Assessment of the Central Effects of Natural Uranium via Behavioural Performances and the Cerebrospinal Fluid Metabolome

International audienceNatural 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 NU via lactation and drinking water (1.5, 10, or 40 mg⋅L −1 for male rats and 40 mg⋅L −1 for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg⋅L −1 NU. In male rats, spatial working memory and anxiety-and depressive-like behaviour were only altered by exposure to 40 mg⋅L −1 NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function

Concerns regarding nanosized titanium dioxide nasal exposure and neurotoxicity study by Ze et al.

International audienceScientific articles dealing with nanotoxicology are particularly awaited and important, as in the field of nanotechnology, a relatively new domain; they likely have a significant impact not only on our perception of the risk and danger potentially associated with nanomaterials but also on regulatory decisions with regard to their use in consumer products. Because nanotoxicology refers to the work of researchers from different domains of expertise, it appears also more difficult to secure accurate review and thus accurate conclusions. In that context, particular attention must be drawn on these studies. Still for the readers of such articles, of which most of are not experts in several aspects of nanotoxicology it would be tempting to take the messages for granted, thinking the studies are well conducted and reported with accuracy. In the case of the article by Ze and colleagues, we have noticed a certain number of critical comments that should be brought to the attention of the readers of J. Biomed Mater res A, because this study presents several problems. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A 103A 2198-2200, 2015. © 2014 Wiley Periodicals, Inc

Uranium appauvri: Perturbateur métabolique?

The presence of uranium in the environment can lead to long-term contamination of the food chain and of water intended for human consumption and thus raises many questions about the scientific and societal consequences of this exposure on population health. Although the biological effects of chronic low-level exposure are poorly understood, results of various recent studies show that contamination by depleted uranium (DU) induces subtle but significant biological effects at the molecular level in organs including the brain, liver, kidneys and testicles. For the first time, it has been demonstrated that DU induces effects on several metabolic pathways, including those metabolising vitamin D, cholesterol, steroid hormones, acetylcholine and xenobiotics. This evidence strongly suggests that DU might well interfere with many metabolic pathways. It might thus contribute, together with other man-made substances in the environment, to increased health risks in some regions.Année de parution : 2011 La présence d’uranium dans l’environnement peut conduire à long terme à une contamination de la chaîne alimentaire et/ou des eaux destinées à la consommation humaine, soulevant alors de nombreuses interrogations scientifiques et sociétales quant aux conséquences de cette exposition sur la santé des populations. Les effets biologiques d’une exposition chronique à de faibles niveaux sont peu connus. Cependant, les résultats de différentes études récentes montrent que ce type de contamination à l’uranium appauvri induirait des effets biologiques de types moléculaires subtils, mais significatifs, dans des organes tels que le cerveau, le foie, les reins et les testicules. La grande nouveauté dans les effets induits après contamination interne par l’uranium est la mise en évidence d’effets sur un certain nombre de métabolismes majeurs de l’organisme comme le métabolisme de la vitamine D, du cholestérol, des hormones stéroïdiennes, de l’acétylcholine et des xénobiotiques. Ces données scientifiques suggèrent fortement que l’uranium est susceptible d’interférer avec de nombreuses voies 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

Neuro-inflammatory response in rats chronically exposed to 137Cesium

After the Chernobyl nuclear accident, behavioural disorders and central nervous system diseases were frequently observed in populations living in the areas contaminated by 137Cs. Until now, these neurological disturbances were not elucidated, but the presence of a neuro-inflammatory response could be one explanation. Rats were exposed for 3 months to drinking water contaminated with 137Cs at a dose of 400 Bq kg-1, which is similar to that ingested by the population living in contaminated areas in the former USSR countries. Pro-inflammatory and anti-inflammatory cytokine genes were assessed by real-time PCR in the frontal cortex and the hippocampus. At this level of exposure, gene expression of TNF-α and IL-6 increased in the hippocampus and gene expression of IL-10 increased in the frontal cortex. Concentration of TNF-α, measured by ELISA assays, was also increased in the hippocampus. The central NO-ergic pathway was also studied: iNOS gene expression and cNOS activity were significantly increased in the hippocampus. In conclusion, this study showed for the first time that sub-chronic exposure with post-accidental doses of 137Cs leads to molecular modifications of pro- and anti-inflammatory cytokines and NO-ergic pathway in the brain. This neuro-inflammatory response could contribute to the electrophysiological and biochemical alterations observed after chronic exposure to 137Cs. © 2008 Elsevier Inc. All rights reserved

