation-induced anomalies has remained unexplored. To assess the efficacy of FA in preventing radiation-induced defects, pregnant C57BL6/J mice were X-irradiated at embryonic day (E)7.5 and were fed FA-fortified food. FA partially prevented radiation-induced (1.0 Gy) anophthalmos, exencephaly and gastroschisis at E18, and reduced the number of pre-natal deaths, fetal weight loss and defects in the cervical vertebrae resulting from irradiation. Furthermore, FA food fortification counteracted radiation-induced impairments in vision and olfaction, which were evidenced after exposure to doses ≥0.1 Gy. These findings coincided with the observation of a reduction in thickness of the retinal ganglion cell and nerve fiber layer, and a decreased axial length of the eye following exposure to 0.5 Gy. Finally, MRI studies revealed a volumetric decrease of the hippocampus, striatum, thalamus, midbrain and pons following 0.5 Gy irradiation, which could be partially ameliorated after FA food fortification. Altogether, our study is the first to offer detailed insights into the long-term consequences of X-ray exposure during neurulation, and supports the use of FA as a radioprotectant and antiteratogen to counter the detrimental effects of X-ray exposure during this crucial period of gestation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnbeh.2020.609660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820780PMC
January 2021

Cognitive effects of low dose of ionizing radiation - Lessons learned and research gaps from epidemiological and biological studies.

Environ Int 2021 Feb 17;147:106295. Epub 2020 Dec 17.

Barcelona Institute for Global Health (ISGlobal), Campus Mar, Barcelona Biomedical Research Park (PRBB), Dr Aiguader 88, 08003 Barcelona, Spain; University Pompeu Fabra, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), Carlos III Institute of Health, Madrid, Spain.

The last decades have seen increased concern about the possible effects of low to moderate doses of ionizing radiation (IR) exposure on cognitive function. An interdisciplinary group of experts (biologists, epidemiologists, dosimetrists and clinicians) in this field gathered together in the framework of the European MELODI workshop on non-cancer effects of IR to summarise the state of knowledge on the topic and elaborate research recommendations for future studies in this area. Overall, there is evidence of cognitive effects from low IR doses both from biology and epidemiology, though a better characterization of effects and understanding of mechanisms is needed. There is a need to better describe the specific cognitive function or diseases that may be affected by radiation exposure. Such cognitive deficit characterization should consider the human life span, as effects might differ with age at exposure and at outcome assessment. Measurements of biomarkers, including imaging, will likely help our understanding on the mechanism of cognitive-related radiation induced deficit. The identification of loci of individual genetic susceptibility and the study of gene expression may help identify individuals at higher risk. The mechanisms behind the radiation induced cognitive effects are not clear and are likely to involve several biological pathways and different cell types. Well conducted research in large epidemiological cohorts and experimental studies in appropriate animal models are needed to improve the understanding of radiation-induced cognitive effects. Results may then be translated into recommendations for clinical radiation oncology and imaging decision making processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2020.106295DOI Listing
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.reprotox.2019.10.002DOI Listing
January 2020

An appraisal of folates as key factors in cognition and ageing-related diseases.

Crit Rev Food Sci Nutr 2020 7;60(5):722-739. Epub 2019 Feb 7.

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

Folic acid (FA) is often consumed as a food supplement and can be found in fortified staple foods in various western countries. Even though FA supplementation during pregnancy is known to prevent severe congenital anomalies in the developing child (e.g., neural tube defects), much less is known about its influence on cognition and neurological functioning. In this review, we address the advances in this field and situate how folate intake during pregnancy, postnatal life, adulthood and in the elderly affects cognition. In addition, an association between folate status and ageing, dementia and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis is discussed. While its role in the incidence and severity of these diseases is becoming apparent, the underlying action of folates and related metabolites remains elusive. Finally, the potential of FA as a nutraceutical has been proposed, although the efficacy will highly depend on the interplay with other micronutrients, the disease stage and the duration of supplementation. Hence, the lack of consistent data urges for more animal studies and (pre)clinical trials in humans to ascertain a potential beneficial role for folates in the treatment or amelioration of cognitive decline and ageing-related disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10408398.2018.1549017DOI Listing
March 2020

A detailed characterization of congenital defects and mortality following moderate X-ray doses during neurulation.

Birth Defects Res 2018 04 28;110(6):467-482. Epub 2017 Nov 28.

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

Background: Both epidemiological and animal studies have previously indicated a link between in utero radiation exposure and birth defects such as microphthalmos, anophthalmos, and exencephaly. However, detailed knowledge on embryonic radiosensitivity during different stages of neurulation is limited, especially in terms of neural tube defect and eye defect development.

Methods: To assess the most radiosensitive stage during neurulation, pregnant C57BL6/J mice were X-irradiated (0.5 Gy or 1.0 Gy) at embryonic days (E)7, E7.5, E8, E8.5, or E9. Next, the fetuses were scored macroscopically for various defects and prenatal resorptions/deaths were counted. In addition, cranial skeletal development was ascertained using the alcian-alizarin method. Furthermore, postnatal/young adult survival was followed until 5 weeks (W5) of age, after X-irradiation at E7.5 (0.1 Gy, 0.5 Gy, or 1.0 Gy). In addition, body and brain weights were registered at adult age (W10) following X-ray exposure at E7.5 (0.1 Gy, 0.5 Gy).

