Exposure to environmental pollution and the increase in the incidence of multifactorial diseases ... more 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 quest...
Changes in metabolomics over time were studied in rats to identify early biomarkers and highlight... more Changes in metabolomics over time were studied in rats to identify early biomarkers and highlight the main metabolic pathways that are significantly altered in the period immediately following acute low-dose uranium exposure. A dose response relationship study was established from urine and plasma samples collected periodically over 9 months after the exposure of young adult male rats to uranyl nitrate. LC-MS and biostatistical analysis were used to identify early discriminant metabolites. As expected, low doses of uranium lead to time-based non-toxic biological effects, which can be used to identify early and delayed markers of exposure in both urine and plasma samples. A combination of surrogate markers for uranium exposure was validated from the most discriminant early markers for making effective predictions. N-methyl-nicotinamide, kynurenic acid, serotonin, tryptophan, tryptamine, and indole acetic acid associated with the nicotinate–nicotinamide and tryptophan pathway seem to ...
Un modele experimental animal, mimant la contamination chronique des populations vivant sur des t... more Un modele experimental animal, mimant la contamination chronique des populations vivant sur des territoires contamines a ete utilise dans le cadre du programme de recherche ENVIRHOM-Sante de l’Institut de radioprotection et de surete nucleaire (IRSN). Il a revele que l’ingestion chronique de radionucleides a faibles doses entrainait des atteintes biologiques multiples de faibles amplitudes caracterisees par des ruptures subtiles d’equilibres metaboliques consecutives a l’exposition interne. En effet, il a ete montre qu’une contamination interne de radionucleides etait capable d’affecter in vivo un certain nombre de metabolismes majeurs de l’organisme, tels que le metabolisme du cholesterol, de la vitamine D, du fer, des hormones steroidiennes et des xenobiotiques sans effet toxique ou apparition de pathologie. Pour completer et affiner ces connaissances, des etudes associant pour la premiere fois une approche metabolomique a la radiotoxicologie des faibles doses ont ete initiees en ...
Effects of uranium on reproductive function in rats exposed from fetal life to adulthood. 2. Jour... more Effects of uranium on reproductive function in rats exposed from fetal life to adulthood. 2. Journees du GdR 3606 Repro
Exposure to uranium low dose on a rat model, male and female, induces global DNA méthylation chan... more Exposure to uranium low dose on a rat model, male and female, induces global DNA méthylation changes in F0 gonads. •-The changes are conserved through F1 and F2 generations. •-These modifications are associated with variations in methylation /demethylation gene expression.
Protracted radioiodine release, may requires repeated intake of potassium iodide (KI) to protect ... more Protracted radioiodine release, may requires repeated intake of potassium iodide (KI) to protect thyroid gland. It is well established that iodine excess inhibits transiently the thyroid function. As developing foetus depends on maternal thyroid hormones (TH) supply, more knowledge are 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 1 ACCEPTED MANUSCRIPT the conséquences 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 behaviour test. Pituitary and thyroid hormones level, anti-thyroid antibodies level, organs morphology, genes 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 TSH (-28%) and FT4 (-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.
Depleted uranium has several civilian and military applications that may lead, with its natural p... more Depleted uranium has several civilian and military applications that may lead, with its natural presence in high concentration in various areas, to contamination of human population mainly by chronic ingestion. Currently, the accumulation of this radionuclide in various organs (bone, kidney, liver...) after an acute or chronic contamination is described and can lead to a chemical and/or radiological toxicity. Cellular and molecular effects of uranium contamination on important metabolic functions in the liver and the kidney, as the detoxication of xenobiotics, are not shown in the literature. The aim of this present study was thus to evaluate possible biological effects on xenobiotic biotransformation cytochromes P450 (CYPs) enzymes after chronic exposure to depleted uranium. The experiments were carried out in Sprague-Dawley rats after a chronic contamination by depleted uranium through drinking water at 40 mg/L. The expression of CYPs mRNA and the associated nuclear receptors was ...
