Dans le domaine du nucléaire, les techniques actuelles de mesure de radiation n’offrent pas la possibilité d’effectuer un contrôle le long d’un objet filaire. Le projet Droïd a pour but de développer un dosimètre linéique utilisant une fibre optique comme élément sensible. L’atténuation radio-induite (ARI) du guide d’onde, lue par réflectométrie optique, permet non seulement de quantifier, mais également de localiser le dépôt de dose le long de la fibre. Chaque portion du câble fait alors office de capteur de rayonnement. Il est envisageable d’effectuer des mesures réparties sur de longues distances (plusieurs dizaines de mètres) et d’obtenir des cartographies de dose en une, deux ou trois dimensions selon la disposition de l’objet dans l’espace. Le projet se structure en deux volets. Le premier est le développement d’une fibre optique hautement sensible aux radiations. En effet, les technologies commerciales standard ne le sont pas suffisamment pour des applications comme la radioprotection du personnel dans le milieu du nucléaire. Définir la composition chimique de la fibre permet de maîtriser sa réponse aux rayonnements. Le second volet du projet concerne la modélisation liant l’atténuation radio-induite à la dose reçue par le guide d’onde. Dans le cas général d’une fibre avec fading, le développement et l’inversion d’un modèle non linéaire sont primordiaux pour le bon fonctionnement du dosimètre et constituent un verrou scientifique majeur à lever. / In the nuclear domain, current radiation monitoring techniques do not offer the possibility to locally determine the dose received by a wire along its path. The purpose of the Droïd project is to develop a linear dosimeter based on an optical fiber as a sensitive element. The Radiation-Induced Attenuation (RIA) of the waveguide, read by optical reflectometry, can be used not only to quantify, but also to locate the dose deposition along the fiber. Each portion of the cable acts as a radiation sensor. It becomes possible to make measurements over long distances (several tens of meters) and to obtain dose maps in one, two or three dimensions depending on the spatial arrangement of the fiber. The project is structured in two parts. The first one is the development of an optical fiber that is highly sensitive to radiation. Indeed, standard commercial technologies are not reactive enough for applications such as staff radioprotection. Defining the chemical composition of the fiber permits to master its behavior under radiation. The second part of the project deals with modeling the non-linear relationship between the RIA and the dose received by the waveguide. In the general case of a sensor with fading, building and inverting such a model are a requirement for the final device and constitute a major scientific challenge.

