Histological long-term effects in relevant tissues after 131I contamination of two Wistar rat models

Procedures using iodine-131 (131I) represent about 90% of all therapies in nuclear medicine [1, 2]. It is important to evaluate the long-term biological effects of 131I treatment on non-target organs in order to improve the patient radioprotection. The aim of this work is to use an experimental animal model to contribute to the understanding of some biological effects induced by 131I contamination, and especially histological effects. Two models of Wistar rats with (Tr+) and without thyroid (Tr-) were orally contaminated with iodine and after 8 months they were sacrificed and the histological effects on some relevant tissues such as thyroid, testes, liver and kidneys were been studied. Thyroid tissue analysis revealed that in the case of the Tr+ model compared to their control (Tr+ uncontaminated), 50% of the slides examined had remodeled the thyroid tissue with rare follicles choked by fibrosis and with epithelial changes. However, for Tr- compared to their control, the examined slides reveal the presence of a small, completely atrophied thyroid mass associated with vesicular fibrosis and with detachment of the colloid. For the renal organ, disturbances are observed: inflammation of the presence of tissue fibrosis and glomerular necrosis. For the liver, there is an appearance of inflammatory focus in different degrees around the portals. However, the results of the testes of both models compared to their controls revealed no histological abnormalities. The observed histological effects are correlated with the corresponding absorbed dose received by each organ and calculated using the RODES software [3, 4]

Cholesterol, Bile Acid, And Lipoprotein Metabolism In Two Strains Of Hamster, One Resistant, The Other Sensitive (LPN) To Sucrose-Induced Cholelithiasis

A comprehensive study of cholesterol, bile acid, and lipoprotein metabolism was undertaken in two strains of hamster that differed markedly in their response to a sucrose-rich/low fat diet. Under basal conditions, hamsters from the LPN strain differed from Janvier hamsters by a lower cholesterolemia, a higher postprandial insulinemia, a more active cholesterogenesis in both liver [3- to 4-fold higher 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoAR) activity and mRNA] and small intestine, and a lower hepatic acyl-coenzyme A:cholesterol acyltransferase activity. Cholesterol saturation indices in the gallbladder bile were similar for both strains, but the lipid concentration was 2-fold higher in LPN than in Janvier hamsters. LPN hamsters had a lower capacity to transform cholesterol into bile acids, shown by the smaller fraction of endogenous cholesterol converted into bile acids prior to fecal excretion (0.34 vs. 0.77). In LPN hamsters, the activities of cholesterol 7 -hydroxylase (C7OHase) and sterol 27-hydroxylase (S27OHase), the two rate-limiting enzymes of bile acid synthesis, were disproportionably lower (by 2-fold) to that of HMG-CoAR. When fed a sucrose-rich diet, plasma lipids increased, dietary cholesterol absorption improved, hepatic activities of HMG-CoA reductase, C7Ohase, and S27OHase were reduced, and intestinal S27OHase was inhibited in both strains. Despite a similar increase in the biliary hydrophobicity index due to the bile acid enrichment in chenodeoxycholic acid and derivatives, only LPN hamsters had an increased lithogenic index and developed cholesterol gallstones (75% incidence), whereas Janvier hamsters formed pigment gallstones (79% incidence). These studies indicate that LPN hamsters have a genetic predisposition to sucrose-induced cholesterol gallstone formation related to differences in cholesterol and bile acid metabolism

Antilithiasic Effect Of Beta-Cyclodextrin In LPN Hamster: Comparison With Cholestyramine

