Effect of repetitive potassium iodide on elderly rat’s thyroid

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

Modelling fungal sink competitiveness with grains for assimilates in wheat infected by a biotrophic pathogen

Experiments have shown that biotrophic fungi divert assimilates for their growth. However, no attempt has been made either to account for this additional sink or to predict to what extent it competes with both grain filling and plant reserve metabolism for carbon. Fungal sink competitiveness with grains was quantified by a mixed experimentalmodelling approach based on winter wheat infected by Puccinia triticina. One week after anthesis, plants grown under controlled conditions were inoculated with varying loads. Sporulation was recorded while plants underwent varying degrees of shading, ensuring a range of both fungal sink and host source levels. Inoculation load significantly increased both sporulating area and rate. Shading significantly affected net assimilation, reserve mobilization and sporulating area, but not grain filling or sporulation rates. An existing carbon partitioning (sourcesink) model for wheat during the grain filling period was then enhanced, in which two parameters characterize every sink: carriage capacity and substrate affinity. Fungal sink competitiveness with host sources and sinks was modelled by representing spore production as another sink in diseased wheat during grain filling. Data from the experiment were fitted to the model to provide the fungal sink parameters. Fungal carriage capacity was 056 001 g dry matter Cd-1 per lesion, much less than grain filling capacity, even in highly infected plants; however, fungal sporulation had a competitive priority for assimilates over grain filling. Simulation with virtual crops accounted for the importance of the relative contribution of photosynthesis loss, anticipated reserve depletion and spore production when light level and disease severity vary. The grain filling rate was less reduced than photosynthesis; however, over the long term, yield loss could double because the earlier reserve depletion observed here would shorten the duration of grain filling. Sourcesink modelling holds the promise of accounting for plantpathogen interactions over time under fluctuating climatic/lighting conditions in a robust way

Effect of Caesium-137 chronic low dose exposure on neovascularization

International audienceBackgroundNeovascularization is crucial for tissue irrigation adaptation in response to pathological conditions such as ischemia. This process consists of the formation of new blood vessels either by angiogenesis or by vasculogenesis. Recent studies reported that acute exposure to low doses of ionising radiation, induces an increase of angiogenesis and vasculogenesis (Ministro A, 2016; Lerman O, 2017). Furthermore, nitric oxide is stimulated in these conditions. However, effects of chronic low dose radioelements, particularly Caesium-(Cs)137, one of the most released in the environment; on neovascularization has so far not been investigated. AimWe investigated the effect of chronic low dose contamination with Cs on NO-dependent neovascularization. MethodsC57BL/6 mice received 20KB/L, 100KB/L Cs or vehicle for 6 months in drinking water. 3 other groups received the same treatment, with addition of 500µg/mL L-NAME(LN), a NO synthase blocker. We evaluated angiogenesis with aortic rings sprouting . Moreover unilateral hindlimb femoral artery ligation was performed induce surgical ischemia. Cutaneous blood flow of the ischemic and non-ischemic limb was measured with Laser Doppler Imaging and capillary density was assessed by immunohistochemistry on hindlimb muscles. Vasculogenesis was assessed by measuring the capacity of bone marrow cells differentiation into EPCs and their ability to form tubular structures in vivo in matrigel after subcutaneous injection of SDF-1 in control or mice treated with CsLN. Results/conclusionsOur preliminary results indicated a dose-dependent increase of ischemic/non-ischemic blood flow ratio in Cs-treated mice, as compared to controls. An increased blood flow ratio was also observed in Cs20KB/L -treated as compared to control/LN-treated group. A reduction of blood flow was observed in Cs100KB/L - vs Cs100KB/LN-treated group. These results suggest a dose-dependent stimulation of post-ischemic neovascularization after Cs contamination. Reduction of stimulation in Cs100KB/LN -treated group may be due to LN

Effect of repetitive potassium iodide on elderly rat’s thyroid

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 [

Inhalation of tungsten particles: impact on the central nervous system, an unsuspected target organ

