Class of 2016 Abstract / Objectives: The purpose of this study was to evaluate if fluconazole 200 mg is an acceptable alternative to the fluconazole 400 mg for fungal prophylaxis in allogenic hematopoietic stem cell patients. Lower fluconazole doses will decrease cost of therapy and may reduce adverse events associated with higher doses. Methods: This study was a retrospective chart review conducted at the Arizona Cancer Center. A total of 58 patients qualified for the study. Primary endpoints were number of days on fluconazole 200 mg and type and number of fungal infections that occurred within 1 year post transplant. Results: Out of the fifty-eight patients who qualified for the study, only eight patients had a breakthrough fungal infection while on 200 mg (13.7%) after one year. Three of those eight were identified as having systemic fungal infections (5.2%). Conclusions: Fluconazole 200 mg is a reasonable low-cost and low side effect alternative to fluconazole 400 mg for antifungal prophylaxis in allogenic hematopoietic stem cell patients.

<p>We hypothesize that South African medicinal plants contain compounds that can act in synergism with synthetic antifungal compounds. Four fungicides - Sporekill&trade / , Rovral&trade / , Terminator&trade / and Teldor&trade / at doses 0.1, 0.2, 0.4 and 0.8 mL L-1 and plant species Galenia africana, Elytropappus rhinocerotis and Tulbaghia violacea were tested aloneand in different combinations for their potency (efficacy) on radial growth inhibition of Botrytis cinerea strains on potato dextrose plates. Four doses of plant extract for each of the respective plant species were used. A total of 48 combinations were tested for each strain. Mixtures of plant extracts were far more effective in controlling strains compared to the individual components alone, representing significant levels of in vitro synergistic interactions. Combinations of these components represent an attractive future prospect for the development of new management strategies for controlling B. cinerea. Since the in vitro tests of these mixtures showed inhibitory activity, the mixtures were tested for activity in assays on Granny Smith apples. In vitro tests can be used to screen mixtures to obtain information on their inhibitory activity on a pathogen, however, the environmental conditions of the fruit and the ability of the pathogen to grow into the fruit cannot be simulated in vivo. A series of two-fold doses of medicinal plant extracts were combined with fungicides to conduct decay inhibition studies. The incidence of gray mold was significantly reduced by mixtures of plant extracts and fungicides. Under conditions similar to those in commercial storage, a drench treatment with G. africana and Rovral&trade / significantly (p=0.05) inhibit gray mold on the apples and was more effective than the plant extract and fungicide alone. The treatments exerted synergistic effects and were markedly better than the components applied alone. The wound colonization assay was used for optimal decay control. In a drench, much higher volumes of the treatments are used to ensure that the components of the suspension are deposited evenly over the entire fruit surface. Drenching of fruit to apply other chemicals is an established practise in the pome (fleshy) fruit industry, and simplifies the commercial application of the mixtures, as no additional infrastructure at commercial packing houses will be required. This approach not only makes it possible to reduce fungicide concentrations while maintaining adequate decay control, but also ensures a reduction of the chemical residue on the fruit.</p>

<p>We hypothesize that South African medicinal plants contain compounds that can act in synergism with synthetic antifungal compounds. Four fungicides - Sporekill&trade / , Rovral&trade / , Terminator&trade / and Teldor&trade / at doses 0.1, 0.2, 0.4 and 0.8 mL L-1 and plant species Galenia africana, Elytropappus rhinocerotis and Tulbaghia violacea were tested aloneand in different combinations for their potency (efficacy) on radial growth inhibition of Botrytis cinerea strains on potato dextrose plates. Four doses of plant extract for each of the respective plant species were used. A total of 48 combinations were tested for each strain. Mixtures of plant extracts were far more effective in controlling strains compared to the individual components alone, representing significant levels of in vitro synergistic interactions. Combinations of these components represent an attractive future prospect for the development