Natural uranium is an ubiquitous element present in the environment and human exposure to low levels of uranium is unavoidable. Although the main target of acute uranium toxicity is the kidney, some concerns have been recently raised about neurological effects of chronic exposure to low levels of uranium. Only very few studies have addressed the molecular mechanisms of uranium neurotoxicity, indicating that the cholinergic and dopaminergic systems could be altered. The main objective of this study was to investigate the mechanisms of natural uranium toxicity, after 7-day continuous exposure, on terminally differentiated human SH-SY5Y cells exhibiting a dopaminergic phenotype. Cell viability was first assessed showing that uranium cytotoxicity only occurred at high exposure concentrations (> 125 μM), far from the expected values for uranium in the blood even after occupational exposure. SH-SY5Y differentiated cells were then continuously exposed to 1, 10, 125 or 250 μM of natural uranium for 7 days and uranium quantitative subcellular distribution was investigated by means of micro-PIXE (Particle Induced X-ray Emission). The subcellular element imaging revealed that uranium was located in defined perinuclear regions of the cytoplasm, suggesting its accumulation in organelles. Uranium was not detected in the nucleus of the differentiated cells. Quantitative analysis evidenced a very low intracellular uranium content at non-cytotoxic levels of exposure (1 and 10 μM). At higher levels of exposure (125 and 250 μM), when cytotoxic effects begin, a larger and disproportional intracellular accumulation of uranium was observed. Finally the expression of dopamine-related genes was quantified using real time qRT-PCR. The expression of monoamine oxidase B (MAO-B) gene was statistically significantly decreased after exposure to uranium while other dopamine-related genes were not modified. The down regulation of MAO-B was confirmed at the protein level. This original result suggests that the inhibition of dopamine catabolism, but also of other MAO-B substrates, could constitute selective effects of uranium neurotoxicity.

天然铀是环境中普遍存在的元素，人类不可避免地暴露于低水平的铀。尽管急性铀中毒的主要靶标是肾脏，但最近有人对长期暴露于低浓度铀中的神经系统影响提出了一些担忧。只有很少的研究探讨了铀神经毒性的分子机制，这表明胆碱能和多巴胺能系统可能会发生改变。这项研究的主要目的是研究连续暴露7天后天然铀对表现出多巴胺能表型的终分化人类SH-SY5Y细胞的毒性作用机理。首先评估了细胞活力，表明铀的细胞毒性仅在高暴露浓度（> 125μM）下发生，即使在职业接触后，血液中铀的期望值也远没有达到预期值。然后，将SH-SY5Y分化的细胞连续暴露于1、10、125或250μM天然铀中7天，并通过micro-PIXE（颗粒诱导X射线发射）研究铀定量亚细胞分布。亚细胞元素成像显示铀位于细胞质的特定核周区域中，表明铀在细胞器中积累。在分化的细胞核中未检测到铀。定量分析表明，在无细胞毒性暴露水平（1和10μM）下，细胞内铀含量非常低。在较高的暴露水平（125和250μM）下，当开始产生细胞毒性作用时，观察到更大且不成比例的铀细胞内积累。最后，使用实时qRT-PCR定量多巴胺相关基因的表达。单胺氧化酶B（暴露于铀后，MAO-B）基因在统计学上显着降低，而其他多巴胺相关基因未修饰。在蛋白质水平上证实了MAO-B的下调。该原始结果表明，多巴胺分解代谢的抑制作用以及其他MAO-B底物的抑制作用可能构成铀神经毒性的选择性作用。