International audienceBeing the main cause of contamination in nuclear facilities, particulate aerosols represent a health risk factor raising serious concerns. The brain represents a direct target for inhaled aerosols, in particular through the involvement of the olfactory nerve entry pathway. There is a lack of knowledge about the toxicity of tungsten (W) in the central nervous system, although it is considered as an emerging contaminant. To study the potential effects of exposure to W particles, preliminary metrological work was carried out to optimize and control the generation of the aerosol at concentrations in the order of the Occupational Exposure Limit Value, and to characterize its granulometry. Adult rats were exposed to optimized and controlled W aerosols via inhalation at two different concentrations (5 and 80 mg.m-3) in a single acute or fractionated mode (4X daily exposures). Various assays were used to examine biological processes involved in brain toxicity, such as neuroinflammation, oxidative stress, cell death and neurogenesis.Results obtained 24 hours after exposure suggest site-specific and concentration-dependent modifications of the transcripts of genes involved in these target processes. The impact of oxidative stress is currently being further evaluated using the Dihydroethidium probe sensitive to reactive oxygen species, complemented by immunohistochemistry and protein expression of 4HNE and Nrf2, which respectively reflect lipid peroxidation and antioxidant signalling. Immunohistochemistry experiments suggest a potential effect on the density and morphology of microglial cells involved in neuroinflammation, as well as an abnormal phenotype of the nuclei of some mature neurons indicating neuronal damage. At the cellular level, the effects were also site-specific, dependent on the mode of exposure and the concentration and could involve several signalling pathways, recently investigated by transcriptomics. ICP-MS assays show an increase in the concentration of W in brain structures in groups exposed to high concentrations, which could contribute to site-specificity of observed effects. Current work aims to investigate whether these effects are related to adaptive mechanisms or are neurotoxic and can ultimately alter neuronal integrity depending on exposure patterns. Co-exposure to W aerosols and ionizing radiation is another focus for our future research.These results can help close knowledge gaps in understanding neurological health effects of particulate aerosols, especially metallic ones, and thus help improve the system of human (radio)protection

Pravastatin Limits Radiation-Induced Vascular Dysfunction in the Skin

About half of people with cancer are treated with radiation therapy; however, normal tissue toxicity still remains a dose-limiting factor for this treatment. The skin response to ionizing radiation may involve multiple inflammatory outbreaks. The endothelium is known to play a critical role in radiation-induced vascular injury. Furthermore, endothelial dysfunction reflects a decreased availability of nitric oxide. Statins have been reported to preserve endothelial function through their antioxidant and anti-inflammatory activities. In this study, wild type and endothelial nitric oxide synthase (eNOS)-/- mice were subjected to dorsal skin irradiation and treated with pravastatin for 28 days. We demonstrated that pravastatin has a therapeutic effect on skin lesions and abolishes radiation-induced vascular functional activation by decreasing interactions between leukocytes and endothelium. Pravastatin limits the radiation-induced increase of blood CCL2 and CXCL1 production expression of inflammatory adhesion molecules such as E-selectin and intercellular adhesion molecule-1, and inflammatory cell migration in tissues. Pravastatin limits the in vivo and in vitro radiation-induced downregulation of eNOS. Moreover, pravastatin has no effect in eNOS-/- mice, demonstrating that eNOS plays a key role in the beneficial effect of pravastatin in radiation-induced skin lesions. In conclusion, pravastatin may be a good therapeutic approach to prevent or reduce radiation-induced skin damage

