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Molecular imaging with PET offers an alternative method to quantify programmed-death-ligand 1 (PD-L1) to accurately select patients for immunotherapies. More and more clinical and preclinical trials involve radiolabeling of antibody fragments for their desirably fast clearance and high tumor penetration. As the radiolabeling strategy can significantly impact pharmacokinetics and biodistribution, we explored in this work a site-specific radiofluorination strategy on an anti-PD-L1 fragment antigen-binding (Fab) and compared the pharmacokinetic and biodistribution properties with the same Fab labeled using stochastic radiolabeling chemistry. We applied an enzymatic bioconjugation mediated by a variant of the lipoic acid ligase (LplA) that promotes the formation of an amide bond between a short peptide cloned onto the C terminus of the Fab. A synthetic analogue of the enzyme natural substrate, lipoic acid, was radiolabeled with fluorine-18 for site-specific conjugation by LplA. We compared the biodistribution of the site-specifically labeled Fab with a stochastically labeled Fab on lysine side chains in tumor-bearing mice. The two methods of fluorination demonstrate a comparable whole-body biodistribution. The

Glioblastoma (GBM) is the most common and deadly form of primary brain tumor. Between 30% and 60% of GBM are characterized by overexpression of the Epidermal Growth Factor Receptor (EGFR). The anti-EGFR antibody Cetuximab (CTX) showed a favorable effect for EGFRUsing positron emission tomography (PET) imaging, we have previously demonstrated that focused ultrasound (FUS) combined with microbubbles (µB) allowed significant and persistent delivery of CTX across the BBB in healthy mice. In the current study, we investigated by PET imaging the combination impact of CTX and FUS on orthotopic GBM preclinical model.After radiolabeling CTX with the long half-life isotopeEx vivo analysis confirmed that FUS enhanced and homogenized the delivery of CTX into all the FUS exposure area, including the tumor and the contralateral hemisphere at the early-time-point. Interestingly, FUS did not improve the long-term accumulation and retention of CTX in the tumor compared with the control group (no FUS). No significant difference in the CTX treatment efficacy, determined by the survival between FUS and non-FUS groups, has been either observed. This result is consistent with the absence of change in the CTX distribution through the GBM tumor after FUS. The neuroinflammation induced by FUS is not significant enough to explain the failure of the CTX delivery improvement.All together, these data suggest that the role of FUS combined with µB on the CTX distribution, even after multiple therapeutic sessions and glial cell activation is insufficient to improve survival of GBM mice compared with CTX treatment alone in this model.

International audience; Male infertility is a major public health issue that can be induced by a host of lifestyle risk factors such as environment, nutrition, smoking, stress, and endocrine disruptors. Regarding the human population exposed to uranium, it is necessary to explore these effects on male reproduction in multigenerational studies. The sensitivity of mass spectrometry (MS)-based methods has already proved to be extremely useful in metabolite identification in rats exposed to low doses of uranium, but also in human sperm. We applied this method to rat sperm over three generations (F0, F1 and F2) with multigenerational uranium exposure. Our results show a significant content of uranium in generation F0, and a reduction in the pregnancy rate only in generation F1. Based on principal component analysis (PCA), we observed discriminant profiles between generations. The partial least squares discriminant analysis (PLS-DA) of the 48 annotated variables confirmed that parental exposure of generation F0 (during both the preconceptional and prenatal periods) can have metabolic effects on spermatozoa for the next two generations. Metabolomics applied to epididymal spermatozoa is a novel approach to detecting the multigenerational effects of uranium in an experimental model, but could be also recommended to identify potential biomarkers evaluating the impact of uranium on sperm in exposed infertile men.

International audience; Purpose A protocol of chronic exposure to low dose of uranium was established in order to distinguish the sexual differences and the developmental process that are critical windows for epigenetic effects over generations. Methods Both male and female rats were contaminated through their drinking water with a non-toxic solution of uranyl nitrate for 9 months. The exposed generation (F0) and the following two generations (F1 and F2) were examined. Clinical monitoring, global DNA methylation profile and DNA methyltransferases (DNMTs) gene expression were analyzed in kidneys. Results While the body weight of F1 males increased, a small decrease in kidney and body weight was observed in F2 males. In addition, global DNA hypermethylation profile in kidney cells was observed in F1 and F2 males. qPCR results reveal a significant increase of methyltransferase genes expression (DNMT1 and DNMT3a) for F2 females. Conclusions In the field of public health policy and to raise attention to generational effects for the risk assessment of the environmental exposures, low doses of uranium do not imply clinical effects on adult exposed rats. However, our results confirm the importance of the developmental windows’ sensitivity in addition to the sexual dimorphisms of the offspring. © 2018, Copyright © 2018 Taylor and Francis Group LLC.

