RESUMO
It has been suggested that uranium uptake and toxicity could be mediated by endocytosis and/or the type IIa sodium-dependent phosphate cotransporter (NaPi-IIa). The aim of this study was therefore to characterize in vitro the role of these two cellular mechanisms in the uptake and toxicity of low (200-3200 nM) and high (0.5 and 0.8 mM) concentrations of uranium, respectively. At low concentrations, uranium uptake in LLC-PK(1) cells was saturable (V(max) = 3.09 +/- 0.22 ng/mg protein) and characterized by a K(0.5) of 1022 +/- 63 nM and a Hill coefficient of 3.0 +/- 0.4. The potential involvement of endocytosis and NaPi-IIa in the uptake of uranium was assessed by the use of various drugs and culture conditions known to alter their relative activity, and (233)uranium uptake was monitored. Interestingly, the inhibitory effect of colchicine, cytochalasin D, phorbol 12-myristate 13-acetate, and chlorpromazine on endocytosis was highly correlated with their effect on uranium uptake, a relationship that was not true when the NaPi-IIa transport system was studied. Whereas the competitive inhibition of the NaPi-IIa by phosphonoformic acid (PFA) significantly decreased uranium uptake, this effect was not reproduced when NaPi-IIa inhibition was mediated by the replacement of extracellular Na(+) with N-methyl-D-glucamine. Uranium uptake was also not significantly altered when NaPi-IIa expression was stimulated in MDCK cells. More surprisingly, we observed by transmission electron microscopy that uranium cytotoxicity was dependent upon the extent of its intracellular precipitation, but not on its intracellular content, and was suppressed by PFA. In conclusion, our results suggest that low-dose uranium uptake is mainly mediated by absorptive endocytosis, and we propose PFA as a potential uranium chelator.
Assuntos
Endocitose , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/fisiologia , Nitrato de Uranil , Animais , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endocitose/efeitos dos fármacos , Foscarnet/farmacologia , Cinética , Células LLC-PK1 , Microscopia Eletrônica de Transmissão , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/antagonistas & inibidores , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/metabolismo , Suínos , Nitrato de Uranil/metabolismo , Nitrato de Uranil/toxicidadeRESUMO
Recent reports suggest that uranium can accumulate not only in known target organs, that is, kidneys or bones, but also in others such as central nervous system. In the present work, the accumulation of uranium in the brain of rats was studied after repeated exposure by inhalation, chronic exposure by ingestion and acute exposure by injection. For each route of administration, the amount of uranium entering the brain was low. The results showed different accumulation in the brain areas according to the route of intake. Injection gave a rather homogeneous distribution in the different brain areas, whereas both inhalation and ingestion yielded heterogeneous but specific accumulation. These differences in distribution suggest the operation of different mechanisms of delivery of uranium to the brain tissues.
Assuntos
Encéfalo/metabolismo , Radiometria/métodos , Urânio/farmacocinética , Animais , Masculino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Doses de Radiação , Ratos , Ratos Sprague-Dawley , Eficiência Biológica Relativa , Urânio/análiseRESUMO
Since the Chernobyl accident, the most significant problem for the population living in the contaminated areas is chronic exposure by ingestion of radionuclides, notably (137)Cs, a radioactive isotope of cesium. It can be found in the whole body, including the central nervous system. The present study aimed to assess the effect of (137)Cs on the central nervous system and notably on open-field activity and the electroencephalographic pattern. Rats were exposed up to 90 days to drinking water contaminated with (137)Cs at a dosage of 400 Bq kg(-1), which is similar to that ingested by the population living in contaminated territories. At this level of exposure, no significant effect was observed on open-field activity. On the other hand, at 30 days exposure, (137)Cs decreased the number of episodes of wakefulness and slow wave sleep and increased the mean duration of these stages. At 90 days exposure, the power of 0.5-4 Hz band of (137)Cs-exposed rats was increased in comparison with controls. These electrophysiological changes may be due to a regional (137)Cs accumulation in the brain stem. In conclusion, the neurocognitive effects of (137)Cs need further evaluation and central disorders of population living in contaminated territories must be considered.
Assuntos
Radioisótopos de Césio/toxicidade , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Acidente Nuclear de Chernobyl , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sono REM/efeitos dos fármacosRESUMO
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 mgm(-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.
Assuntos
Comportamento Animal/efeitos da radiação , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Transtornos Mentais/etiologia , Lesões por Radiação/etiologia , Urânio/efeitos adversos , Urânio/farmacocinética , Administração por Inalação , Poluentes Radioativos do Ar/efeitos adversos , Poluentes Radioativos do Ar/farmacocinética , Animais , Carga Corporal (Radioterapia) , Cinética , Masculino , Transtornos da Memória/etiologia , Taxa de Depuração Metabólica , Especificidade de Órgãos , Doses de Radiação , Lesões por Radiação/metabolismo , Radiometria , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Urânio/administração & dosagemRESUMO
Uranium is a heavy metal known to induce toxicity in kidneys. It is also known to enter the central nervous system, thus inducing neurophysiological effects, after exposure to relatively high concentrations. The effect of chronic uranium exposure (40 mg l(-1) in drinking water, for 90 days) on electroencephalographic architecture has been studied on freely moving rats using a telemetry technique. The main effects of uranium on the sleep-wake cycle were an increase in rapid eye movement sleep (REM-sleep) and theta band power during the light period, as early as Day 30 after exposure commenced. The most probable explanation for these effects is that uranium directly affects the brain. This increase in REM-sleep was previously described in human depression or models of chronically stressed rats and it may be assimilated with some protective or compensatory mechanisms.
Assuntos
Sono/efeitos dos fármacos , Compostos de Urânio/farmacologia , Animais , Química Encefálica , Eletroencefalografia/efeitos dos fármacos , Rim/química , Masculino , Ratos , Ratos Sprague-Dawley , Sono REM/efeitos dos fármacos , Compostos de Urânio/análiseRESUMO
Uranium is well known to induce chemical toxicity in kidneys, but several other target organs, such as central nervous system, could be also affected. Thus in the present study, the effects on sleep-wake cycle and behavior were studied after chronic oral exposure to enriched or depleted uranium. Rats exposed to 4% enriched uranium for 1.5 months through drinking water, accumulated twice as much uranium in some key areas such as the hippocampus, hypothalamus and adrenals than did control rats. This accumulation was correlated with an increase of about 38% of the amount of paradoxical sleep, a reduction of their spatial working memory capacities and an increase in their anxiety. Exposure to depleted uranium for 1.5 months did not induce these effects, suggesting that the radiological activity induces the primary events of these effects of uranium.