of new management strategies for controlling B. cinerea. Since the in vitro tests of these mixtures showed inhibitory activity, the mixtures were tested for activity in assays on Granny Smith apples. In vitro tests can be used to screen mixtures to obtain information on their inhibitory activity on a pathogen, however, the environmental conditions of the fruit and the ability of the pathogen to grow into the fruit cannot be simulated in vivo. A series of two-fold doses of medicinal plant extracts were combined with fungicides to conduct decay inhibition studies. The incidence of gray mold was significantly reduced by mixtures of plant extracts and fungicides. Under conditions similar to those in commercial storage, a drench treatment with G. africana and Rovral&trade / significantly (p=0.05) inhibit gray mold on the apples and was more effective than the plant extract and fungicide alone. The treatments exerted synergistic effects and were markedly better than the components applied alone. The wound colonization assay was used for optimal decay control. In a drench, much higher volumes of the treatments are used to ensure that the components of the suspension are deposited evenly over the entire fruit surface. Drenching of fruit to apply other chemicals is an established practise in the pome (fleshy) fruit industry, and simplifies the commercial application of the mixtures, as no additional infrastructure at commercial packing houses will be required. This approach not only makes it possible to reduce fungicide concentrations while maintaining adequate decay control, but also ensures a reduction of the chemical residue on the fruit.</p>

Submitted by GIANMARCO JOSE TIRONI GALLARDO null (gian.ayoyo@gmail.com) on 2017-10-09T16:20:54Z No. of bitstreams: 1 Dissertação_Gian.pdf: 919750 bytes, checksum: 599eb4e6715547e953b49f95ff681528 (MD5) / Approved for entry into archive by Monique Sasaki (sayumi_sasaki@hotmail.com) on 2017-10-09T19:18:57Z (GMT) No. of bitstreams: 1 gallardo_gjt_me_jabo.pdf: 919750 bytes, checksum: 599eb4e6715547e953b49f95ff681528 (MD5) / Made available in DSpace on 2017-10-09T19:18:57Z (GMT). No. of bitstreams: 1 gallardo_gjt_me_jabo.pdf: 919750 bytes, checksum: 599eb4e6715547e953b49f95ff681528 (MD5) Previous issue date: 2017-08-07 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Panicum maximun está entre as plantas daninhas mais importantes nas culturas tropicais, justificando plenamente a necessidade de controlá-la, o que é feito basicamente com o emprego de herbicidas. Diante disso, objetivou-se avaliar o efeito de subdoses de glyphosate nas trocas gasosas, crescimento e morfologia de P. maximun. O experimento foi realizado em casa-de-vegetação, sendo as plantas cultivadas em vasos, em delineamento inteiramente casualizado, com quatro repetições. Os tratamentos experimentais foram constituídos por uma testemunha (sem aplicação do produto) e nove doses (3,78; 8,10; 16,64; 33,48; 67,70; 135,00; 270,00; 540,00 e 1080,00 g e.a. ha-1). Foram avaliados os parâmetros fisiológicos: fotossíntese líquida, condutância estomática, transpiração, temperatura foliar, concentração interna de CO2. Também foram avaliados o número de perfilhos e intoxicação das plantas e, ao final do experimento determinou-se o acúmulo de massa seca da parte aérea e área foliar. Os dados obtidos foram submetidos à análise de variância e as médias comparadas pelo teste de Tukey a 5% de probabilidade. Quando significativos, realizou-se análise de regressão usando os modelos para as curvas de dose-resposta. Os parâmetros fisiológicos avaliados, foram influenciados positivamente pelas subdoses de glyphosate, apresentando maiores valores que a testemunha. A concentração interna de CO2 foi negativamente afetada, mas houve incremento na temperatura da folha de forma progressiva. Além disso, promoveram aumento na massa seca da parte aérea e da área foliar. Diante disso, concluiu-se que houve efeito hormético nas plantas de Panicum maximun, quando submetidas as doses de 3,78 a 270 g e.a ha-1 de glyphosate. / Panicum maximum is among most important weed specie in tropical crops, justifying the need to control it, basically with herbicides. Therefore this work aimed to evaluate glyphosate sub dose in the gas exchange, dry mass and morphological in P.maximum. The experiment was conducted in a green house, plants were grown in plots, with a casually randomized design, with four replications. The experimental treatments were constituted with one control ( without application of the product) and nine doses of glyphoste(3.78: 