International audience; 1 Background Humans can be exposed at low concentrations to toxic agents with anthropogenic and natural origins such as uranium and fluoride. Because of its functions of filtration, transport and reabsorption the kidney is a primary target organ of toxicity to foreign compounds. Uranium and fluoride are both known to be nephrotoxic, nevertheless there is a lack of knowledge of their mechanisms of nephrotoxicity and of the underlying molecular pathways involved [1, 2]. This study aims to compare these agents to identify the cellular and molecular pathways of nephrotoxicity in mouse. 2 Methods and results C57Bl6 mice are exposed to uranyl nitrate (UN) (0, 2, 4, 5 mg/kg) or sodium fluoride (NaF) (0, 2, 5, 7.5, 10 mg/kg) by intraperitoneal injection and put into metabolism cages for 24 hours before and directly after injection. Collected urines are used to quantify uranium or fluoride, to measure specific and sensitive biomarkers of nephrotoxicity levels and to assess clinical bioassays. Finally, animals are euthanized 48h and 72h after exposure, chosen as the peak of nephrotoxicity is observed after intraperitoneal injection [3]. The protocol is shown in figure 1.Renal phenotypic aspects and biological mechanisms are evaluated by urinary biochemistry, gene and protein expressions, enzyme activity, and histological analyses. Exposure to UN and NaF induces nephrotoxicity in a dose-dependent manner. A 5 mg/kg injection of UN induces mild histopathological alterations and respectively 44 and 6-fold increase in gene expressions of nephrotoxicity markers KIM1 and osteopontin. In comparison, 10 mg/kg of NaF induces high nephrotoxicity with histopathological alterations scored as severe and late appearing parameters of toxicity whereas 7.5 mg/kg induces mild histopathological scoring and gene expressions of KIM1 and clusterin enhanced respectively by 70 and 4-fold compared to control. No signs of nephrotoxicity are observed below 5 mg/kg of NaF. Clusterin is respectively increased by 2.4 and 4.4-fold in urines after 7.5 and 10 mg/kg injection of NaF, whereas 4 and 5 mg/kg of UN induce respectively a 2.2 and 2.7-fold increase of clusterin in urines. Apoptosis is evaluated through caspases 3/7 activity which is increased by 210% after UN treatment (5mg/kg) whereas NaF does not induce apoptosis significantly. Inflammation is implied in UN and NaF acute nephrotoxicity as shown by gene and in situ overexpressions of ICAM and VCAM measurement by immunohistochemical staining.3 ConclusionsUN and NaF acute exposures resulted in dose and time-dependent nephrotoxicity with a higher nephrotoxicity after 72h. Inflammation and apoptosis are both involved in UN or NaF toxicity. These observations allow us to identify the mechanisms that will be studied in a low-dose exposure protocol after a chronic exposure.

International audience; Protracted radioiodine release may require repeated intake of potassium iodide (KI) to protect thyroid gland. It is well established that iodine excess inhibits transiently the thyroid function. As developing fetus depends on maternal thyroid hormones (TH) supply, more knowledge is needed about the plausible effects that repeated KI intake can cause in this sensitive population, especially that even subtle variation of maternal thyroid function may have persistent consequences on progeny brain processing. The aim of this study is to assess the consequences of repeated intake of KI during pregnancy on the progeny's thyroid function and brain development. To do so pregnant Wistar rats received KI over eight days, and then thirty days after the weaning, male progeny was subjected to behavior test. Pituitary and thyroid hormones level, anti-thyroid antibodies level, organs morphology, gene expression and global DNA methylation were assessed. Thirty days after the weaning, KI-exposed male progeny showed an uncommon hormonal status, characterized by a decrease of both thyroid-stimulating hormone (− 28%) and free thyroxine (− 7%) levels. Motor coordination was altered in KI-exposed male progeny. At the cerebellar level, we observed a decrease of mRNA expression of DCX (− 42%) and RC3 (− 85%); on the other hand, at the cortical level, mRNA expression of MBP (+ 71%), MOBP (+ 90%) and Kcna1 (+ 42%) was increased. To conclude, repeated KI prophylaxis is not adequate during pregnancy since it led to long-term irreversible neurotoxicity in the male progeny.