Cellular therapy treatment of chronic radiation cystitis in rats

International audienceBacgrounf and aimChronic radiocystitis (CRC) is a pathology resulting from irradiation of the pelvic area without long term effective treatment. CRC is characterized by chronic inflammation progressing to fibrosis, fistulas and cystectomy in the most severe cases. Our laboratory have previously demonstrated that MSC treatment reverse similar damages in irradiated colon. Furthermore in a clinical phase 1/2 treatments using MSCs for hemorrhagic cystitis, which is pathology similar to CRC, was sucessfull (Ringden O et al., 2007). Based on these previous results, our objective is to evaluate whether adipose derived mesenchymal stem cells (MSCs) could be an innovative treatment of CRC. Methods, results and conclusionPreclinical modeling of CRC in rats (Sprague Dawley) was established by irradiating the entire bladder with a single dose of 40 Gray using the Small Animal Radiation Research Platform (SARRP, figure 1)). At four months after irradiation, animals received a treatment consisting in tree intravenous injections of 5 million of MSCs every two weeks. After irradiation and treatment, a physiological, histological and molecular follow-up was performed on 14 months (figure 2). Results have shown, without MSC treatment, an initiation of CRC at 6 months, with chronic inflammation, hypoxia, hematuria, disorganization of the urothelium and fibrosis. Analysis of urinary parameters has revealed hematuria increasing with time. Transcriptomic analysis indicates chronic inflammation (IL1β, CCL2, IL6) and hypoxia (HIF1α). Histological observations reveal a disorganization of the urothelium with loss of superficial cells and fibrosis (figure 3). Study is in progress to evaluate whether MSC treatment could limite fibrogenesis by inhibiting the inflammatory pathways and increasing angiogenesis, in our model CRC preclinical model. Our results will provide data regarding the anti-fibrotic potential of MSCs and could support their use in the treatment of CRC.Ringden O, Uzunel M, Sundberg B, et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007: 21: 2271–2276

microRNA blood signature for localized radiation injury

Abstract A radiological accident, whether from industrial, medical, or malicious origin, may result in localized exposure to high doses of ionizing radiations, leading to the development of local radiation injury (LRI), that may evolve toward deep ulceration and necrosis of the skin and underlying tissues. Early diagnosis is therefore crucial to facilitate identification and management of LRI victims. Circulating microRNAs (miRNA) have been studied as potential diagnostic biomarkers of several diseases including hematological defects following whole-body irradiation (WBI). This study aims to identify a blood miRNA signature associated with LRI in a preclinical C57BL/6J mouse model of hindlimb irradiation using different 10-MV X-ray doses that lead to injuries of different severities. To this end, we first performed broad-spectrum plasma miRNA profiling, followed by a targeted validation step, on two independent animal cohorts. Using a multivariate sparse partial least square discriminant analysis, we identified a panel of eight circulating miRNAs able to segregate mice according to LRI severity. Interestingly, these miRNAs were previously associated with WBI (miR-150-5p, miR-342-3p, miR-146a-5p), inflammation (miR-18a-5p, miR-148b-3p, miR-532-5p) and skin diseases (miR-139-5p, miR-195-5p). Our results suggest the use of circulating miRNAs as suitable molecular biomarkers for LRI prognosis and diagnosis

Effect of repetitive potassium iodide on thyroid and cardiovascular functions in elderly rats

International audienceBackground: To date, paediatric thyroid cancer has been the most severe health consequence of the Chernobylaccident, caused by radioactive iodine (131I) aerosol’s dispersion. WHO recommends a single dose of potassiumiodide (KI) to reduce this risk. Following the Fukushima accident, it became obvious that repetitive doses of KImay be necessary due to multiple exposures to 131I. Knowledge about the effects of repeated ITB (Iodine ThyroidBlocking) is scarce and controversial. KI may affect the thyroid hormones synthesis; which is crucial for thecardiovascular function. Furthermore, myocardial and vascular endothelial tissues are sensitizes to subtlechanges at the concentration of circulating pituitary and/or thyroid hormones.Objective: In this preclinical study, we aimed to assess the effects of repeated ITB in elderly male rats.Methods: Twelve months old male Wistar rats were subjected to either KI or saline solution for eight days. Analyses were performed 24 h and 30 days after the treatment discontinuation.Findings: We reported a significant increase (18%) in some urinary parameters related to renal function, a subtledecrease of plasma TSH level, a significant increase (379%) in renin and a significant decrease (50%) in aldosterone upon KI administration. At the molecular level, the expression of thyroid and cardiovascular genes wassignificantly affected by the treatment. However, in our experimental settlement, animal heart rate was notsignificantly affected thirty days after KI discontinuation. ECG patterns did not change after administration of KI,and arrhythmia was not observed in these conditions despite the PR-intervals decreased significantly. Cardiovascular physiology was preserved.Conclusion: Our results indicate that repeated ITB in elderly rats is characterized by molecular modifications ofcardiovascular key actors, particularly the Renin-angiotensin-aldosterone axis with a preserved physiologicalhomeostasis. This new scientific evidence may be useful for the maturation of ITB guidelines especially forelderly sub-population