The extensive use of depleted uranium (DU) in both civilian and military applications results in ... more The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40 mg/l) were treated by acetaminophen (APAP, 400 mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p < 0.01) and AST (p < 0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p < 0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination.
La preoccupation du public a l'egard de la qualite de l'environnement et des risques qui ... more La preoccupation du public a l'egard de la qualite de l'environnement et des risques qui la menace a ete alimentee par plusieurs crises sanitaires illustrees, dans le domaine du nucleaire, par l'accident de Tchernobyl. Depuis cet evenement, le deficit des connaissances sur les effets biologiques et sanitaires induits par une ingestion chronique de radionucleides dont le cesium-137 est en passe d'etre reduit par la mise en place de plusieurs programmes de recherche a travers le monde.
Natural uranium (NU), a component of the earth’s crust, is not only a heavy metal but also an alp... more 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...
Le césium 137 (137 Cs) est un radionucléide retrouvé dans l'environnement suite aux essais aérien... more Le césium 137 (137 Cs) est un radionucléide retrouvé dans l'environnement suite aux essais aériens des armes nucléaires et aux accidents survenus dans des centrales nucléaires comme à Tchernobyl en 1986. Les conséquences sanitaires d'une exposition chronique à ce radionucléide restent mal connues. Après absorption, le césium se distribue de façon relativement homogène dans l'organisme, avec une charge plus importante chez l'enfant que chez l'adulte. La toxicité du 137 Cs résulterait essentiellement de ses propriétés radiologiques. Une contamination interne à forte dose induit une insuffisance médullaire, des troubles de la fonction de reproduction, des effets hépatotoxiques et des affections rénales. Des troubles de la minéralisation osseuse et des lésions cérébrales ont également été décrits chez l'homme. À plus faible dose, le 137 Cs entraîne chez l'animal des perturbations du cycle veille-sommeil, mais sans troubles comportementaux. Une atteinte du système cardiovasculaire a également été observée. Des systèmes physiologiques tels que les métabolismes de la vitamine D, du cholestérol et des hormones stéroïdiennes sont modifiés, mais sans engendrer toutefois l'apparition de pathologies avec symptomatologie clinique. Chez l'homme, le 137 Cs induit une atteinte du système immunitaire, des malformations congénitales et foetales, une augmentation des cancers de la thyroïde ainsi que des troubles neurologiques. Enfin, il semblerait que les enfants soient plus sensibles aux effets toxiques du césium que les adultes. En termes de prise en charge thérapeutique des patients contaminés par le 137 Cs, le bleu de Prusse (Radiogardase 1) est actuellement le seul traitement efficace pour décorporer le 137 Cs après ingestion. L'administration de pectine pour traiter une contamination interne au 137 Cs a été évoquée, notamment chez les enfants, mais son utilisation fait encore aujourd'hui débat. En conclusion, les données scientifiques actuellement disponibles, et plus particulièrement celles décrites après contamination chronique, suggèrent que le 137 Cs est susceptible d'affecter de nombreuses fonctions physiologiques et métaboliques. Ainsi, il pourrait contribuer, avec d'autres substances artificielles présentes dans l'environnement, à l'augmentation des risques sanitaires dans certaines régions du globe.