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Le traitement du cancer à l’aide d’une exposition aux radiations ionisantes (RI) peut mener au développement de plusieurs effets secondaires importants, dont un retard de réparation et de régénération des tissus. Les mécanismes responsables de ces effets demeurent largement inconnus encore aujourd’hui, ce qui a pour effet de limiter le développement d’approches thérapeutiques. À l’aide d’un modèle de guérison de plaie cutanée chez la souris, nous avons cherché à déterminer les mécanismes par lesquels l’exposition aux RI limite la régénération de la peau. Nos résultats démontrent que l’induction de la "stromal-derived growth factor 1α" (SDF-1α), une cytokine normalement surexprimée dans les tissus hypoxiques, est sévèrement diminuée dans les plaies de souris irradiées versus non-irradiées. Ce défaut corrèle avec un retard de guérison des plaies et est encore évident plusieurs mois suivant l’exposition aux RI, suggérant qu’il y a une altération permanente de la capacité de la peau à se réparer. Parce que SDF-1α est secrété principalement par les fibroblastes du derme, nous avons évalué le potentiel des cellules stromales multipotentes (MSCs), qui sont reconnues pour secréter des niveaux élevés de SDF-1α, à accélérer la régénération de la peau chez les souris irradiées. L’injection de MSCs en périphéries des plaies a mené à une accélération remarquable de la guérison de la peau chez les souris exposées aux RI. Les actions des MSCs étaient principalement paracrines, dû au fait que les cellules n’ont pas migré à l’extérieur de leur site d’injection et ne se sont pas différentiées en kératinocytes. L’inhibition spécifique de l’expression de SDF-1α a mené à une réduction drastique de l’efficacité des MSCs à accélérer la fermeture de plaie indiquant que la sécrétion de SDF-1α par les MSCs est largement responsable de leur effet bénéfique. Nous avons découvert aussi qu’un des mécanismes par lequel SDF-1α accélère la guérison de plaie implique l’augmentation de la vascularisation au niveau de la peau blessée. Les résultats présentés dans ce mémoire démontrent collectivement que SDF-1α est une importante cytokine dérégulée au niveau des plaies cutanées irradiées, et que le déclin du potentiel de régénération des tissus qui est observé suivant une exposition au RI peut être renversé, s’il est possible de restaurer le microenvironnement de la blessure avec un support stromal adéquat. / Cancer treatment using ionizing radiation (IR) may lead to significant side effects, like delayed tissue repair and regeneration. The mechanisms mediating these defects remain largely unknown at present, thus limiting the development of therapeutic approaches. Using a wound healing model, we investigate the mechanisms by which IR exposure limits skin regeneration. Our results show that induction of the stromal-derived growth factor 1α (SDF-1α), a cytokine normally overexpressed in hypoxic tissues, is severely impaired in the wounded skin of irradiated, compared to non-irradiated, mice. This defect is correlated with delayed healing, and is evident for several months following exposure to IR, suggesting permanent impairment of skin repair. Because SDF-1α is secreted mainly by dermal fibroblasts, we evaluated the potential of multipotent stromal cells (MSCs), which secrete high levels of SDF-1α, to improve skin regeneration in irradiated mice. Injection of MSCs into the wound margin led to remarkable enhancement of skin healing in mice exposed to IR. The MSC actions were mainly paracrine, as the cells did not migrate away from the injection site or differentiate into keratinocytes. Specific knockdown of SDF-1α expression led to drastically reduced efficiency of MSCs in improving wound closure, indicating that SDF-1α secretion by MSCs is largely responsible for their beneficial action. We also found that one mechanism by which SDF-1α enhances wound closure likely involves increased skin vascularization. Findings presented in this thesis collectively indicate that SDF-1α is an important deregulated cytokine in irradiated wounded skin, and that the decline in tissue regeneration potential following IR can be reversed, given adequate microenvironmental support.

Epigenetics plays an important role in carcinogenesis with heritable changes in DNA methylation and histone modifications intricately linked to the initiation, promotion, and progression of cancer. Evidence shows that a number of chemical and physical agents can induce epigenetic changes during carcinogenesis. Two such agents, estrogen and ionizing radiation, are generally recognized as being carcinogenic. Yet the epigenetic repercussions of these carcinogens remain relatively unknown. More importantly, the combined effect of these carcinogens has never been addressed in vivo from an epigenetic standpoint. Therefore, we focused on the effect of estrogen and ionizing radiation applied separately or in conjunction. We have found that the exposure to estrogen, either alone or in combination with radiation, induced pronounced morphological alterations, which was paralleled by modifications to the epigenomic landscape in the mammary gland. The results obtained from these rodent models can potentially be extrapolated to humans. / xiv, 190 leaves : ill. (chiefly col.) ; 29 cm

For over 100 years, cancer radiation therapy has provided patients with increased survival rates. Despite this success, radiation exposure poses a threat to the progeny of exposed parents. It causes transgenerational genome instability that is linked to transgenerational carcinogenesis. The exact mechanisms in which this instability occurs have yet to be discovered. Current evidence points to their epigenetic nature, specifically changes in DNA methylation. Using mouse and rat models, this thesis investigated the transgenerational effects of radiation in the offspring from parents who received whole body or localized exposure to ionizing radiation (IR). Both types of exposure resulted in significant global DNA hypomethylation in the somatic tissues of the progeny. These changes were paralleled by the significantly decreased levels of methyltransferases and methyl-CpG-binding protein. In summary, our results suggest that both localized and whole body parental exposures to IR result in transgenerational epigenetic instability within the unexposed offspring. / vii, 106 leaves : ill. ; 29 cm.