International audience

Background Despite their differences in physicochemical properties, both uranium (U) and fluoride (F) are nephrotoxicants at high doses but their adverse effects at low doses are still the subject of debate. METHODS: This study aims to improve the knowledge of the biological mechanisms involved through an adaptive response model of C57BL/6 J mice chronically exposed to low priming doses of U (0, 10, 20 and 40 mg/L) or F (0, 15, 30 and 50 mg/L) and then challenged with acute exposure of 5 mg/kg U or 7.5 mg/kg NaF. Results We showed that an adaptive response occurred with priming exposures to 20 mg/L U and 50 mg/L F, with decreased levels of the biomarkers KIM-1 and CLU compared to those in animals that received the challenge dose only (positive control). The adaptive mechanisms involved a decrease in caspase 3/7 activities in animals exposed to 20 mg/L U and a decrease in in situ VCAM expression in mice exposed to 50 mg/L F. However, autophagy and the UPR were induced independently of priming exposure to U or F and could not be identified as adaptive mechanisms to U or F. Conclusion Taken together, these results allow us to identify renal adaptive responses to U and F at doses of 20 and 50 mg/L, probably through decrease apoptosis and inflammatory cell recruitment.

Phospholipid-detergent conjugates are proposed as fusogenic carriers for gene delivery. Eleven compounds are prepared and their properties are investigated. The ability of the conjugates to promote fusion with a negatively charged model membrane is determined. Their DNA delivery efficiency and cytotoxicity are assessed in vitro. Lipoplexes are administered in the mouse lung, and transgene expression Indeterminate inflammatory activity are measured. The results show that conjugation of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) with C12 E4 produces a carrier that can efficiently deliver DNA to cells, with negligible -associated toxicity. Fusogenicity of the conjugates shows good correlation with in vitro transfection efficiency and crucially depends on the length of the polyether moiety of the detergent. Finally, DOPC-C12 E4 reveals highly potent for in vivo DNA delivery and favorably compares to GL67A, the current golden standard for gene delivery to the airway, opening the way for further promising developments.

Background: Nuclear power plant emergencies had often been accompanied by radioactivity release into the environment, thyroid cancer is one of the major health consequences due to the effect of radioactive iodine (131I) that emits ϒ ray and β particles resulting in thyroid DNA damage and late onset thyroid cancer. Intake of a single dose of potassium iodide (KI) is recommended to reduce this risk. However in case of prolonged radioiodine release as noticed during Chernobyl and Fukushima accidents, more than one dose of KI may be basic to ensure adequate protection [1]. Whereas a single dose of KI is admitted to be safe, knowledge about the effects of repeated KI administration are scarce, few studies demonstrated the potential efficiency of repetitive KI intake in humans [2] and non-human primates [3] without hormonal variations. These studies are relevant in the field of radiation protection and give a base evidence of the possible use of repetitive KI. On the other hand, we have studies on rodents that showed an impact of chronic iodine excess on pituitary thyroid axis function [4]. Our previous work on adult male rats demonstrated the safety of repeated administration of KI over 8 days [5]. Indeed in the elderly persons KI administration in case of nuclear emergency remains a topic of debate, because of the possible impact in cardiovascular diseases. Thyroid hormones are well-known for their profound effects on cardiovascular function and metabolism; myocardial and vascular endothelial tissues have receptors for thyroid hormones and are sensitive even to subtle changes in the concentrations of circulating pituitary and/or thyroid hormones i.e. subclinical hypothyroidism and hyperthyroidism. It is well established that hyperthyroidism induces a hyper-dynamic cardiovascular state, which is associated with a faster heart rate, enhanced left ventricular systolic and diastolic function whereas hypothyroidism is characterized by the opposite changes. Atrial fibrillation is the most common cardiac arrhythmia in the elderly, the prevalence and incidence increase with advancing age [6]. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events. Objective: The aim of this study is to assess the effects of repeated KI intake on the thyroid function of aged male rats. Methods: A twelve months old male rats were subjected to either KI or saline solution over 8 days. Clinical biochemistry, pituitary and thyroid hormones level, and thyroid genes expression were analyzed 30 days after the treatment discontinuation. Findings: urinary assessment shows a subtle increase of some parameters (Creatinin, Uric Acid, Urea, Glucose, Potassium, Sodium and Chlorine), plasma biochemistry reveals a subtle variation of some parameters (an increase of Creatinin, Glucose and phosphorus; and a decrease of Chlorine level). Regarding pituitary-thyroid hormones we get a significant decrease of TSH level without thyroid hormones variation. At the molecular level, we observe a significant increase of TPO (+100%), AIT (+299%) and Tg (+38%) mRNA expression. On the other hand we get a significant decrease of TSHR (-51%) mRNA expression. Conclusion and perspectives: Our first results indicate that repeated KI intake affects the clinical biochemistry and the pituitary-thyroid axis function in elderly rats. To go further we are investigating the impact of these variations on the cardiovascular function and its parameters. Cardiac output data, cardiovascular gene expression, oxidative stress and inflammatory analysis are being processed. This study will contribute to the evolution of iodine policy and the harmonization of the current KI guidelines.