Results: Several malformations, including microphthalmos and exencephaly, were most evident after irradiation at E7.5, with significance starting respectively at 0.5 Gy and 1.0 Gy. Prenatal mortality and weight were significantly affected in all irradiated groups. Long-term follow-up of E7.5 irradiated animals revealed a reduction in survival at 5 weeks of age after high dose exposure (1.0 Gy), while lower doses (0.5 Gy, 0.1 Gy) did not affect brain and body weight at postnatal week 10.

Conclusions: With this study, we gained more insight in radiosensitivity throughout neurulation, and offered a better defined model to further study radiation-induced malformations and the underlying mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdr2.1161DOI Listing
April 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874625PMC
July 2017

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: .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12859-016-1068-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865096PMC
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1866-1955-7-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448911PMC
June 2015

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09553002.2014.905724DOI Listing
July 2014

MorphoNeuroNet: an automated method for dense neurite network analysis.

Cytometry A 2014 Feb 12;85(2):188-99. Epub 2013 Nov 12.

Radiobiology Unit, Molecular and Cellular Biology Expert Group, Belgian Nuclear Research Centre, SCK•CEN, Mol, Belgium; Cell Systems and Imaging Research Group (CSI), Department of Molecular Biotechnology, Ghent University, Ghent, Belgium.

High content cell-based screens are rapidly gaining popularity in the context of neuronal regeneration studies. To analyze neuronal morphology, automatic image analysis pipelines have been conceived, which accurately quantify the shape changes of neurons in cell cultures with non-dense neurite networks. However, most existing methods show poor performance for well-connected and differentiated neuronal networks, which may serve as valuable models for inter alia synaptogenesis. Here, we present a fully automated method for quantifying the morphology of neurons and the density of neurite networks, in dense neuronal cultures, which are grown for more than 10 days. MorphoNeuroNet, written as a script for ImageJ, Java based freeware, automatically determines various morphological parameters of the soma and the neurites (size, shape, starting points, and fractional occupation). The image analysis pipeline consists of a multi-tier approach in which the somas are segmented by adaptive region growing using nuclei as seeds, and the neurites are delineated by a combination of various intensity and edge detection algorithms. Quantitative comparison showed a superior performance of MorphoNeuroNet to existing analysis tools, especially for revealing subtle changes in thin neurites, which have weak fluorescence intensity compared to the rest of the network. The proposed method will help determining the effects of compounds on cultures with dense neurite networks, thereby boosting physiological relevance of cell-based assays in the context of neuronal diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cyto.a.22408DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073857PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774774PMC
May 2014

Differential response to acute low dose radiation in primary and immortalized endothelial cells.

Int J Radiat Biol 2013 Oct 21;89(10):841-50. Epub 2013 Jun 21.

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

Purpose: The low dose radiation response of primary human umbilical vein endothelial cells (HUVEC) and its immortalized derivative, the EA.hy926 cell line, was evaluated and compared.

Material And Methods: DNA damage and repair, cell cycle progression, apoptosis and cellular morphology in HUVEC and EA.hy926 were evaluated after exposure to low (0.05-0.5 Gy) and high doses (2 and 5 Gy) of acute X-rays.

Results: Subtle, but significant increases in DNA double-strand breaks (DSB) were observed in HUVEC and EA.hy926 30 min after low dose irradiation (0.05 Gy). Compared to high dose irradiation (2 Gy), relatively more DSB/Gy were formed after low dose irradiation. Also, we observed a dose-dependent increase in apoptotic cells, down to 0.5 Gy in HUVEC and 0.1 Gy in EA.hy926 cells. Furthermore, radiation induced significantly more apoptosis in EA.hy926 compared to HUVEC.

Conclusions: We demonstrated for the first time that acute low doses of X-rays induce DNA damage and apoptosis in endothelial cells. Our results point to a non-linear dose-response relationship for DSB formation in endothelial cells. Furthermore, the observed difference in radiation-induced apoptosis points to a higher radiosensitivity of EA.hy926 compared to HUVEC, which should be taken into account when using these cells as models for studying the endothelium radiation response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09553002.2013.806831DOI Listing
October 2013

Non-conventional apoptotic response to ionising radiation mediated by N-methyl D-aspartate receptors in immature neuronal cells.

Int J Mol Med 2013 Mar 15;31(3):516-24. Epub 2013 Jan 15.

Radiobiology Unit, Molecular and Cellular Biology Expert Group, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre, SCK•CEN, B-2400 Mol, Belgium.