8.1: 16.64: 33.48: 67.7: 135: 270: 540: 1080 g a.e. ha-1 ). It was evaluated: Liquid photosintesys, estomatic conductance, transpiration, leaf temperature, intern CO2 concentration. Besides it was evaluated tillering and intoxication, at the end of the experiment it was determined the aerial dry mass and leaf area. The data obtained was submitted to a variance analysis test and means submitted to a Tukey test at 5 % probability and when significative was used regression using the models for dose response curves. The physiological parameters evaluated where positive influenciated by the glyphosate sub dose showing higher values than the control, furthermore the intern CO2 concentration was negative influenced, beyond it was observed increment in the leaf temperature progressively, also promote an increment for aerial dry mass accumulation and leaf area besides. Further more, concluding that in the Panicum maximun plants submitted to the glyphosate doses of 3,78 to 270 g a.e. ha-1 showed and hormetic effect. / CNPq: 133038/2015-7

Philosophiae Doctor - PhD / We hypothesize that South African medicinal plants contain compounds that can act in synergism with synthetic antifungal compounds. Four fungicides - Sporekill™, Rovral™, Terminator™ and Teldor™ at doses 0.1, 0.2, 0.4 and 0.8 mL L-1 and plant species Galenia africana, Elytropappus rhinocerotis and Tulbaghia violacea were tested aloneand in different combinations for their potency (efficacy) on radial growth inhibition of Botrytis cinerea strains on potato dextrose plates. Four doses of plant extract for each of the respective plant species were used. A total of 48 combinations were tested for each strain. Mixtures of plant extracts were far more effective in controlling strains compared to the individual components alone, representing significant levels of in vitro synergistic interactions. Combinations of these components represent an attractive future prospect for the development of new management strategies for controlling B. cinerea. Since the in vitro tests of these mixtures showed inhibitory activity, the mixtures were tested for activity in assays on Granny Smith apples. In vitro tests can be used to screen mixtures to obtain information on their inhibitory activity on a pathogen, however, the environmental conditions of the fruit and the ability of the pathogen to grow into the fruit cannot be simulated in vivo. A series of two-fold doses of medicinal plant extracts were combined with fungicides to conduct decay inhibition studies. The incidence of gray mold was significantly reduced by mixtures of plant extracts and fungicides. Under conditions similar to those in commercial storage, a drench treatment with G. africana and Rovral™ significantly (p=0.05) inhibit gray mold on the apples and was more effective than the plant extract and fungicide alone. The treatments exerted synergistic effects and were markedly better than the components applied alone. The wound colonization assay was used for optimal decay control. In a drench, much higher volumes of the treatments are used to ensure that the components of the suspension are deposited evenly over the entire fruit surface. Drenching of fruit to apply other chemicals is an established practise in the pome (fleshy) fruit industry, and simplifies the commercial application of the mixtures, as no additional infrastructure at commercial packing houses will be required. This approach not only makes it possible to reduce fungicide concentrations while maintaining adequate decay control, but also ensures a reduction of the chemical residue on the fruit. / South Africa

Philosophiae Doctor - PhD / We hypothesize that South African medicinal plants contain compounds that can act in synergism with synthetic antifungal compounds. Four fungicides - Sporekill™, Rovral™, Terminator™ and Teldor™ at doses 0.1, 0.2, 0.4 and 0.8 mL L-1 and plant species Galenia africana, Elytropappus rhinocerotis and Tulbaghia violacea were tested alone and in different combinations for their potency (efficacy) on radial growth inhibition of Botrytis cinerea strains on potato dextrose plates. Four doses of plant extract for each of the respective plant species were used. A total of 48 combinations were tested for each strain. Mixtures of plant extracts were far more effective in controlling strains compared to the individual components alone, representing significant levels of in vitro synergistic interactions. Combinations of these components represent an attractive future prospect for the development of new management