Beta-Cyclodextrin (BCD), a cyclic oligosaccharide that binds cholesterol and bile acids in vitro, has been previously shown to be an effective plasma cholesterol lowering agent in hamsters and domestic pigs. This study examined the effects of BCD as compared with cholestyramine on cholesterol and bile acid metabolism in the LPN hamster model model for cholesterol gallstones. The incidence of cholesterol gallstones was 65% in LPN hamsters fed the lithogenic diet, but decreased linearly with increasing amounts of BCD in the diet to be nil at a dose of 10% BCD. In gallbladder bile, cholesterol, phospholipid and chenodeoxycholate concentrations, hydrophobic and lithogenic indices were all significantly decreased by 10% BCD. Increases in bile acid synthesis (+110%), sterol 27-hydroxylase activity (+106%), and biliary cholate secretion (+140%) were also observed, whereas the biliary secretion of chenodeoxycholate decreased (-43%). The fecal output of chenodeoxycholate and cholate (plus derivatives) was increased by +147 and +64%, respectively, suggesting that BCD reduced the chenodeoxycholate intestinal absorption preferentially. Dietary cholestyramine decreased biliary bile acid concentration and secretion, but dramatically increased the fecal excretion of chenodeoxycholate and cholate plus their derivatives (+328 and +1940%, respectively). In contrast to BCD, the resin increased the lithogenic index in bile, induced black gallstones in 34% of hamsters, and stimulated markedly the activities of HMG-CoA reductase (+670%), sterol 27-hydroxylase (+310%), and cholesterol 7 alpha-hydroxylase (+390%). Thus, beta-cyclodextrin (BCD) prevented cholesterol gallstone formation by decreasing specifically the reabsorption of chenodeoxycholate, stimulating its biosynthesis and favoring its fecal elimination. BCD had a milder effect on lipid metabolism than cholestyramine and does not predispose animals to black gallstones as cholestyramine does in this animal model

Absorbed dose evaluation at different organs after 131I oral contamination of two Wistar rat models

Iodine-131 (131I) is one of the most frequently used radionuclides for diagnosis and therapy of thyroid diseases. It is administered orally in the treatment of cancer to eliminate the residual postoperative microscopic tumor foci, and the residual normal thyroid tissue for early detection of recurrence [1]. The comparative behavior of 131I concentration into two animalmodels with total and partial thyroid has been investigated in our previous work [2]. The accumulated activities have been measured in fourteen organs. In this study, the mean absorbed doses resulting from 131I accumulated in all organs have been evaluated using RODES software [3, 4]. With this software, mean absorbed doses were calculatedfor selected organs (thyroid, lungs, heart, liver, kidneys, stomach, spleen, large and small intestine, testes, urinary bladder wall) by combining the specific absorbed fractions (SAF) of energy with radiation emission spectra and biokinetic data determined from our previous experimental study [2]. Calculations were based on the 131I photon and electron emissions reported by [5] and SAFs previously calculated by Monte Carlo simulation in the voxel phantom of an adult male rate [3, 4]. The obtained results show high absorbed dosesdeliveredto stomach and lungs for both models compared to other organs. The dose received by the testes and salivary glands is found to be higher in the case of the rat model without thyroid. Conversely, the spleen and bladder wall received lower doses in this latter model compared to those received by the rat model with thyroid. One can also note that the difference in mean absorbed dose received by liver, lungs, heart, and walls of the stomach is not significant between the two rat models

Etude des effets des radionucléides (uranium et cesium 137) sur le métabolisme de la vitamine D chez le rat

