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International audience; Participatory research approaches in environmental health are still rarely applied to radiation research. Opportunities for greater implication of the civil society and related challenges differ at each step of such research activities. The LILAS project aimed, as a preparatory step toward the development of participatory research projects on multiple environmental exposures to ionizing radiation and other stressors

International audience; Preparedness for nuclear accident responsiveness includes interventions to protect pregnancies against prolonged exposure to radioactive iodine. The aim of this study was to investigate a new design consisting of repeated administration of potassium iodide (KI, 1 mg/kg) for 8 days in late pregnancy gestational day 9–16 (GD9–GD16) in rats. The later-life effects of this early-life iodine thyroid blocking (ITB) strategy were assessed in offspring two months afterbirth. Functional behavioral tests including forced swimming test (FST) and rotarod test (RRT) in rats of both genders showed lower FST performance in KI-treated females and lower RRT performance in KI-treated male pups. This performance decline was associated with metabolic disruptions in cortex involving amino acid metabolism, tyrosine metabolism, as well as docosahexaenoic acid (DHA) lipids and signaling lipids in males and females. Beyond these behavior-associated metabolic changes, a portion of the captured metabolome (17–25%) and lipidome (3.7–7.35%) remained sensitive to in utero KI prophylactic treatment in both cortex and plasma of post-weaning rats, with some gender-related variance. Only part of these disruptions was attributed to lower levels of TSH and T4 (males only). The KI-induced metabolic shifts involved a broad spectrum of functions encompassing metabolic and cell homeostasis and cell signaling functions. Irrespective Regardless of gender and tissues, the predominant effects of KI affected neurotransmitters, amino acid metabolism, and omega-3 DHA metabolism. Taken together, data demonstrated that repeated daily KI administration at 1 mg/kg/day for 8 days during late pregnancy failed to protect the mother-fetus against nuclear accident radiation.

15th Coordination and Planning Meeting of the World-Health-Organization's Radiation-Emergency-Medical-Preparedness-and-Assistance-Network (WHO-REMPAN), Geneva, SWITZERLAND, JUL 03-05, 2017; Single dose of potassium iodide (KI) is recommended to prevent the risk of thyroid cancer during nuclear accidents. However in the case of repeated/protracted radioiodine release, a unique dose of KI may not protect efficiently the thyroid against the risk of further developing a radiation-induced cancer. The new WHO guidelines for the use in planning for and responding to radiological and nuclear emergencies identify the need of more data on this subject as one of the four research priorities. The aims of the PRIODAC project are (1) to assess the associated side effects of repeated intakes of KI, (2) to better understand the molecular mechanisms regulating the metabolism of iodine, (3) to revise the regulatory French marketing authorization of 65-mg KI tablets and (4) to develop new recommendations related to the administration of KI toward a better international harmonization. A review of the literature and the preliminary data are presented here.

90Sr is one of the radionuclides released after nuclear accidents that can significantly impact human health in the long term. 90Sr accumulates mostly in the bones of exposed populations. Previous research has shown that exposure induces changes in bone physiology both in humans and in mice. We hypothesize that, due to its close location with bone marrow stromal cells (BMSCs), 90Sr could induce functional damage to stromal cells that may explain these biological effects due to chronic exposure to 90Sr. The aim of this work was to verify this hypothesis through the use of an in vitro model of MS5 stromal cell lines exposed to 1 and 10 kBq.mL−1 of 90Sr. Results indicated that a 30-minute exposure to 90Sr induced double strand breaks in DNA, followed by DNA repair, senescence and differentiation. After 7 days of exposure, MS5 cells showed a decreased ability to proliferate, changes in cytokine expression, and changes in their ability to support hematopoietic progenitor proliferation and differentiation. These results demonstrate that chronic exposure to a low concentration of 90Sr can induce functional changes in BMSCs that in turn may explain the health effects observed in following chronic 90Sr exposure.