strategies for controlling B. cinerea. Since the in vitro tests of these mixtures showed inhibitory activity, the mixtures were tested for activity in assays on Granny Smith apples. In vitro tests can be used to screen mixtures to obtain information on their inhibitory activity on a pathogen, however, the environmental conditions of the fruit and the ability of the pathogen to grow into the fruit cannot be simulated in vivo. A series of two-fold doses of medicinal plant extracts were combined with fungicides to conduct decay inhibition studies. The incidence of gray mold was significantly reduced by mixtures of plant extracts and fungicides. Under conditions similar to those in commercial storage, a drench treatment with G. Africana and Rovral™ significantly (p=0.05) inhibit gray mold on the apples and was more effective than the plant extract and fungicide alone. The treatments exerted synergistic effects and were markedly better than the components applied alone. The wound colonization assay was used for optimal decay control. In a drench, much higher volumes of the treatments are used to ensure that the components of the suspension are deposited evenly over the entire fruit surface

L'exposition durant la vie périnatale à des perturbateurs endocriniens (PE) anti-androgéniques, induit des altérations durables du système reproducteur mâle. Si leur action a été objectivée chez l’homme et l’animal, la question du seuil de toxicité reste entière, car l’exposition environnementale correspond à de faibles doses. Ici, nous exposons in utero des rats mâles à de faibles doses de flutamide: 10 mg/kg/j ; 1; 3 doses faibles selon la définition de l'OMS 0.1; 0.01; 0.001 et 0. L'exposition fœtale induit chez l’adulte (1) des altérations morphologiques à la dose 10 mg/kg/j (diminution du poids des organes du tractus génital et une diminution du compte spermatique); (2) des altérations cellulaires à partir de 1mg (augmentation de l'apoptose des cellules germinales) et (3) des altérations moléculaires à toutes les doses testées pour MCL1, BCL2, XIAP, HSPA2, ELAVL1 et MOV10L1. Ces altérations s’intègrent dans la dérégulation de 2 voies de signalisation expliquant l’apoptose des cellules germinalesLorsque l’exposition a lieu à l’âge l’adulte dans les mêmes conditions, les effets morphologiques et cellulaires sont observés uniquement à 10mg, les effets moléculaires uniquement aux doses 10 et 1 mg. Ces effets ne sont plus observés 2 mois après l’arrêt de l’exposition. En conclusion : Nous avons (i) identifié des voies de signalisation impliquées dans le phénotype d’infertilité induite par une exposition à de faibles doses d’anti-androgène ; (ii) montré que ces voies étaient actives aux plus faibles doses testées prédisposant à une infertilité masculine programmée in utero / Exposure during perinatal life to anti-androgenic endocrine disruptors (ED) induces sustained alterations of the male reproductive system. Although their action has been objectified in humans and animals, the question of the threshold of toxicity remains unchanged, as environmental exposure corresponds to low doses. Here, we exposed male rats, in utero, to low doses of flutamide: 10 mg/kg/d; 1; 3 low doses as defined by WHO 0.1; 0.01; 0.001 and 0. Fetal exposure induced in adults (1) morphological alterations at a dose of 10 mg/kg/day (decrease in the weight of organs of the genital tract and a decrease in the sperm count); (2) cellular alterations from 1mg (increase in germ cell apoptosis) and (3) molecular alterations at all doses tested for MCL1, BCL2, XIAP, HSPA2,LAVL1 and MOV10L1. These alterations are integrated in the deregulation of 2 signaling pathways explaining the apoptosis of the germ cellsWhen exposure occurs at adult age under the same conditions, morphological and cellular effects are observed only at 10mg, molecular effects only at doses 10 and 1 mg. These effects are no longer observed 2 months after discontinuation of exposure. In conclusion: We have (i) identified signaling pathways involved in the phenotype of infertility induced by exposure to low doses of antiandrogen; (ii) showed that these pathways were active at the lowest doses tested predisposing to programmed male infertility in utero

