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Accueil du site > ANGLAIS > Research > CIS - Chemical Imaging and Speciation > Research projects > Uranium neurotoxicology


Uranium neurotoxicology

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The main objective of this study was to describe the mechanisms of toxicity of natural uranium, after a continuous exposure of 7 days, on human SH-SY5Y cells presenting a dopaminergic phenotype. Cell viability was assessed for the first time on this cell type, showing that the cytotoxicity of uranium only occurred at high concentrations (> 125 μM), far above the expected values for uranium in the blood, even after occupational or accidental exposure. The SH-SY5Y differentiated cells were continuously exposed to 1, 10, 125 or 250 μM of natural uranium for 7 days and the quantitative subcellular distribution of uranium was studied using micro-PIXE imaging. Subcellular imaging revealed that uranium was located in well-defined perinuclear regions of the cytoplasm, suggesting its accumulation in organelles. Uranium was not detected in the nucleus of differentiated cells. In addition, the expression of genes linked to the dopaminergic pathway has been quantified. The expression of the monoamine oxidase B gene (MAO-B) is statistically significantly reduced after exposure to uranium while the other genes were not modified. This original finding suggests that the inhibition of dopamine catabolism, but also other MAO-B substrates, may be selective neurotoxicity effects of uranium (Carmona et al., 2018). In addition, another component of this project involved the isotopic analysis of uranium in neuronal cells. In collaboration with the CEA teams, we revealed the isotopic fractionation of uranium after cellular uptake suggesting the existence of a high-affinity transport protein for uranium (Paredes et al., 2016 and 2018).

Figure. Optical and micro-PIXE imaging of single SH-SY5Y cells after 7-day continuous exposure to 125 µM uranium. (A) Bright field optical microscopy. (B) Epifluorescence optical microscopy of Hoechst 33542 nuclear dye. (C) Nucleus position derived from the epifluorescence image (false color, for overlay). (D) Phosphorus distribution. (E) Uranium distribution. (F) Overlay image of nucleus and uranium distribution. (Carmona et al., 2018).

Collaborations

Laboratory of Protein-Metal Interactions (LIPM), Institute of Biosciences and Biotechnologies of Aix Marseille (BIAM), UMR7265 CEA – CNRS - Aix Marseille Univ, CEA Cadarache.

CEA, DRF, Biosciences and Biotechnologies Institute (BIAM), Bagnols-sur-Cèze.

Den – Service d’Etudes Analytiques et de Réactivité des Surfaces (SEARS), CEA, Université Paris-Saclay, Gif sur Yvette.

Publications

Uranium exposure of human dopaminergic cells results in low cytotoxicity, accumulation within sub-cytoplasmic regions, and down regulation of MAO-B
Carmona A., Malard V., Avazeri E., Roudeau S., Porcaro F., Paredes E., Vidaud C., Bresson C., Ortega R. (2018), NeuroToxicology, 68, 177-188. [pubmed] [link]


A new procedure for high precision isotope ratio determinations of U, Cu and Zn at nanogram levels in cultured human cells : what are the limiting factors?
Paredes E., Avazeri E., Malard V., Vidaud C., Ortega R., Nonell A., Isnard H., Chartier F., Bresson C. (2018), Talanta, 178, 894-904.[link]


Evidence of isotopic fractionation of natural uranium in cultured human cells

Paredes E., Avazeri E., Malard V., Vidaud C., Reiller P., Ortega R., Nonell A., Isnard H., Chartier F., Bresson C. (2016), Proc. Natl. Acad. Sci. USA., 113, 14007-14012. [pubmed] [link]