International audience; Intestine is the gateway for newly absorbed tocopherols. This organ also plays a crucial role in cholesterol metabolism. Because tocopherols are known to impact cholesterol metabolism in the liver, we hypothesized that tocopherols could also modulate cholesterol metabolism in the intestine. This study aimed to verify this hypothesis and to unveil the mechanisms involved, using Caco-2 cells as a model of the human intestinal cell. Both α- and γ-tocopherol significantly (P

Natural uranium (NU), a component of the earth’s crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NUvialactation and drinking water (1.5, 10, or 40 mg·L−1for male rats and 40 mg·L−1for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg·L−1NU. In male rats, spatial working memory and anxiety- and depressive-like behaviour were only altered by exposure to 40 mg·L−1NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function.

Introduction Data are sparse about the potential health risks of chronic low-dose contamination of humans by uranium (natural or anthropogenic) in drinking water. Previous studies report some molecular imbalances but no clinical signs due to uranium intake. Objectives In a proof-of-principle study, we reported that metabolomics is an appropriate method for addressing this chronic low-dose exposure in a rat model (uranium dose: 40 mg L−1; duration: 9 months, n = 10). In the present study, our aim was to investigate the dose–effect pattern and identify additional potential biomarkers in urine samples. Methods Compared to our previous protocol, we doubled the number of rats per group (n = 20), added additional sampling time points (3 and 6 months) and included several lower doses of natural uranium (doses used: 40, 1.5, 0.15 and 0.015 mg L−1). LC–MS metabolomics was performed on urine samples and statistical analyses were made with SIMCA-P+ and R packages. Results The data confirmed our previous results and showed that discrimination was both dose and time related. Uranium exposure was revealed in rats contaminated for 9 months at a dose as low as 0.15 mg L−1. Eleven features, including the confidently identified N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide and 4-hydroxyphenylacetylglycine, discriminated control from contaminated rats with a specificity and a sensitivity ranging from 83 to 96 %, when combined into a composite score. Conclusion These findings show promise for the elucidation of underlying radiotoxicologic mechanisms and the design of a diagnostic test to assess exposure in urine, in a dose range experimentally estimated to be above a threshold between 0.015 and 0.15 mg L−1. Electronic supplementary material The online version of this article (doi:10.1007/s11306-016-1092-8) contains supplementary material, which is available to authorized users.

National audience; The IRSN ENVIRHOM-Health research program, using an experimental animal model mimicking chronic contamination of residents of contaminated territories (such as those around Chernobyl and Fukushima), showed that chronic ingestion of low-dose radionuclides results in extensive but low-amplitude biological damage, with the subtle ruptures of metabolic equilibrium that are characteristic of internal exposure. In vivo internal contamination of radionuclides can affect numerous important metabolic systems of the organism, including those of cholesterol, vitamin D, iron, steroid hormones, and xenobiotics, without producing any toxic effects or visible pathology. To complement and refine these findings, in collaboration with the broad-spectrum metabolic analysis platform of the University of Aix-Marseille (CRIBIOM), we conducted studies that combined a metabolomic approach to low-dose radiotoxicology for the first time. The results of these experimental studies, which focused on the biological effects on rats of chronic ingestion of cesium 137 and natural uranium over several months, showed modifications of the metabolome after this internal exposure. Individuals exposed to these low doses could be identified metabolomically, even though their conventional clinical markers were unaffected. Thus, a metabolomic approach using simple blood or urine analysis appears useful for defining the biological signature of internal contamination by a low radionuclide dose. Finally, the identification and the simultaneous quantification of many affected molecules defined a specific fingerprint of exposure and could help to identify exposure biomarkers, early biological effects, and toxicity leading to the eventual development of pathology. In conclusion, metabolomics is one of the modern analytical approaches with considerable potential in the area of low-dose toxicology. Copyright © 2015 JOHN LIBBEY EUROTEXT.; Un modèle expérimental animal, mimant la contamination chronique des populations vivant sur des territoires contaminés a été utilisé dans le cadre du programme de recherche ENVIRHOM-Santé de l’Institut de radioprotection et de sûreté nucléaire (IRSN). Il a révélé que l’ingestion chronique de radionucléides à faibles doses entraînait des atteintes biologiques multiples de faibles amplitudes caractérisées par des ruptures subtiles d’équilibres métaboliques consécutives à l’exposition interne. En effet, il a été montré qu’une contamination interne de radionucléides était capable d’affecter in vivo un certain nombre de métabolismes majeurs de l’organisme, tels que le métabolisme du cholestérol, de la vitamine D, du fer, des hormones stéroïdiennes et des xénobiotiques sans effet toxique ou apparition de pathologie. Pour compléter et affiner ces connaissances, des études associant pour la première fois une approche métabolomique à la radiotoxicologie des faibles doses ont été initiées en collaboration avec la plate-forme d’analyse métabolique à large spectre de l’université d’Aix-Marseille (CRIBIOM). Les résultats de ces études expérimentales, qui portent sur les effets biologiques d’une ingestion chronique de césium 137 ou d’uranium naturel chez le rat pendant plusieurs mois, ont permis de montrer que, suite à ces expositions internes, il était possible d’identifier des individus contaminés par de faibles doses de radionucléides (bien que leurs taux de marqueurs cliniques classiques n’étaient pas affectés) par une modification de leur métabolome. Aussi, une simple analyse sanguine ou urinaire par approche métabolomique semble pertinente pour définir la signature biologique d’une contamination interne à faible dose de radionucléide. Enfin, l’identification et la quantification simultanée de plusieurs acteurs moléculaires impactés ont permis de définir « l’empreinte métabolique » spécifique de l’exposition et pourraient permettre de révéler des biomarqueurs d’exposition, d’effets biologiques précoces, de toxicité voire d’éventuels développements pathologiques. En conclusion, la métabolomique fait partie des approches analytiques modernes dont le potentiel reste considérable dans le domaine des faibles doses.