Objetivo Avaliar o perfil da exposição ocupacional a agentes químicos, em laboratórios, e verificar os impactos na avaliação de risco decorrentes das mudanças nos limites de exposição ocupacional (LEO) e na legislação federal brasileira. Metodologia Revisão de literatura relativa à exposição ocupacional a substâncias químicas, referentes a: conceituação de risco; desenho das curvas dose-resposta; identificação dos fatores que interferem na relação dose-efeito; conceitos de exposição por longo período, da exposição múltipla e em baixas concentrações; e fatores de confusão na monitoração ocupacional. Realização de estudo transversal no Centro de Pesquisas da Petrobras, para avaliar o perfil de exposição a agentes químicos de 3.000 trabalhadores, com atividades preponderantes em laboratórios, metade das quais com exposição em baixas concentrações e por longo período, tendo por base as avaliações ambientais do ano de 2004. Análise temporal dos valores de LEO da American Conferrence of Governmental Industrial Hygienists (ACGIH) e levantamento das mudanças nas legislações federal previdenciária, trabalhista e de saúde nos aspectos relacionados à exposição a agentes químicos. Resultados Foram identificadas 484 substâncias químicas em 243 postos de trabalho, resultando em 2.550 situações de exposição, com média de 3,73 substâncias químicas por local. Os 1.563 trabalhadores com exposição formaram 168 Grupos Homogêneos de Exposição (GHE), cuja composição variou de 1 a 44 trabalhadores (média de 4,55, mediana de 3 e moda de 1). Em cada local de trabalho foram identificados, em média, 4,91 GHE. Foram medidas 977 amostras. Com relação ao GHE, foi notado que em 91,9% das avaliações ocorreram resultados abaixo do nível de ação, correspondendo a 92,5% dos empregados, configurando a exposição a baixas concentrações. Verificou-se ainda que 49,6% dos GHE (49,9% dos empregados) tinham concentrações inferiores ao limite de detecção das técnicas analíticas, enquanto que em 8,1% dos GHE e 7,5% dos empregados, as concentrações estavam em nível igual ou acima do nível de ação. Comprovou-se que nos últimos dez anos foram implantados ou revisados 135 (18,5%) LEO. O número de substâncias cuja redução do LEO é igual ou superior a 50% corresponde à quase totalidade das reduções e, em todos os períodos, as maiores são iguais ou superiores a 80% ultrapassando, portanto, o nível de ação. Ainda que não exista concordância nos valores dos LEO foi constatado que, entre as diferentes agências têm ocorrido freqüentes mudanças na legislação. Estes fatos têm obrigado os profissionais a incorporarem estes conhecimentos a sua prática de trabalho. Conclusões A exposição a substâncias químicas em laboratórios é predominantemente em baixa concentração, variada e múltiplas. Na proteção da saúde de trabalhadores, a aceitação do risco quando a concentração ambiental da substância química é abaixo do nível de ação, deve ser usado com parcimônia, pois os valores de LEO têm apresentado tendência de redução e exclui parcela significativa da população. Nesta se incluem os hipersensíveis, os expostos a substâncias com efeito estocástico, misturas com efeitos aditivos e com curva dose-resposta bifásica / Objective The aim of this study was to assess the profile of occupational exposure to chemicals in laboratories and check the impacts on risk assessment that derive from changes in occupational exposure limits (OEL) and in Brazilian federal laws applicable thereto. Methodology Review of publications on occupational exposure to chemicals concerning the following: risk concept, dose-response curve drawing, identifying factors that interfere with dose-effect relationship; concepts of lengthy exposure, multiple exposure, and low concentration exposure; confusing factors in occupational monitoring. A transversal study was carried out at the Petrobras Research Center in order to assess the profile of exposure to chemicals among 3,000 employees whose job was predominantly performed inside a laboratory, half of which were low concentration, lengthy exposures (the study was based on environmental assessments carried out in 2004). Time analysis of American Conference of Governmental Industrial Hygienists (ACGIH) OEL values. Survey on the changes made in security, labor, and health federal laws as relates to exposure to chemicals. Results 484 chemicals were identified in 243 workplaces. This resulted in 2,550 exposure situations with an average of 3.73 chemicals per location. The 1,563 workers under exposure were divided into 168 Homogeneous Exposure Groups (HEG) comprised by 1 to 44 subjects (mean = 4.55; median = 3; mode = 1). On average, 4.91 HEG were identified in each workplace. 