International audience; There is increasing evidence that environmental exposures early in fetal development influence phenotype and give rise to disease risk in the next generations. We previously found that lifelong exposure to uranium, an environmental contaminant, induced subtle testicular and hormonal defects; however, its impact on the reproductive system of multiple subsequent generations was unexplored. Herein, rats were exposed to a supra-environmental and non-nephrotoxic concentration of natural uranium (U, 40 mg·L−1 of drinking water) from postnatal life to adulthood (F0), during fetal life (F1), and only as the germ cells from the F1 generation (F2). General parameters (reproductive indices, epididymal weight) and sperm morphology were assessed in the three generations. In order to identify the epigenetic effects of U, we analyzed also the global DNA methylation profile and described for the first time the mRNA expression levels of markers involved in the (de)methylation system in rat epididymal spermatozoa. Our results showed that the F1 generation had a reduced pregnancy rate. Despite the sperm number being unmodified, sperm morphology was affected in the F0, F1 and F2 generations. Morphometric analysis for ten parameters was detailed for each generation. No common parameter was detected between the three generations, but the head and the middle-piece were always modified in the abnormal sperms. In the F1 U-exposed generation, the total number of abnormal sperm was significantly higher than in the F0 and F2 generations, suggesting that fetal exposure to uranium was more deleterious. This effect could be associated with the pregnancy rate to produce the F2 generation. Interestingly, global DNA methylation analysis showed also hypomethylation in the sperm DNA of the last F2 generation. In conclusion, our study demonstrates that uranium can induce morphological sperm defects and changes in the DNA methylation level after multigenerational exposure. The epigenetic transgenerational inheritance of U-induced reproductive defects should be assessed in further experiments.; Il existe de plus en plus de preuves de ce que les expositions environnementales auxquelles les individus sont soumis durant leur développement influencent le phénotype et le risque d’apparition de maladies chez les générations futures. Nous avons précédemment constaté que l’uranium, un contaminant environnemental, induisait après une exposition durant la vie entière de subtiles anomalies testiculaires et hormonales, mais son impact sur le système reproducteur des générations suivantes restait inexploré. Dans cette étude, des rats ont été exposés à une concentration supra-environnementale et non néphrotoxique d’uranium (U, 40 mg·L−1 dans l’eau de boisson) de la vie postnatale à l’âge adulte (F0), pendant la vie fœtale (F1), et seulement en tant que cellules germinales de la génération F1 (F2). Les paramètres généraux (indices reproductifs, poids) et la morphologie des spermatozoïdes ont été évalués sur les trois générations. Afin d’identifier les effets épigénétiques de l’uranium, nous avons également analysé le profil global de méthylation de l’ADN et décrit, pour la première fois, les niveaux d’expression d’ARNm des marqueurs impliqués dans le système de (dé)méthylation des spermatozoïdes épididymaires de rats. Nos résultats ont montré que la génération F1 avait un taux de naissance réduit. Bien que le nombre de spermatozoïdes n’ait pas été modifié, la morphologie des spermatozoïdes a été affectée chez les générations F0, F1 et F2. L’analyse morphométrique de dix paramètres a été détaillée pour chaque génération. Aucun paramètre commun n’a été détecté entre les trois générations, mais la tête et la pièce intermédiaire ont toujours été modifiées dans ces spermatozoïdes anormaux. Chez les générations F1 exposées à l’U, le nombre total de spermatozoïdes anormaux était significativement plus élevé que chez les générations F0 et F2, ce qui suggère que l’exposition fœtale à l’uranium était plus nocive et pouvait affecter le taux de naissance pour produire la génération F2. Il est intéressant de noter aussi que l’analyse globale de méthylation de l’ADN a montré une hypométhylation dans l’ADN des spermatozoïdes de la dernière génération F2. En conclusion, notre étude démontre que l’uranium peut induire des défauts morphologiques des spermatozoïdes et un changement de méthylation de l’ADN après une exposition multigénérationnelle. La transmission transgénérationnelle épigénétique des anomalies du système reproducteur induites par l’uranium devra être évaluée dans de futures expériences.