Chapitre 30; Culture cellulaire de testicule et d'ovaire pour l'étude de la fonction de reproduction

Because uranium is a natural element present in the earth’s crust, the population may be chronically exposed to low doses of it through drinking water. Additionally, the military and civil uses of uranium can also lead to environmental dispersion that can result in high or low doses of acute or chronic exposure. Recent experimental data suggest this might lead to relatively innocuous biological reactions. The aim of this study was to assess the biological changes in rats caused by ingestion of natural uranium in drinking water with a mean daily intake of 2.7 mg/kg for 9 months and to identify potential biomarkers related to such a contamination. Subsequently, we observed no pathology and standard clinical tests were unable to distinguish between treated and untreated animals. Conversely, LC–MS metabolomics identified urine as an appropriate biofluid for discriminating the experimental groups. Of the 1,376 features detected in urine, the most discriminant were metabolites involved in tryptophan, nicotinate, and nicotinamide metabolic pathways. In particular, N-methylnicotinamide, which was found at a level seven times higher in untreated than in contaminated rats, had the greatest discriminating power. These novel results establish a proof of principle for using metabolomics to address chronic low-dose uranium contamination. They open interesting perspectives for understanding the underlying biological mechanisms and designing a diagnostic test of exposure. Electronic supplementary material The online version of this article (doi:10.1007/s11306-013-0544-7) contains supplementary material, which is available to authorized users.