Cardiovascular system impairment has been observed in children and in liquidators exposed to the ... more Cardiovascular system impairment has been observed in children and in liquidators exposed to the Chernobyl nuclear power plant accident. No experimental studies of animals have analyzed whether these disorders might be attributed to chronic ingestion of low levels of cesium 137 ((137)Cs). Biochemical, physiological, and molecular markers of the cardiovascular system were analyzed in rats exposed through drinking water to (137)Cs at a dose of 500 Bq kg(-1) (6500 Bq l(-1)). Plasma concentrations of CK and CK-MB were higher (+52%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in contaminated rats. No histological alteration of the heart was observed, but gene expression was modified in the atria. Specifically, levels of ACE (angiotensin converting enzyme) and BNP (brain natriuretic peptide) gene expression increased significantly (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). ECG analysis did not disclose any arrhythmia except ST- and RT-segment shortening (-9% and -11%, respectively, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in rats exposed to (137)Cs. Mean blood pressure decreased (-10%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), and its circadian rhythm disappeared. Overall, chronic contamination by an extreme environmental dose of (137)Cs for 3 months did not result in cardiac morphological changes, but the cardiovascular system impairments we observed could develop into more significant changes in sensitive animals or after longer contamination.
After the Chernobyl nuclear accident, epidemiological studies on human populations living in 137C... more After the Chernobyl nuclear accident, epidemiological studies on human populations living in 137Cs-contaminated areas revealed the increase frequencies of thyroid cancer and evoked the apparition of cardiovascular diseases, hormonal effect, liver alteration, and lipid disorder. Actually, it raises a problem of public safety for the populations living on these territories that are exposed to low levels of 137Cs during a long period through food. Then it is necessary to study potential effect of this chronic contamination. To mimic this situation, the authors investigate the potential biological effects of chronic exposure to 137Cs at a postaccidental dose (150 Bq/rat/day) on hepatic metabolism of cholesterol in rat. Plasma lipid level, gene expression and activity were analyzed. It was observed that in 137Cs-exposed rats, gene expression of low-density lipoprotein receptor (LDLr), apolipoprotein B (apoB), and liver X receptor alpha (LXRalpha) are increased (95%, p &lt; .05; 34%, p &lt; .05; 20%, p &lt; 0.05, respectively), whereas transporter adenosine triphosphate-binding cassette transporter G5 (ABCG5) is decreased (42%, p &lt; .05). In addition, cytochrome P450 27A1 (CYP27A1) activity is increased (34%, p &lt; .05) in contaminated rat liver. In conclusion, the results suggest that 137Cs contamination at low-level induces molecular modifications of the liver cholesterol metabolism without leading to a dysregulation of its homeostasis. These results suggest that chronic long term exposure at low-level of 137Cs may evolve to lipid disorder.
Animal-based studies have provided important insights into the structural and functional conseque... more Animal-based studies have provided important insights into the structural and functional consequences of noise exposure on the cochlea. Yet, less is known about the molecular mechanisms by which noise induces cochlear damage, particularly at relatively low exposure levels. While there is ample evidence that noise exposure leads to changes in inner ear metabolism, the specific effects of noise exposure on the cochlear metabolome are poorly understood. In this study we applied liquid chromatographycoupled tandem mass spectrometry (LC-MS/MS)-based metabolomics to analyze the effects of noise on the mouse inner ear. Mice were exposed to noise that induces temporary threshold shifts, synaptopathy and permanent hidden hearing loss. Inner ears were harvested immediately after exposure and analyzed by targeted metabolomics for the relative abundance of 220 metabolites across the major metabolic pathways in central carbon metabolism. We identified 40 metabolites differentially affected by noise. our approach detected novel noise-modulated metabolites and pathways, as well as some already linked to noise exposure or cochlear function such as neurotransmission and oxidative stress. Furthermore, it showed that metabolic effects of noise on the inner ear depend on the intensity and duration of exposure. Collectively, our results illustrate that metabolomics provides a powerful approach for the characterization of inner ear metabolites affected by auditory trauma. This type of information could lead to the identification of drug targets and novel therapies for noise-induced hearing loss.