977 samples were measured. Regarding the HEG, it was observed that 91.9% of the assessments showed results below action level. This is equivalent to 92.5% of the amount of workers and fits into the low concentration exposure category. It was also observed that 49.6% of HEG (i.e. 49.9% of workers) showed concentrations lower than detection limit in analytical techniques, whereas concentrations were equal to or greater than action level among 8.1% of HEG and 7.5% of workers. 135 (i.e. 18.5%) OEL were proven to have been implemented or revised. The amount of chemicals whose OEL decrease is equal to or greater than 50% is equivalent to nearly all decreases. Moreover, the highest decreases are equal to or greater than 80%, and therefore exceeded action level. Although there is no common agreement on OEL values, it was observed that applicable laws have been changed by several agencies on a regular basis. These facts have led professionals into considering such information in their work practice. Conclusions Exposure to chemicals in laboratories occurs basically under low, varied, multiple concentration. In the field of workers healthcare, one should be careful while considering a risk for environmental concentration of a chemical below action level. This is because OEL levels have shown to be prone to decrease and thus exclude a significant part of the population. Such part includes hypersensitive individuals, people exposed to chemicals with stochastic effect, mixtures with additive effects and biphasic dose-response curve

Suite aux accidents nucléaires de Tchernobyl (1986) ou Fukushima (2011), de grandes quantités de radioéléments ont été disséminées dans l’environnement. Parmi ces derniers, le césium 137 est le radionucléide le plus abondant et constitue la principale source d’exposition des populations avoisinantes sur le long terme, notamment par son intégration dans la chaîne alimentaire. Ce sont quelques milliers de becquerels qui sont quotidiennement ainsi ingérés. Un important questionnement concerne donc les effets potentiels que peuvent induire une telle exposition sur les fonctions physiologiques.Concernant le système cardiovasculaire, il existe une corrélation entre la dose d’exposition et la fréquence d’apparition de pathologies cardiovasculaires. Cependant, lorsqu’il s’agit d’une exposition à faibles doses, comme en cas de situations post-accidentelles, les études ne sont pas toutes en accord, dû au caractère multifactoriel de ces maladies, une grande prudence est nécessaire quant à l’interprétation des données épidémiologiques. Ainsi, ce travail de thèse vise à compléter les études épidémiologiques disponibles suivant une exposition interne à faibles doses de césium 137, et plus particulièrement dans le cadre de la pathologie athéromateuse. En effet, l’athérosclérose est reconnue comme étant la 1ère cause de mortalité/morbidité dans les pays industrialisés. Des animaux prédisposés à la pathologie (souris ApoE-/-), ont été exposés à des concentrations de césium de 4 à 100 kBq.L-1 pendant 3, 6 ou 9 mois.Ainsi, au bout de 3 mois d’exposition, les animaux ayant reçu la plus forte concentration présentent une augmentation de certains paramètres inflammatoires, notamment IFN-γ et VCAM-1, ainsi qu’une augmentation de l’épaisseur média-intima comparé aux animaux témoins. De plus, nous avons noté des variations concomitantes de l’expression d’enzymes pro/anti oxydantes (p47, p67, GPx). Ces observations ne perdurent pas au fil du temps. En effet, après 6 et 9 mois d’exposition, les plaques d’athérome qui se sont formées présentent des caractéristiques de stabilité plus importantes que les animaux témoins, avec des paramètres pro-inflammatoires (CRP, TNF-α, MCP-1 et IFN-γ) diminués, une augmentation du contenu en collagène, ainsi qu’une baisse de l’expression de certaines collagénases.L’ensemble de ces résultats suggèrent qu’une exposition interne chronique à faibles doses de césium 137 ne potentialise pas la pathologie athéromateuse dans notre modèle expérimental. Une telle exposition induit la mise en place d’une réponse adaptative au cours du temps, allant en faveur d’une amélioration du phénotype des plaques d’athérome, en agissant sur la balance des cytokines pro/anti inflammatoires, ainsi qu’une modulation du système anti-oxydant. / Large amounts of radionuclides were released in the environment after the Chernobyl (1986) or Fukushima-Daichii (2011) nuclear accidents, and mostly cesium 137. Populations living in contaminated territories are chronically exposed to radionuclides by ingestion of contaminated food. There is a real interrogation about the potential effects that could be induced following such ionizing exposure on physiological functions in the long term.Concerning the cardiovascular