International audience; Uranium nanoparticles (

International audience; Concomitant with the expansion of the nuclear industry, the concentrations of several pollutants, radioactive or otherwise, including uranium, caesium, cadmium and cobalt, have increased over the last few decades. These elemental pollutants do exist in the environment and are a threat to many organisms. Behavior represents the integration of all the anatomical adaptations and physiological processes that occur within an organism. Compared to other biological endpoints, the effects of pollutants on animal behavior have been the focus of only a few studies. However, behavioral changes appear to be ideal for assessing the effects of pollutants on animal populations, because behavior links physiological functions with ecological processes. The alteration of behavioral responses can have severe implications for survival of individuals and of population of some species. Behavioral disruptions may derive from several underlying mechanisms: disruption of neuro-sensorial activity and of endocrines, or oxidative and metabolic disruptions. In this review, we presented an overview of the current literature in which the effects of radioactive pollutants on behavior in humans, rodents, fish and wildlife species are addressed. When possible, we have also indicated the potential underlying mechanisms of the behavioral alterations and parameters measured. In fried, chronic uranium contamination is associated with behavior alterations and mental disorders in humans, and cognitive deficits in rats. Comparative studies on depleted and enriched uranium effects in rats showed that chemical and radiological activities of this metal induced negative effects on several behavioral parameters and also produced brain oxidative stress. Uranium exposure also modifies feeding behavior of bivalves and reproductive behavior of fish. Studies of the effects of the Chernobyl accident shows that chronic irradiation to 137Cs induces both nervous system diseases and mental disorders in humans leading to increased suicides, as well as modification of preferred nesting sites, reduced hatching success and fecundity in birds that live in the Chernobyl zone. No significant effect from caesium exposure was shown in laboratory experiments with rats, but few studies were conducted. Data on radioactive cadmium are not available in the literature, but the effects of its metallic form have been well studied. Cadmium induces mental retardation and psychomotor alterations in exposed populations and increases anxiety in rats, leading to depression. Cadmium exposure also results in well-documented effects on feeding and burrowing behavior in several invertebrate species (crustaceans, gastropods, annelids, bivalves) and on different kinds of fish behavior (swimming activity, fast-start response, antipredatory behavior). Cobalt induces memory deficits in humans and may be involved in Alzheimer's disease; gamma irradiation by cobalt also decreases fecundity and alters mating behavior in insects. Collectively, data are lacking or are meagre on radionuclide pollutants, and a better knowledge of their actions on the cellular and molecular mechanisms that control animal behavior is needed.

Uranium is an alpha-particle-emitting heavy metal. Its genotoxicity results from both its chemical and its radiological properties that vary with its isotopic composition (12% enriched uranium in 235U (EU) has a specific activity 20 times higher than 0.3% depleted uranium in 235U (DU)). The influence of the isotopic composition of uranium on its genotoxic profile (clastogenic/aneugenic) has never been described. The present study evaluated genotoxic profile of uranium with the cytokinesis-block micronucleus centromere assay. C3H10T1/2 mouse embryo fibroblasts were contaminated with either DU or EU at different concentrations (5 μM, 50 μM and 500 μM). Cells received low doses ranging from 0.3 μGy to 760.5 μGy. The frequency of binucleated cells with one micronucleus increased with increasing concentrations of both DU and EU in the same way. EU induced more centromere-negative micronuclei and nucleoplasmic bridges than DU. A correlation between these two clastogenic markers and ionizing radiation doses was observed. Finally, this study showed that the genotoxic profile of uranium depends on its isotopic composition. DU and EU are low and high clastogens, respectively. However, DU aneugenic effects remain high. Thus, there is a need to study the potential role of aneugenic effects of DU in carcinogenic risk assessment linked to uranium internal exposure. © 2009 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND: A pilot study was carried out in the AREVA NC Pierrelatte nuclear facility in order to investigate a possible carcinogenic effect of internal radiation exposure among nuclear workers in France. The objective of this study was to develop a method for retrospective reconstruction of the occupational exposure to internal radiation from uranium and associated chemical exposures. METHODS: A plant- and period-specific job exposure matrix (JEM) was designed. Job groups and exposure agents groups including uranium compounds and other chemical agents known as being carcinogenic, mutagenic or toxic were defined by an expert committee. Exposure was evaluated by active and retired workers included in the evaluator committee. A quantitative assignment of quantity and frequency of handling (both coded from 0 to 3) was performed for each agent groups using a method derived from the Delphi technique. RESULTS: In all, 23 experts and 353 evaluators participated to the JEM elaboration. A final JEM involved 232 "job-periods" presenting throughout the plant period 1960-2006 and 22 exposure agents groups in use at the plant. Six of them involved uranium compounds classified by their blood-transferability and toxicity characteristics. A first validation of the JEM by experts in radiological protection and industrial hygiene showed an acceptable internal consistency. CONCLUSION: In the context of missing past exposure measurement data, the plant- and period-specific job exposure matrices may be considered as a valid alternative for exposure estimation. This method may be applied to other nuclear plants and offers allowance to investigate a possible carcinogenic effect of internal radiation exposure among nuclear workers., Objectifs : Afin d’étudier les effets cancérigènes de la contamination interne chez lestravailleurs du secteur nucléaire en France, une étude pilote est mise en place au sein del’établissement AREVA NC Pierrelatte. Son objectif est de développer une méthodepermettant d’évaluer l’exposition interne à l’uranium ainsi que les expositions chimiquesassociées.Méthodes : Une matrice emplois-expositions (MEE) période et site spécifique a été élaborée.La liste des emplois et la liste des expositions - produits uranifères et ceux classéscancérogènes, mutagènes ou toxiques pour la reproduction (CMR) - ont été définies par uncomité d’experts pluridisciplinaire. Un comité d’évaluateurs composé des travailleurs del’établissement en activité et des travailleurs retraités a évalué les expositions. Pour chaqueproduit retenu, deux paramètres d’exposition ont été évalués sur une échelle à 4 niveaux: lafréquence d’utilisation du produit et la quantité du produit avec laquelle le travailleur a été encontact. Le processus d’évaluation a été standardisé. Les notes finales de la matrice ont étéobtenues à partir des réponses du comité d’évaluateurs, en utilisant une technique dérivée dela méthode Delphi, puis validées par le comité d’experts.Résultats : La construction de la MEE spécifique de l’établissement AREVA NC Pierrelattes’appuie sur le travail de 23 experts et 353 évaluateurs. La MEE finale met en correspondance232 postes-périodes existant entre 1960 et 2006 et 22 catégories de produits utilisés dansl’établissement. Les produits uranifères sont classés en six catégories selon leur puretéchimique et leur transférabilité dans les tissus biologiques. L’examen de la MEE par le comitéd’experts montre une cohérence interne satisfaisante et constitue sa première validation.Conclusion : Dans un contexte d’absence des données individuelles d’exposition, la MEEpériode et site spécifique constitue une alternative valide d’évaluation rétrospective del’exposition. Cette méthode peut être transposée à d’autres établissements de l’industrie nucléaire et permet d’évaluer le rôle de l’exposition interne à l’uranium et des expositionsassociées chez les travailleurs.