Ionizing radiation (IR), along with being an important diagnostic and treatment modality, is a potent tumor-causing agent, and the risk of secondary radiation treatment-related cancers is a growing clinical problem. Now some studies propose to link secondary radiation-induced cancers to an enigmatic phenomenon of bystander effects, whereby the exposed cells send signal damage and distress to their naïve neighbors and result in genome destabilization and carcinogenesis. Yet, no data existed on the bystander effects in an organ other than an exposed one. With this in mind, we focused on the analysis of existence and mechanisms of radiation-induced bystander effects in vivo. We have found that bystander effects occur in vivo in distant skin and spleen following half-body or cranial irradiation. These bystander effects resulted in elevated DNA damage, profound dysregulation of epigenetic machinery, and pronounced alterations in apoptosis, proliferation and gene expression. Bystander effects also exhibited persistency and sex specificity. The results obtained while using the animal model systems can potentially be extrapolated to different animals and humans. / xiii, 208 leaves : ill. ; 29 cm.

Bystander effects are traditionally known as a phenomenon whereby unexposed cells exhibit the molecular symptoms of stress exposure when adjacent or nearby cells are traversed by ionizing radiation. However, the realm of bystander effects can be expanded to include any systemic changes to cellular homeostasis in response to a number of biotic or abiotic stresses, in any molecular system. This thesis encompasses three independent experiments looking at bystander and bystander-like responses in both plant and animal models. In plants, an investigation into the regulation of small RNAs has given us some insights into the regulation of the plant hormone auxin in both stress-treated and systemic (bystander) leaves. Another plant model shows that a bystander-like plant-plant signal can be induced upon ionizing radiation to increase the genome instability of neighbouring unexposed (bystander) plants. In animals, it is shown that the microRNAome is largely affected in the bystander cells in a three-dimensional human tissue model. In silico and bioinfomatic analysis of this data provide us with clues as to the nature of bystander signalling in this human ‘in vivo’ model. / xiv, 141 p. : ill. ; 29 cm.

The general public is at risk of ionising-radiation exposure. The development of high-throughput methods to triage exposures is warranted. Current biodosimetry techniques are low-throughput and encumbered by time and technical expertise. Although there has been an emergence of gene-profiling tools for the purpose of photon biodosimetry, similar capacities do not exist for alpha-particle radiation. Herein is the first genomic study useful for alpha-particle radiation biodosimetric triage. This work has identified robust alpha-particle induced gene-based biomarkers in isolated, ex-vivo irradiated leukocytes from multiple donors. It was found that alpha-particle and photon radiation elicited similar transcriptional responses, which could potentially be distinguished by aggregate-signature analysis. Although no distinct genes were sole indicators of exposure type, clustering algorithms and principal component analysis were able to demarcate radiation type with some success. By comparing the biological effects elicited by photon and alpha-particle radiation, significant contributions have been made to the field of radiation biodosimetry.

Fifty percent of solid cancers are treated with radiation therapy (RT). The dose used in RT is adjusted to the most sensitive individuals so that not more than 5% of the patients will have severe adverse healthy tissue effects. As a consequence, the majority of the patients will receive a suboptimal dose, as they would have tolerated a higher total dose and received a better tumor control. Thus, if RT could be individualized based on radiation sensitivity (RS), more patients would be cured and the most severe adverse reactions could be avoided. At present the mechanisms behind RS are not known. The long term aim of this thesis was to develop diagnostic tools to assess the individual RS of breast cancer patients and to better understand the mechanisms behind the RS and radiation effects after low dose exposures. The approach was based on the hypothesis that biomarkers of individual RS, in terms of acute adverse skin reactions after breast cancer RT, can be found in whole blood that has been stressed by low doses of ionizing radiation (IR).  To reach this goal two different approaches to identify biomarkers of RS have been investigated. A protocol for the analysis of differential protein expression in response to low dose in vitro irradiated whole blood was developed (paper I). This protocol was then used to investigate the proteomic profile of radiation sensitive and normo-sensitive patients, using isotope-coded protein labeled proteomics (ICPL). The results from the ICPL study (paper III) show that the two patient groups have different protein expression profiles both at the basal level and after IR. In paper II the potential biomarker 8-oxo-dG was investigated in serum after IR. The relative levels of IR induced 8-oxo-dG from radiation sensitive patients differ significantly from normo-sensitive patients. This indicates that the sensitive patients differ in their cellular response to IR and that 8-oxo-dG is a potential biomarker for RS. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.</p>