International audience; Introduction: An increased health problem in industrialised countries is the contemporary concern of public and scientific community as well. This has been attributed in part to accumulated environmental pollutants especially radioactive substances and the use of nuclear power plants worldwide. However, the outcome of chronic exposure to low doses of a radionuclide such as uranium remains unknown. Recently, a paradigm shift in the perception of risk of radiotoxicology has emerged through investigating the possibility of transmission of biological effects over generations, in particular by epigenetic pathways. These processes are known for their crucial roles associated with the development of several diseases.Objective: The current work investigates the epigenetic effect of chronic exposure to low doses of uranium and its inheritance across generations.Materials and Methods To test this proposition, a rodent multigenerational model, males and females, were exposed to a non-toxic concentration of uranium (40 mg L−1 drinking water) for nine months. The uranium effects on were evaluated over three generations (F0, F1 and F2) by analysing the DNA methylation profile and DNMT genes expression in ovaries and testes tissues.Results: Here we report a significant hypermethylation of testes DNA (p

Lung diseases are among the more representative causes of mortality and morbidity worldwide and gene therapy is considered as a promising therapeutic approach for their treatment. However the design of efficient nucleic acid carriers for airway administration still is a challenge and there is a pressing need for new developments in this field. Herein, new synthetic DNA carriers based on the conjugation of a phospholipid and C12E4, a nonionic detergent, are developed. DNA complexes with phosphatidylcholine-detergent conjugates are administered in mouse airways, and transgene expression and inflammatory activity as an index of toxicity are investigated as a function of time, DNA dose, and presence of helper and stealth lipids. Introduction of a biodegradable linker between the phosphatidylcholine and detergent moieties significantly attenuates the severity of inflammatory response that characterizes cationic lipid-mediated gene transfer. Concurrent introduction of polyunsaturated fatty acid chains in the carrier scaffold improves transgene expression and further reduces airway inflammation. Finally, the biodegradable phosphatidylcholine-detergent conjugates favorably compare to GL67A, the gold standard for DNA delivery to the airway that is currently under clinical evaluation. Our findings indicate that the lipid formulations described herein may have great potential as nucleic acid carriers for gene therapy.

The ability of a nonviral nucleic acid carrier to deliver its cargo to cells with low associated toxicity is a critical issue for clinical applications of gene therapy. We describe biodegradable cationic DOPC-C12 E4 conjugates in which transfection efficiency is based on a Trojan horse strategy. In situ production of the detergent compound C12 E4 through conjugate hydrolysis within the acidic endosome compartment was expected to promote endosome membrane destabilization and subsequent release of the lipoplexes into cytosol. The transfection efficiency of the conjugates has been assessed in vitro, and associated cytotoxicity was determined. Cellular uptake and intracellular distribution of the lipoplexes have been investigated. The results show that direct conjugation of DOPC with C12 E4 produces a versatile carrier that can deliver both DNA and siRNA to cells in vitro with high efficiency and low cytotoxicity. SAR studies suggest that this compound might represent a reasonable compromise between the membrane activity of the released detergent and susceptibility of the conjugate to degradation enzymes in vitro. Although biodegradability of the conjugates had low impact on carrier efficiency in vitro, it proved critical in vivo. Significant improvement of transgene expression was obtained in the mouse lung tuning biodegradability of the carrier. Importantly, this also allowed reduction of the inflammatory response that invariably characterizes cationic-lipid-mediated gene transfer in animals.