CLERMONT FD-BCIU Sci.et Tech. (630142101) / SudocSudocFranceF

DU METABOLOME A L’EPIGENOME : EXEMPLE D’ETUDE MULTIOMIQUE SUR LES EFFETS DES EXPOSITIONS A FAIBLES DOSES D’URANIUM

International audiencePour d'étudier les effets biologiques des expositions chroniques à de faibles doses d’uranium auxquelles les populations humaines peuvent être exposées, un protocole in vivo d'exposition chronique à l'uranium a été élaboré et des analyses omiques ont été utilisées en complément d’un suivi clinique. Les résultats des analyses métabolomiques ont révélés l’existence d’un dimorphisme sexuel fort observable au niveau des reins, de l'urine et du plasma sanguin chez les animaux contaminés. Elles ont aussi montré que les principaux métabolismes affectés par l’uranium étaient ceux du nicotinate-nicotinamide et de la biosynthèse des acides gras insaturés. Plus en amont des métabolismes, l'analyse du transcriptomique des reins a aussi permis de mettre en évidence l’existence d’une activité génique et épigénétique associée à l’exposition à l’uranium et sensible au sexe des animaux. D’un point de vue épigénétique, l’analyse des profils de méthylation de l’ADN des reins a révélé chez les mâles nés de femelles exposées durant la gestation, des profils de méthylation de l’ADN modifiés sur deux générations alors que les femelles n’étaient à ce niveau pas affectées.Ces résultats ont montré qu’il existait des liens entre les différents profils moléculaires d’analyse omiques (de l'expression génique au métabolisme) des rats exposés à de faibles doses chroniques d'uranium. Ces approches multiéchelles pourraient être utiles pour décrypter les mécanismes d’action biologiques liés aux faibles doses d’expositions environnementales. Elles mettent en évidence l’importance du sexe des individus et attirent l’attention sur la nécessité de prendre en compte cette composante génétique en matière d'évaluation des risques et d’évolution des normes de radioprotection

Utilisation des analyses omiques pour la radiotoxicologie des faibles doses et l'évaluation des risques pour la santé : cas de l'uranium

International audienceAbstract Exposure to environmental pollution and the increase in the incidence of multifactorial diseases in the population have become health problems for industrialized countries. In this context, the question of the health impact of exposure to these pollutants is not clearly identified in the low-dose range. This article looks at this problem using the example of preclinical studies of the effects of chronic low-dose exposure to uranium in rats. These studies demonstrate the value of molecular screening analyses (omics) and multimodal integrative approaches, of which the extreme sensitivity and breadth of observation spectrum make it possible to observe all the biological processes affected and the mechanisms of action triggered at the molecular level by exposure to low doses. They also show the value of these analytical approaches for finding diagnostic biomarkers or indicators of prognosis, which can be necessary to evaluate a risk. Finally, the results of these studies raise the question of the health risk caused by epigenomic deregulations occurring during critical developmental phases and their potential contribution to the development of chronic diseases that are metabolic in origin or to the development of certain cancer liable in the long term to affect the exposed adult and possibly its progeny

A systems biology approach to propose a new mechanism of regulation of repetitive prophylaxis of stable iodide on sodium/iodide symporter (NIS).

International audienceOur group showed that repetitive dose of potassium iodide (KI) for eight days offers an efficient protection for exposure to repeated radioactive emissions without adverse effects on adult rats. However, differential expression of genes implicated in Wolff-Chaikoff effect was observed. To understand the Wolff-Chaikoff regulation and its molecular constituents during repetitive administration of KI, a biochemical reaction network was constructed as a "geographical" map of the thyrocyte depicting iodide and thyroid hormone synthesis. Path analysis of the network has been performed to investigate the presence of a regulatory circuit of the node iodide to the node "nis transcription". NIS is responsible for the uptake of KI and plays an important role in the Wolff-Chaikoff effect. The map is a source for the most updated information about iodide and thyroid hormone metabolism. Based on this map, we propose a hypothesis that shows a putative mechanism behind NIS regulation and KI uptake

Prophylaxie par iodurede potassium en situationd’accident nucléaire: Une prescription désormais jusqu’à 7 jours

En l’absence de mesures de protectionadaptées, l’exposition des populationsaux iodes radioactifs peutêtre responsable de l’apparition decancers de la thyroïde. En effet, uneaugmentation de l’incidence decette pathologie a été observée chez despersonnes qui étaient enfants et adolescentsau moment de l’accident de Tchernobyl,dans les territoires contaminéspar les retombées radioactives.Au Japon, les conséquences réelles del’accident de Fukushima sur l’incidencedu cancer de la thyroïde ne seront, quantà elles, connues que dans plusieurs années