system, there is a correlation between the irradiation dose and the appearance of cardiovascular diseases. However, when we focused on post-accidental situations, with a low dose exposure, available data are not all in accordance, due to multifactorial aspect of these pathologies. Epidemiological results should be interpreted carefully.Thus, the aim of my thesis is to complete epidemiological studies about chronic internal γ low dose exposure, using cesium 137, in an atheromatous context. Atherosclerosis and its consequences are known to be the main cause of mortality/morbidity in industrialized countries.Predisposed animals (ApoE-/- mice) were exposed to 137Cs through the drinking water. The concentration range was 4 to 100 kBq.L-1, to surround concentration found in contaminated territories around Chernobyl. Exposure times were 3, 6 or 9 months to follow atherosclerosis progression.After 3 months exposure, for the early stages, mice exposed to the highest dose presented an increase in some inflammatory cytokines, notably IFN-γ and VCAM-1, with an intimal-medial thickness increased compared to non-exposed animals. Moreover, at this time exposure, we noticed concomitant variation of genic expression of pro and anti-oxydative enzymes (p47, p67, GPx). These effects are only transient and do not perdure over the time. Indeed, after 6 and 9 months exposure, atheromatous plaque observed in the aortic sinus, present more stability parameters than the control group (collagen), with also a decrease in pro-inflammatory profile cytokines expression (CRP, TNF-α, MCP-1 et IFN-γ), and MMPs expression, and increase in GPx activity compared to the control group.All together, these results suggest that chronic internal exposure to low dose ionizing radition with 137Cs do not potentiate atherosclerosis progression. Such exposure induces an adaptive response along the experimental process, with an amelioration of atheromatous plaque phenotype, acting on the balance of pro/anti-inflammatory cytokines, pro/anti oxydant system.

Les perturbateurs endocriniens (PE) font l’objet d’une controverse scientifique à l’heure actuelle car, pour certains scientifiques, ces molécules n’auraient pas de seuil de toxicité et agiraient à de très faibles concentrations. Cette particularité proviendrait du fait que les PE, quelles que soient leurs origines, agissent sur les hormones et leurs récepteurs. A ce titre, ils seraient assujettis aux mêmes règles que les hormones endogènes. Leurs effets à de très faibles doses s’expliqueraient par la sensibilité des récepteurs hormonaux aux faibles fluctuations de concentrations. L’absence de seuil d’effet pour les PE s’expliquerait par différents mécanismes, dont des différences d’affinité suivant la concentration entre substrat et récepteur, qui engendreraient des effets doses non monotones. Un certain nombre de revues remettent en cause ces hypothèses et les observations qui les accompagnent. Elles indiquent notamment le fait que ces données manquent de répétitions, qu’elles sont principalement issues d’études in vitro ou sur des modèles d’organismes en développement et non-nécessairement misent en perspective avec des effets toxiques pour l’organisme. Ainsi ces données ne seraient pas suffisantes pour statuer dans ce débat.Dans ce contexte, afin d’apporter de nouvelles données expérimentales au débat, nous avons cherché à caractériser les effets aux faibles doses d’un PE de référence, le flutamide (FLU), sur l’appareil reproducteur du rat mâle adulte. Pour ce faire, nous avons conduit trois études successives au cours desquelles nous avons exposé des rats Wistar de 7 semaines à une large gamme de doses de FLU. La dose la plus forte est connue pour induire des lésions testiculaires et une atrophie de la prostate. Les autres doses correspondent à la NOAEL définie dans une étude publiée précédemment, et à cette valeur divisée par 10, 100 et 1000, ce qui correspond à des faibles doses selon la définition de l’OMS. Pour chaque étude, chaque groupe était composé de 16 animaux gavés quotidiennement pendant 28 jours. Ces études ont permis d'explorer différents paramètres. Dans le cadre de la caractérisation du mode d'action du flutamide sur le testicule (Exposition --> blocage des récepteurs aux androgènes de l'hypophyse --> augmentation de la LH circulante --> prolifération des cellules de Leydig --> Hyperplasie), nous avons montré que, pour chaque évènement clé, l’effet dose est monotone et qu’il est possible de définir un seuil. Par ailleurs, nous proposons le Pdgfd, un facteur de croissance, comme