The Journal of Steroid Biochemistry and Molecular Biology, 2010
Depleted uranium (DU) is a radioactive heavy metal derived from the nuclear energy production. It... more Depleted uranium (DU) is a radioactive heavy metal derived from the nuclear energy production. Its wide use in civilian and military items increases the risk of its environmental dissemination, and thus the risk of internal contamination of populations living in such contaminated territories. Previous studies have shown that vitamin D and cerebral cholesterol metabolisms were affected following chronic ingestion of DU. Even more than the brain, the liver is a crucial organ in cholesterol homeostasis since it regulates cholesterol distribution and elimination at body level. The aim of this work was to assess the impact of a low-level chronic ingestion of DU on hepatic cholesterol metabolism. Rats were contaminated with DU in their drinking water at a concentration of 40 mg/l for 9 months. The major effect induced by DU was a decrease of CYP7A1 specific activity (−60%) correlated with a matching decrease of its product 7␣hydroxycholesterol in the plasma. Hepatic gene expression of transporters ABC A1, ABC G5, ABC G8 and of nuclear receptor RXR was increased, whereas that of catabolism enzyme CYP7B1 was decreased. Thus, after a chronic ingestion of DU, rats experience a modulation of cholesterol catabolism but overcome it, since their cholesterolemia is preserved and no pathology is declared.
The aim of our present study was to compare the efficiency of conjugated linoleic acids (CLA) and... more The aim of our present study was to compare the efficiency of conjugated linoleic acids (CLA) and fish oil in modulating atherogenic risk markers. Adult male hamsters were given a cholesterol-rich diet (0·6 g/kg) for 8 weeks; the diet was supplemented with 5 g cis-9,trans-11-CLA isomer/kg, 12 g CLA mixture (CLA-mix)/kg, 12 g fish oil/kg or 12 g fish oil + 12 g CLA-mix/kg. The plasma cholesterol status was improved only with the cis-9,trans-11-CLA (HDL-cholesterol and HDL-cholesterol:LDL-cholesterol ratio, P<0·05), but was of borderline significance for CLA-mix (HDL-cholesterol:LDL-cholesterol ratio, P=0·06), with an increase (33–40 %) in the liver lipoprotein receptors (scavenger receptor-type I and LDL ApoB/E receptor) and HDL-binding protein 2…
Exposure to environmental pollution and the increase in the incidence of multifactorial diseases ... more 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 quest...
Changes in metabolomics over time were studied in rats to identify early biomarkers and highlight... more Changes in metabolomics over time were studied in rats to identify early biomarkers and highlight the main metabolic pathways that are significantly altered in the period immediately following acute low-dose uranium exposure. A dose response relationship study was established from urine and plasma samples collected periodically over 9 months after the exposure of young adult male rats to uranyl nitrate. LC-MS and biostatistical analysis were used to identify early discriminant metabolites. As expected, low doses of uranium lead to time-based non-toxic biological effects, which can be used to identify early and delayed markers of exposure in both urine and plasma samples. A combination of surrogate markers for uranium exposure was validated from the most discriminant early markers for making effective predictions. N-methyl-nicotinamide, kynurenic acid, serotonin, tryptophan, tryptamine, and indole acetic acid associated with the nicotinate–nicotinamide and tryptophan pathway seem to ...
Un modele experimental animal, mimant la contamination chronique des populations vivant sur des t... more Un modele experimental animal, mimant la contamination chronique des populations vivant sur des territoires contamines a ete utilise dans le cadre du programme de recherche ENVIRHOM-Sante de l’Institut de radioprotection et de surete nucleaire (IRSN). Il a revele que l’ingestion chronique de radionucleides a faibles doses entrainait des atteintes biologiques multiples de faibles amplitudes caracterisees par des ruptures subtiles d’equilibres metaboliques consecutives a l’exposition interne. En effet, il a ete montre qu’une contamination interne de radionucleides etait capable d’affecter in vivo un certain nombre de metabolismes majeurs de l’organisme, tels que le metabolisme du cholesterol, de la vitamine D, du fer, des hormones steroidiennes et des xenobiotiques sans effet toxique ou apparition de pathologie. Pour completer et affiner ces connaissances, des etudes associant pour la premiere fois une approche metabolomique a la radiotoxicologie des faibles doses ont ete initiees en ...