During cortical development, N-methyl D-aspartate (NMDA) receptors are highly involved in neuronal maturation and synapse establishment. Their implication in the phenomenon of excitotoxicity has been extensively described in several neurodegenerative diseases due to the permissive entry of Ca2+ ions and massive accumulation in the intracellular compartment, which is highly toxic to cells. Ionising radiation is also a source of stress to the cells, particularly immature neurons. Their capacity to induce cell death has been described for various cell types either by directly damaging the DNA or indirectly through the generation of reactive oxygen species responsible for the activation of a battery of stress response effectors leading in certain cases, to cell death. In this study, in order to determine whether a link exists between NMDA receptors-mediated excitotoxicity and radiation-induced cell death, we evaluated radiation-induced cell death in vitro and in vivo in maturing neurons during the fetal period. Cell death induction was assessed by TUNEL, caspase-3 activity and DNA ladder assays, with or without the administration of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist which blocks neuronal Ca2+ influx. To further investigate the possible involvement of Ca2+-dependent enzyme activation, known to occur at high Ca2+ concentrations, we examined the protective effect of a calpain inhibitor on cell death induced by radiation. Doses ranging from 0.2 to 0.6 Gy of X-rays elicited a clear apoptotic response that was prevented by the injection of dizocilpine (MK-801) or calpain inhibitor. These data demonstrate the involvement of NMDA receptors in radiation-induced neuronal death by the activation of downstream effectors, including calpain-related pathways. An increased apoptotic process elicited by radiation, occurring independently of the normal developmental scheme, may eliminate post-mitotic but immature neuronal cells and deeply impair the establishment of the neuronal network, which in the case of cortical development is critical for cognitive capacities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijmm.2013.1245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597540PMC
March 2013

Ionizing radiation biomarkers for potential use in epidemiological studies.

Mutat Res 2012 Oct-Dec;751(2):258-286. Epub 2012 Jun 4.

Centre for Research in Environmental Epidemiology (CREAL), Radiation programme, IMIM (Hospital del Mar Research Institute) and CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona Biomedical Research Park (PRBB), Doctor Aiguader, 88, 08003 Barcelona, Spain. Electronic address:

Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of health risks at low doses and dose-rates (below 100mSv and/or 0.1mSvmin(-1)) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of potential confounding factors, are also essential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mrrev.2012.05.003DOI Listing
November 2012

Unraveling the fundamental molecular mechanisms of morphological and cognitive defects in the irradiated brain.

Brain Res Rev 2007 Feb 22;53(2):312-20. Epub 2006 Dec 22.

Laboratory of Health sciences and Biology, Belgian Nuclear Research Center (SCK-CEN), Boeretang 200, Mol B-2400, Belgium.

Prenatal radiation exposure may have serious consequences for normal brain development. Results of epidemiological studies clearly pointed towards an increased risk of mental retardation in children of the surviving women of the Hiroshima/Nagasaki atomic bombing when in utero exposure had occurred between weeks 8 and 15 of pregnancy or, at a lower extend between weeks 15 and 25. The high sensitivity of the developing brain, in comparison to the adult brain is related to its higher number of non-differentiated, dividing neural precursor cells. Exposure of the developing brain to ionizing radiation can lead to three main outcomes in the developing brain, depending on the radiation dose and the elapsed period after irradiation. A first event occurs early after irradiation and triggers disturbances in cell proliferation, migration, differentiation, and cell death. A second event involves the generation of morphological abnormalities in the developing brain, if the radiation dose is sufficient. A third event involves cognitive dysfunctions that are a direct consequence from a disturbance in regional brain formation. The latter results from exposure to low doses and is usually only observed in the later period of development. In order to understand the mechanisms of radiation-induced cognitive dysfunctions, it is important to track back the underlying changes in specific molecular pathways. In this review, we present the possible relationships within and between molecular pathways potentially involved in cognitive dysfunctions induced by ionizing radiation in the developing brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainresrev.2006.09.004DOI Listing
February 2007

A genomic approach reveals a novel mitotic pathway in papillomavirus carcinogenesis.

Cancer Res 2004 Feb;64(3):895-903

Unit of Gene Expression and Diseases, Unité de Recherche Associée 1644 of Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France.

More than 90% of cervical carcinomas are associated with human papillomavirus (HPV) infection. The two viral oncogenes E6 and E7 play a major role in transforming the cells by disrupting p53- and pRb-dependent cell cycle checkpoints. A hallmark of HPV-associated cervical carcinoma is loss of the expression of the viral E2 protein, often by disruption of E2-encoding gene. We showed previously that reintroduction of E2 in HPV18-associated cervical carcinoma cells induces cell cycle arrest in G(1) because of the transcriptional repression of the viral oncogenes E6 and E7 and concomitant reactivation of the p53 and pRb pathways. Here we describe global gene profiling of HeLa cells expressing different HPV18 E2 mutants to study the effects of repression of the viral oncogenes. We identified 128 genes transcriptionally regulated by the viral oncogenes in cervical carcinoma. Surprisingly, E2 repressed a subset of E2F-regulated mitotic genes in an E6/E7-dependent pathway. This was corroborated by the observation that E2 delayed mitotic progression, suggesting the involvement of a mitotic pathway in HPV carcinogenesis. These mitotic genes constitute an as yet unrecognized set of genes, which were also found deregulated in other HPV-associated cervical carcinoma cell lines and therefore represent new targets for both diagnosis and therapeutic approaches in cervical cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.can-03-2349DOI Listing
February 2004