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Pulmonary toxicity of cobalt oxide particles : a Trojan-horse mechanism

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In case of internal contamination in nuclear power plants, the isotope most frequently found among workers is 60Co from Co oxide particles. The lung is the critical organ, most of the time after exposure by inhalation of contaminated vapors. The purpose of this study conducted in collaboration with CEA teams within the frame of the Nuclear Toxicology Program (ToxNuc) was to describe the chemical mechanisms of cobalt toxicity either in soluble form or as oxide, on human lung cells.

Cobalt oxide particles of 400 nm diameter, representative of exposures in nuclear power plants, have been studied in vitro on human lung cells. We combined micro ion beam chemical imaging (AIFIRA CENBG), confocal microscopy, flow cytometry and mass spectrometry (ICP-MS).

Ion beam micro-analytical imaging techniques allowed to show a small intracellular solubilization, of the order of a one per thousand. The particles are incorporated in human lung cells by endocytosis before being partially solubilized at acidic pH in lysosomes, releasing a small amount of cobalt ions which is eventually distributed in the cytoplasm and nucleus.

We have shown for the first time that this small fraction of solubilized intracellular cobalt is behind all of the observed toxicity effects. These results introduce a new paradigm in the field of particle toxicity of low or very low solubility: toxicity is due mainly to the toxic effects of the metal in solution due to the slow dissolution of intracellular particles (Trojan horse effect).

The methodology is applicable to the study of the mechanisms of toxicity of many other metallic or oxymetal particles.

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Figure. Micro-PIXE quantitative imaging of a human lung cell after exposure to cobalt oxide particles. (A) a large fraction of cobalt is in the cytoplasm in an insoluble form. (B) PIXE micro-analysis of the local distribution of cobalt shows that a small fraction of total cobalt (black spectrum) is detected as a diffuse solubilized form (red spectrum), especially in the nucleus (blue spectrum). In this example about 0.1 % of the intracellular cobalt was dissolved.


Low-solubility particles and a Trojan-horse type mechanism of toxicity : the case of cobalt oxide on human lung cells
Ortega R., Bresson C., Darolles C., Gautier C., Roudeau S., Perrin L., Janin M., Floriani M., Aloin V., Carmona A., Malard V. (2014), Particle & Fibre Toxicology, 11:14. [pubmed] [link]