médiateur de l’effet mitogène de la LH sur les cellules de Leydig.Pour la prostate, le mode d'action du flutamide n’étant pas complètement élucidé à ces niveaux de doses, le travail a été plus exploratoire. Afin d'expliquer, aux niveaux moléculaire et cellulaire, l'origine de la baisse du poids des prostates induites par le flutamide dès 1 mg/kg/j, nous avons exploré trois hypothèses: (1) l'augmentation de l'apoptose, avec un test d'activité des caspases 3 et 9 qui montre une activité supérieure pour le groupe forte dose de 10 mg/kg/j de flutamide, (2) la diminution de la prolifération, avec un marquage ki67 qui ne montre pas de différence entre le groupe témoin et la forte dose, et enfin (3) la baisse de la fonction de sécrétion de la prostate, évaluée par un western blot dirigé contre la probasine qui montre une baisse de sa production. Dans le même temps, nous avons montré, au niveau des transcrits hépatiques (RT-qPCR), que le flutamide exerce un effet-dose monotone sur certaines enzymes impliquées dans le métabolisme des xénobiotiques. En conclusion, dans ce modèle, pour l'ensemble des paramètres explorés, sur le testicule, l’hypophyse, la prostate, le sang et le foie, nous n'avons observé que des effets à seuil et aucun effet non monotone. / The dose-response characterization of Endocrine disrupting chemicals (EDCs) toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low concentration. A part of the scientific community, suggests these molecules have no toxicity threshold and act at very low concentrations. This assumption stems from the fact that EDCs, whatever their origins, act on hormones and their receptors. As such, they would be subject to the same rules as the endogenous hormones. Effects at very low doses could be explained by the sensitivity of the hormone receptor to small fluctuations in concentrations. The lack of threshold for EDCs may be explained by different mechanisms, including affinity differences according to concentrations between substrate and receptor, which would generate non-monotonic dose-responses. A number of reviews challenge this assumption and the linked observations. They argue that the data are missing replication; they are mainly from in vitro studies or conducted in developing models and not-necessarily associated with toxic effects on the organism. Thus, these data are not sufficient to rule in this debate.In this context, in order to provide new experimental data to this debate, we worked to characterize the effects at low doses of a reference EDCs, flutamide (FLU) on the reproductive system of adult male rats. In that aim, we conducted three successive studies exposing Wistar rats of 7 weeks at a wide range of Flu doses. The highest dose is known to induce testicular damage and atrophy of the prostate gland. Other doses correspond to the defined NOAEL in a study published earlier, and to this value divided by 10, 100 and 1000, corresponding to low doses according to the WHO definition. For each study, each group consisted of 16 animals exposed daily by gavage for 28 days. During characterization of flutamide mode of action on the testis (Exposition -> androgen receptors blocking in the pituitary gland -> increase in circulating LH -> Leydig cells proliferation -> Leydig cells Hyperplasia), we have shown that for every key event, dose-response curve is monotonous and we were able to define a threshold. Furthermore, we suggest that the Pdgfd, a growth factor, mediates the mitogenic effect of LH on Leydig cells.In the prostate gland, the mode of action of flutamide is not completely elucidated at these dose levels, so the work was more exploratory. To explain, at the molecular and cellular levels, the origin of prostate atrophy induced by flutamide from 1 mg/kg/day, we explored three hypotheses: (1) the increase in apoptosis, with a caspases 3 and 9 activity test, which shows a higher activity for the high dosage group of 10 mg/kg/day of flutamide, (2) the decreasing of epithelium proliferation, with Ki67 marker which shows no difference between the control group and the high dose, and finally (3) the decrease in prostate secretory function, assessed by western blot against the Probasin which shows a drop in production.At the same time, we have shown in liver that flutamide has an effect on enzymes involved in the metabolism of xenobiotics with monotonic dose-response.In conclusion, in this model, for all investigated parameters on the testis, pituitary, prostate, blood and liver, we only observed threshold effects and no non-monotonic dose-responses.