Effects of uranium on reproductive function in rats exposed from fetal life to adulthood. 2. Jour... more Effects of uranium on reproductive function in rats exposed from fetal life to adulthood. 2. Journees du GdR 3606 Repro
Exposure to uranium low dose on a rat model, male and female, induces global DNA méthylation chan... more Exposure to uranium low dose on a rat model, male and female, induces global DNA méthylation changes in F0 gonads. •-The changes are conserved through F1 and F2 generations. •-These modifications are associated with variations in methylation /demethylation gene expression.
Protracted radioiodine release, may requires repeated intake of potassium iodide (KI) to protect ... more Protracted radioiodine release, may requires repeated intake of potassium iodide (KI) to protect thyroid gland. It is well established that iodine excess inhibits transiently the thyroid function. As developing foetus depends on maternal thyroid hormones (TH) supply, more knowledge are 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 1 ACCEPTED MANUSCRIPT the conséquences 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 behaviour test. Pituitary and thyroid hormones level, anti-thyroid antibodies level, organs morphology, genes 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 TSH (-28%) and FT4 (-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.
Depleted uranium has several civilian and military applications that may lead, with its natural p... more Depleted uranium has several civilian and military applications that may lead, with its natural presence in high concentration in various areas, to contamination of human population mainly by chronic ingestion. Currently, the accumulation of this radionuclide in various organs (bone, kidney, liver...) after an acute or chronic contamination is described and can lead to a chemical and/or radiological toxicity. Cellular and molecular effects of uranium contamination on important metabolic functions in the liver and the kidney, as the detoxication of xenobiotics, are not shown in the literature. The aim of this present study was thus to evaluate possible biological effects on xenobiotic biotransformation cytochromes P450 (CYPs) enzymes after chronic exposure to depleted uranium. The experiments were carried out in Sprague-Dawley rats after a chronic contamination by depleted uranium through drinking water at 40 mg/L. The expression of CYPs mRNA and the associated nuclear receptors was ...
The extensive use of depleted uranium (DU) in both civilian and military applications results in ... more The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40 mg/l) were treated by acetaminophen (APAP, 400 mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p < 0.01) and AST (p < 0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p < 0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination.
La preoccupation du public a l'egard de la qualite de l'environnement et des risques qui ... more La preoccupation du public a l'egard de la qualite de l'environnement et des risques qui la menace a ete alimentee par plusieurs crises sanitaires illustrees, dans le domaine du nucleaire, par l'accident de Tchernobyl. Depuis cet evenement, le deficit des connaissances sur les effets biologiques et sanitaires induits par une ingestion chronique de radionucleides dont le cesium-137 est en passe d'etre reduit par la mise en place de plusieurs programmes de recherche a travers le monde.
Natural uranium (NU), a component of the earth’s crust, is not only a heavy metal but also an alp... more 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...