International audience; Cationic carbon dots were fabricated by pyrolysis of citric acid and bPEI25k under microwave radiation. Various nanoparticles were produced in a 20-30 % yield through straightforward modifications of the reaction parameters (stoichiometry of the reactants and energy supply regime). Particular attention was paid to the purification of the reaction products to ensure satisfactory elimination of the residual starting polyamine. Intrinsic properties of the particles (size, surface charge, photoluminescence and quantum yield) were measured and their ability to form stable complexes with nucleic acid was determined. Their potential to deliver plasmid DNA or small interfering RNA to various cell lines was investigated and compared to that of bPEI25k. The pDNA in vitro transfection efficiency of these carbon dots was similar to that of the parent PEI, as was their cytotoxicity. The higher cytotoxicity of bPEI25k/siRNA complexes when compared to that of the CD/siRNA complexes however had marked consequences on the gene silencing efficiency of the two carriers. These results are not fully consistent with those in some earlier reports on similar nanoparticles, revealing that toxicity of the carbon dots strongly depends on their protocol of fabrication. Finally, these carriers were evaluated for in vivo gene delivery through the non-invasive pulmonary route in mice. High transgene expression was obtained in the lung that was similar to that obtained with the golden standard formulation GL67A, but was associated with significantly lower toxicity. Post-functionalization of these carbon dots with PEG or targeting moieties should significantly broaden their scope and practical implications in improving their in vivo and biocompatibility.

Biolabile cationic lipids were developed for efficient intracellular delivery of DNA and siRNA.The compounds have been designed starting from the membrane lipid DOPC in a way they may loose their cationic charge when exposed to an acidic and/or enzymatic stimulus, such as those met during the journey of a lipoplex in biological media.They demonstrated remarkable efficiency to deliver DNA in various cell lines (BHK-21, Calu-3, NCI-H292, and A549), with no significant cytotoxicity. Furthermore, two of the compounds (carbonate-based DOPC derivatives) revealed able to deliver small interfering RNA in U87Luc and A549Luc cancer cells and to mediate a selective 70-80% knockdown of the stably transfected luciferase gene.The results show that the described bioresponsive cationic lipids have high DNA and siARN delivery activity which is encouraging in view of delivering a therapeutic nucleic acid to pulmonary tissues in vivo.

International audience; ContexteLes études épidémiologiques mettent en évidence un lien entre l’exposition aux rayonnements ionisants à des doses modérées (>500mGy) et le développement de pathologies cardiovasculaires.Les études expérimentales ne montrent pas de lien entre exposition chronique à très faibles doses (150mGy-300mGy) de rayonnements ionisants et le développement de l’athérosclérose.Le stress est un des premiers facteurs de risque cardiovasculaire. Il a été montré qu’un stress psychosocial est associé à une augmentation de l’oxydation des lipides mais également des cytokines pro-inflammatoires induisant une aggravation des maladies cardiovasculaires.Aucune étude n’a cependant mis en évidence la réponse d’une co-exposition associant rayonnements ionisants et co-facteur de risque tel que le stress sur les pathologies du coeur et des vaisseaux.MéthodePar une approche in vivo nous allons exposer des souris ApoE-/- aux rayonnements ionisants gamma à faibles doses (dose cumulée de 70mGy et 800mGy) chronique (6μGy/h) et exposer dans le même temps au stress. A l’issue de cette co-exposition l’objectif sera d’évaluer : Les paramètres fonctionnels et physiopathologiques du coeur et des vaisseaux Le profil moléculaire des vaisseaux, du coeur et du sang (approches métabolomiques) Les conséquences sur la vascularisation cérébrale (densité vasculaire et l’inflammation cérébrale)RésultatsCe projet est dans une phase de validation du modèle de stress que nous avons initié par l’ajout de litière de rat. A cette étape de l’étude, les résultats ne mettent pas en évidence de perte de poids mais les mesures de pression artérielle et le dosage d’hormones de stress doivent venir compléter l’étude.ConclusionSIROCCO dispose d’atouts majeurs pour progresser vers l’importance des facteurs risques tels que l’hypercholestérolémie et le stress dans la réponse des faibles doses sur des pathologies chroniques comme les pathologies cardiovasculaires. SIROCCO va également permettre par une approche moléculaire à grande échelle de comprendre les mécanismes à court terme et de faire un lien avec d’éventuelles apparitions de troubles fonctionnels à long terme aussi bien chez les animaux mâles que chez les femelles. Ces études vont permettre en complémentarité avec les études épidémiologiques de mieux comprendre les mécanismes impliqués après exposition à faibles doses dans des contextes micro-environnementaux à risque.Mots-clés (5 maximum)Co-expositions, facteurs de risques, rayonnements ionisants, stress, maladies cardiovasculaires