International audience; The toxicity of uranium has been demonstrated in different organs, including the kidneys, skeleton, central nervous system, and liver. However, few works have investigated the biological effects of uranium contamination on important metabolic function in the liver. In vivo studies were conducted to evaluate its effects on cytochrome P450 (CYP) enzymes involved in the metabolism of cholesterol and xenobiotics in the rat liver. The effects of depleted uranium (DU) contamination on Sprague-Dawley were measured at 1 and 3 days after exposure. Biochemical indicators characterizing liver and kidney functions were measured in the plasma. The DU affected bile acid CYP activity: 7alpha-hydroxycholesterol plasma level decreased by 52% at day 3 whereas microsomal CYP7A1 activity in the liver did not change significantly and mitochondrial CYP27A1 activity quintupled at day 1. Gene expression of the nuclear receptors related to lipid metabolism (FXR and LXR) also changed, while PPARalpha mRNA levels did not. The increased mRNA levels of the xenobiotic-metabolizing CYP3A enzyme at day 3 may be caused by feedback up-regulation due to the decreased CYP3A activity at day 1. CAR mRNA levels, which tripled on day 1, may be involved in this up-regulation, while mRNA levels of PXR did not change. These results indicate that high levels of depleted uranium, acting through modulation of the CYP enzymes and some of their nuclear receptors, affect the hepatic metabolism of bile acids and xenobiotics.

International audience; Uranium is a heavy metal known to induce toxicity in kidneys. It is also known to enter the central nervous system, thus inducing neurophysiological effects, after exposure to relatively high concentrations. The effect of chronic uranium exposure (40 mg l(-1) in drinking water, for 90 days) on electroencephalographic architecture has been studied on freely moving rats using a telemetry technique. The main effects of uranium on the sleep-wake cycle were an increase in rapid eye movement sleep (REM-sleep) and theta band power during the light period, as early as Day 30 after exposure commenced. The most probable explanation for these effects is that uranium directly affects the brain. This increase in REM-sleep was previously described in human depression or models of chronically stressed rats and it may be assimilated with some protective or compensatory mechanisms.