Le césium 137 (137 Cs) est un radionucléide retrouvé dans l'environnement suite aux essais aérien... more Le césium 137 (137 Cs) est un radionucléide retrouvé dans l'environnement suite aux essais aériens des armes nucléaires et aux accidents survenus dans des centrales nucléaires comme à Tchernobyl en 1986. Les conséquences sanitaires d'une exposition chronique à ce radionucléide restent mal connues. Après absorption, le césium se distribue de façon relativement homogène dans l'organisme, avec une charge plus importante chez l'enfant que chez l'adulte. La toxicité du 137 Cs résulterait essentiellement de ses propriétés radiologiques. Une contamination interne à forte dose induit une insuffisance médullaire, des troubles de la fonction de reproduction, des effets hépatotoxiques et des affections rénales. Des troubles de la minéralisation osseuse et des lésions cérébrales ont également été décrits chez l'homme. À plus faible dose, le 137 Cs entraîne chez l'animal des perturbations du cycle veille-sommeil, mais sans troubles comportementaux. Une atteinte du système cardiovasculaire a également été observée. Des systèmes physiologiques tels que les métabolismes de la vitamine D, du cholestérol et des hormones stéroïdiennes sont modifiés, mais sans engendrer toutefois l'apparition de pathologies avec symptomatologie clinique. Chez l'homme, le 137 Cs induit une atteinte du système immunitaire, des malformations congénitales et foetales, une augmentation des cancers de la thyroïde ainsi que des troubles neurologiques. Enfin, il semblerait que les enfants soient plus sensibles aux effets toxiques du césium que les adultes. En termes de prise en charge thérapeutique des patients contaminés par le 137 Cs, le bleu de Prusse (Radiogardase 1) est actuellement le seul traitement efficace pour décorporer le 137 Cs après ingestion. L'administration de pectine pour traiter une contamination interne au 137 Cs a été évoquée, notamment chez les enfants, mais son utilisation fait encore aujourd'hui débat. En conclusion, les données scientifiques actuellement disponibles, et plus particulièrement celles décrites après contamination chronique, suggèrent que le 137 Cs est susceptible d'affecter de nombreuses fonctions physiologiques et métaboliques. Ainsi, il pourrait contribuer, avec d'autres substances artificielles présentes dans l'environnement, à l'augmentation des risques sanitaires dans certaines régions du globe.
Cardiovascular system impairment has been observed in children and in liquidators exposed to the ... more Cardiovascular system impairment has been observed in children and in liquidators exposed to the Chernobyl nuclear power plant accident. No experimental studies of animals have analyzed whether these disorders might be attributed to chronic ingestion of low levels of cesium 137 ((137)Cs). Biochemical, physiological, and molecular markers of the cardiovascular system were analyzed in rats exposed through drinking water to (137)Cs at a dose of 500 Bq kg(-1) (6500 Bq l(-1)). Plasma concentrations of CK and CK-MB were higher (+52%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in contaminated rats. No histological alteration of the heart was observed, but gene expression was modified in the atria. Specifically, levels of ACE (angiotensin converting enzyme) and BNP (brain natriuretic peptide) gene expression increased significantly (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). ECG analysis did not disclose any arrhythmia except ST- and RT-segment shortening (-9% and -11%, respectively, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) in rats exposed to (137)Cs. Mean blood pressure decreased (-10%, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), and its circadian rhythm disappeared. Overall, chronic contamination by an extreme environmental dose of (137)Cs for 3 months did not result in cardiac morphological changes, but the cardiovascular system impairments we observed could develop into more significant changes in sensitive animals or after longer contamination.
After the Chernobyl nuclear accident, epidemiological studies on human populations living in 137C... more After the Chernobyl nuclear accident, epidemiological studies on human populations living in 137Cs-contaminated areas revealed the increase frequencies of thyroid cancer and evoked the apparition of cardiovascular diseases, hormonal effect, liver alteration, and lipid disorder. Actually, it raises a problem of public safety for the populations living on these territories that are exposed to low levels of 137Cs during a long period through food. Then it is necessary to study potential effect of this chronic contamination. To mimic this situation, the authors investigate the potential biological effects of chronic exposure to 137Cs at a postaccidental dose (150 Bq/rat/day) on hepatic metabolism of cholesterol in rat. Plasma lipid level, gene expression and activity were analyzed. It was observed that in 137Cs-exposed rats, gene expression of low-density lipoprotein receptor (LDLr), apolipoprotein B (apoB), and liver X receptor alpha (LXRalpha) are increased (95%, p &lt; .05; 34%, p &lt; .05; 20%, p &lt; 0.05, respectively), whereas transporter adenosine triphosphate-binding cassette transporter G5 (ABCG5) is decreased (42%, p &lt; .05). In addition, cytochrome P450 27A1 (CYP27A1) activity is increased (34%, p &lt; .05) in contaminated rat liver. In conclusion, the results suggest that 137Cs contamination at low-level induces molecular modifications of the liver cholesterol metabolism without leading to a dysregulation of its homeostasis. These results suggest that chronic long term exposure at low-level of 137Cs may evolve to lipid disorder.