Parental exposure to enriched uranium induced delayed hyperactivity in rat offspring

Several recent reports suggest that chronic exposure to uranium could induce behavioural effects in adult rats. As the immature brains are known to be more susceptible to toxic effects, rats were observed in an open field, in a Y-maze and in an elevated plus-maze at 2, 5 and 9 months old after exposure to enriched uranium (40 mg l-1) during gestation and lactation. The rats exposed to enriched uranium showed a significant decrease in alternation in the Y-maze at 2 months old which reflects a slight decrease in the spatial working memory capacities as previously described in adult rats. However, the main result was a delayed hyperactivity in the rats exposed to enriched uranium, which appeared to a slight extent at 5 months old and was more evident at 9 months old. Although this effect could not be directly explained by some uranium accumulation in the target organs, this experiment showed that early exposure to enriched uranium can induce a very late effect on the rat behaviour and that such studies should not be restricted to the effects observed on young rats. © 2006 Elsevier Inc. All rights reserved

Le césium 137 un perturbateur de la fonction physiologique?

National audienceToday, radiation protection is a major issue for the nuclear industry throughout the world, particularly in France. The 2011 disaster of Fukushima Dai-ichi has brought back to public attention questions about the risks associated with nuclear power for civilian purposes. The risk of accidental release of radioactive molecules, including cesium-137 (137Cs), from these facilities cannot be completely eliminated. The non-cancer-related health consequences of chronic exposure to this radionuclide remain poorly understood. After absorption, cesium is distributed throughout the body. The toxicity of 137Cs is due mainly to its radiological properties. Studies in humans report that 137Cs impairs the immune system and induces neurological disorders. Children appear more susceptible than adults to its toxic effects. In animals, and most particularly in rodents, low-dose internal contamination disrupts the sleep-wake cycle, but without behavioural disorders. Impairment of the cardiovascular system has also been observed. Physiologic systems such as the metabolism of vitamin D, cholesterol and steroid hormones are altered, although without leading to the emergence of diseases with clinical symptoms. Recently, a metabolomics study based on contamination levels comparable to those around Chernobyl after the accident showed that it is possible to identify individual rats chronically exposed to low doses of 137Cs, even though the exposure was too low to affect the standard clinical markers. In conclusion, the scientific evidence currently available, particularly that from experimental animal models exposed to chronic contamination, suggests that 137Cs is likely to affect many physiologic and metabolic functions. Thus, it could contribute, with other artificial substances in the environment, to increasing the risk of developing non-cancer diseases in some regions.Aujourd’hui, dans le monde et particulièrement en France, la radioprotection est devenue un des enjeux majeurs pour la filière nucléaire. En effet, la catastrophe de Fukushima Daichi en 2011 a fait ressurgir une nouvelle fois les interrogations sur le risque lié au nucléaire civil. Le risque de rejet accidentel de molécules radioactives, notamment le césium 137 ( 137Cs), ne peut pas être totalement éliminé au niveau de telles installations. Les conséquences sanitaires postaccidentelles d’une exposition chronique à ce radionucléide en termes d’effets biologiques non cancéreux restent encore mal connues. Après absorption, 137Cs se distribue de façon homogène dans l’organisme et sa toxicité résulte essentiellement de ses propriétés radiologiques. Des études chez l’homme ont rapporté que le 137Cs induit une atteinte du système immunitaire, des malformations congénitales ainsi que des troubles neurologiques. Il semblerait aussi que les enfants soient plus sensibles aux effets toxiques du 137Cs que les adultes. Chez l’animal, et plus particulièrement chez le rongeur, une contamination interne à faible dose par le 137Cs entraîne 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 l’apparition de pathologies avec symptomatologie clinique. Récemment, une étude métabolomique basée sur des niveaux de contamination postaccidentelle comparable à celle de l’environnement proche de Tchernobyl ont permis de montrer qu’il était possible d’identifier des rats contaminés chroniquement par de faibles doses de 137Cs, alors que les taux de marqueurs cliniques classiques n’étaient pas affectés. En conclusion, les données scientifiques actuellement disponibles, et plus particulièrement les données décrites sur des modèles expérimentaux, après contamination chronique, suggèrent que le 137Cs 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 d’apparition de pathologies non cancéreuses dans certaines régions du globe