CNEN / Tendo em vista o crescente interesse dos organismos internacionais e nacionais em se conhecer os níveis de radônio no ar, em águas, principalmente em poços, e a escassez destes dados em esfera nacional, o grupo de pesquisa em radiações da UTFPR, em colaboração com o Centro de Desenvolvimento da Tecnologia Nuclear (CDTN / CNEN) e com o Instituto de Radioproteção e Dosimetria (IRD / CNEN) tem mantido uma parceria onde se realizam medidas de radônio no ar, solos e águas. Estas medidas têm sido feitas pelo grupo desde 2003 e o laboratório especializou-se em medidas no ar, por meio de detectores do estado sólido e em solo e água, por meio de equipamento eletrônico de medidas instantâneas. O objetivo desta tese é avaliar a os níveis de concentração de radônio 222Rn em residências e postos de trabalho (indoor) no estado do Paraná, mais especificamente na região metropolitana de Curitiba e verificar os níveis de concentração de 222Rn em águas de poços desta região. O trabalho apresenta os resultados das concentrações de 222Rn em ambientes residenciais, postos de trabalho e em águas de poços da região. As medidas indoor foram feitas por meio de detectores do estado sólido CR-39. A densidade de traços por cm2 para cada detector foi determinada. Os cálculos das concentrações de 222Rn nos ambientes foram feitos a partir de metodologia de calibração do sistema detector, desenvolvida especificamente para estas medidas. O trabalho de calibração foi desenvolvido em conjunto com o CDTN a partir de irradiações feitas no National Institute of Radiological Sciences (NIRS). As concentrações de 222Rn nas residências ficaram, na sua maioria, abaixo de 100 Bq/m3, com apenas um caso onde a concentração ficou entre 200 e 400 Bq/m3. Com relação aos postos de trabalho, todas as medidas de concentração de 222Rn ficaram abaixo de 100 Bq/m3. As concentrações de 222 Rn nas amostras das águas de poços foram medidas, em intervalos de cerca de quatro dias, por meio do monitor de radônio AlphaGUARD PQ2000 PRO. Os cálculos das concentrações de atividade iniciais de radônio na água foram feitos a partir da curva de decaimento do 222Rn e do equilíbrio secular entre o 222Rn e o 226Ra, observados depois de 30 dias. Os resultados indicaram que cerca de 70% dos valores das concentrações de 222Rn ficaram acima do valor recomendado pela USEPA, de 11,1 Bq/L, representando risco radiológico causado por este radionuclídeo. / Considering the growing interest of International Agencies and national Governmental organs in studies and measurements of radon activity in air, soil gas and ground water (mainly from artesian wells) as well as scarceness of such measurements at Brazilian territory, present studies were initiated by the Laboratory of Applied Nuclear Physics of Federal University of Technology – Paraná (UTFPR) in collaboration with the Institute of Radiation Protection and Dosimetry (IRD) and the Center of Nuclear Technology Development (CDTN) of Brazilian Commission on Nuclear Energy (CNEN). This Collaboration started in 2003. Radon monitoring program is based mainly on use of Solid State Nuclear Track Detectors for radon activity measurements in air. Continuous electronic radon detectors are used for radon measurements in soil gas and water. Current work presents the results of indoor 222Rn activity of dwellings and working places of Curitiba-PR and radon concentration in ground water samples from artesian wells from aquifers of the same area. The indoor measurements of radon activity were performed using Solid State Nuclear Track Detectors CR-39. After the exposition, CR-39 detectors were submitted to chemical development which permitted to make alpha particle tracks counting. The results of calibration of CR-39 together with efficiency of used exhalation chambers as well as alpha particle tracks chemical development procedure were erformed in cooperation with CDTN and collaboration with the National Institute of Radiological Sciences (NIRS). The major part of indoor 222Rn concentration in residences was found below 100 Bq/m3. In the case of working places, all measurements present 222Rn concentration bellow 100 Bq/m3. The studies of radon activity in water were performed using the samples of water from artesian wells submitted to recursive measurements by instant radon detector AlphaGUARD PQ2000 PRO during few weeks with intervals of about 4 days between each measurement approximately. The calculations of initial radon activity in water were done considering the 222Rn decay correction as well as equilibrium level of 222Rn and 226Ra observed after 30 days of measurements. Obtained results show that about 70% measured activity levels of 222Rn are higher than recommended value of 11.1 Bq/L which represent the risk for the human health associated with this radionuclide.