Animal-based studies have provided important insights into the structural and functional conseque... more Animal-based studies have provided important insights into the structural and functional consequences of noise exposure on the cochlea. Yet, less is known about the molecular mechanisms by which noise induces cochlear damage, particularly at relatively low exposure levels. While there is ample evidence that noise exposure leads to changes in inner ear metabolism, the specific effects of noise exposure on the cochlear metabolome are poorly understood. In this study we applied liquid chromatographycoupled tandem mass spectrometry (LC-MS/MS)-based metabolomics to analyze the effects of noise on the mouse inner ear. Mice were exposed to noise that induces temporary threshold shifts, synaptopathy and permanent hidden hearing loss. Inner ears were harvested immediately after exposure and analyzed by targeted metabolomics for the relative abundance of 220 metabolites across the major metabolic pathways in central carbon metabolism. We identified 40 metabolites differentially affected by noise. our approach detected novel noise-modulated metabolites and pathways, as well as some already linked to noise exposure or cochlear function such as neurotransmission and oxidative stress. Furthermore, it showed that metabolic effects of noise on the inner ear depend on the intensity and duration of exposure. Collectively, our results illustrate that metabolomics provides a powerful approach for the characterization of inner ear metabolites affected by auditory trauma. This type of information could lead to the identification of drug targets and novel therapies for noise-induced hearing loss.
The Journal of Steroid Biochemistry and Molecular Biology, 2010
Depleted uranium (DU) is a radioactive heavy metal derived from the nuclear energy production. It... more Depleted uranium (DU) is a radioactive heavy metal derived from the nuclear energy production. Its wide use in civilian and military items increases the risk of its environmental dissemination, and thus the risk of internal contamination of populations living in such contaminated territories. Previous studies have shown that vitamin D and cerebral cholesterol metabolisms were affected following chronic ingestion of DU. Even more than the brain, the liver is a crucial organ in cholesterol homeostasis since it regulates cholesterol distribution and elimination at body level. The aim of this work was to assess the impact of a low-level chronic ingestion of DU on hepatic cholesterol metabolism. Rats were contaminated with DU in their drinking water at a concentration of 40 mg/l for 9 months. The major effect induced by DU was a decrease of CYP7A1 specific activity (−60%) correlated with a matching decrease of its product 7␣hydroxycholesterol in the plasma. Hepatic gene expression of transporters ABC A1, ABC G5, ABC G8 and of nuclear receptor RXR was increased, whereas that of catabolism enzyme CYP7B1 was decreased. Thus, after a chronic ingestion of DU, rats experience a modulation of cholesterol catabolism but overcome it, since their cholesterolemia is preserved and no pathology is declared.
The aim of our present study was to compare the efficiency of conjugated linoleic acids (CLA) and... more The aim of our present study was to compare the efficiency of conjugated linoleic acids (CLA) and fish oil in modulating atherogenic risk markers. Adult male hamsters were given a cholesterol-rich diet (0·6 g/kg) for 8 weeks; the diet was supplemented with 5 g cis-9,trans-11-CLA isomer/kg, 12 g CLA mixture (CLA-mix)/kg, 12 g fish oil/kg or 12 g fish oil + 12 g CLA-mix/kg. The plasma cholesterol status was improved only with the cis-9,trans-11-CLA (HDL-cholesterol and HDL-cholesterol:LDL-cholesterol ratio, P<0·05), but was of borderline significance for CLA-mix (HDL-cholesterol:LDL-cholesterol ratio, P=0·06), with an increase (33–40 %) in the liver lipoprotein receptors (scavenger receptor-type I and LDL ApoB/E receptor) and HDL-binding protein 2…
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Papers by Maâmar Souidi