The brain is a target organ after acute exposure to depleted uranium

The health effects of depleted uranium (DU) are mainly caused by its chemical toxicity. Although the kidneys are the main target organs for uranium toxicity, uranium can also reach the brain. In this paper, the central effects of acute exposure to DU were studied in relation to health parameters and the sleep-wake cycle of adult rats. Animals were injected intraperitoneally with 144 ± 10 μg DU kg-1 as nitrate. Three days after injection, the amounts of uranium in the kidneys represented 2.6 μg of DU g-1 of tissue, considered as a sub-nephrotoxic dosage. The central effect of uranium could be seen through a decrease in food intake as early as the first day after exposure and shorter paradoxical sleep 3 days after acute DU exposure (-18% of controls). With a lower dosage of DU (70 ± 8 μg DU kg -1), no significant effect was observed on the sleep-wake cycle. The present study intends to illustrate the fact that the brain is a target organ, as are the kidneys, after acute exposure to a moderate dosage of DU. The mechanisms by which uranium causes these early neurophysiological perturbations shall be discussed. © 2005 Elsevier Ireland Ltd. All rights reserved

Comparison of the effects of enriched uranium and 137-cesium on the behaviour of rats after chronic exposure

Purpose: A radionuclide that accumulates in the central nervous system is likely to exert both a chemical and a radiological effect. The present study aimed at assessing the behavioral effect of two radionuclides previously shown to accumulate in the central nervous system after chronic exposure - uranium and cesium. Materials and methods: Rats were exposed for 9 months to drinking water contaminated with either enriched uranium at a dosage of 40 mg U·l-1 or 137-cesium at a dosage of 6500 Bq·l-1, which correspond to the highest concentrations measured in some wells in the south of Finland (uranium) or in the milk in Belarus in the year following the Chernobyl accident (137-cesium). Results: At this level of exposure, 137-cesium had no effect on the locomotor activity measured in an open-field, on immobility time in a forced swimming test, on spontaneous alternation in a Y-maze and on novel object exploration in an object recognition test. Enriched uranium exposure specifically reduced the spontaneous alternation measured in the Y-maze after 3 and 9 months exposure although it did not affect the other parameters. Conclusion: Enriched uranium exposure altered the spatial working memory capacities and this effect was correlated with previously described accumulation of uranium in the hippocampus which is one of the cerebral areas involved in this memory system. © 2007 Informa UK Ltd

Bioaccumulation and behavioural effects of depleted uranium in rats exposed to repeated inhalations

Depleted uranium has numerous industrial and military uses. Contamination by inhalation of airborne compounds is probably the most important route of exposure. In humans, there are no data clearly demonstrating neurotoxicity of uranium, yet some experimental studies suggest a link between neurological toxicity and uranium exposure. In this work, the bioaccumulation of uranium in male rats after exposure to repeated depleted uranium dioxide inhalation (30 min inhalation at 197 mg m-3, 4 days a week for 3 weeks) has been studied, together with the behavioural effects. The uranium concentrations in the brain 1 day after the end of the exposure period varied as follows: olfactory bulb > hippocampus > frontal cortex > cerebellum, subsequently decreasing rapidly. The spontaneous locomotion activity of exposed rats was increased 1 day post exposure and the spatial working memory was less efficient 6 days post exposure, compared with control rats. These data suggest that depleted uranium is able to enter the brain after exposure to repeated inhalation, producing behavioural changes. © 2005 Elsevier Ireland Ltd. All rights reserved