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Uranium exposure of human dopaminergic cells results in low cytotoxicity, accumulation within sub‐cytoplasmic regions, and down regulation of MAO‐B

A. Carmona,V. Malard,Emilie Avazeri,Stéphane Roudeau,F. Porcaro,E. Paredes,C. Vidaud,C. Bresson,R. Ortega

Published 2018 in Neurotoxicology

ABSTRACT

HighlightsNatural uranium is cytotoxic towards dopaminergic cells but only at high concentrations (> 125 &mgr;M) which are not relevant for the vast majority of human exposures.Uranium is located in defined cytoplasmic regions suggesting its accumulation within organelles yet to be determined.Among the dopamine‐related genes investigated, monoamine oxidase B gene expression is decreased even at 10 &mgr;M uranium exposure, far from cytotoxicity threshold. ABSTRACT 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 &mgr;M), 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 &mgr;M 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 &mgr;M). At higher levels of exposure (125 and 250 &mgr;M), 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.

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