Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells

Richard Ortega (1) , Carole Bresson (2) , Carine Darolles (3) , Celine C. Gautier (4) , Stéphane Roudeau (1) , Laura Perrin (1) , Myriam Janin (5, 6) , Magali Floriani (7) , Valérie Aloin (3) , Asuncion Carmona (1) , Veronique Malard (3)

1 CENBG - Centre d'Etudes Nucléaires de Bordeaux Gradignan
2 LSRM - Laboratoire de Spéciation des Radionucléides et des Molécules
3 LBSP - Laboratoire de Biochimie des Systèmes Perturbés
4 LASE - Laboratoire d’analyse en soutien aux exploitants
5 LANIE - Laboratoire de développement Analytique Nucléaire Isotopique et Elémentaire
6 GIS - Laboratoire de Géochimie Isotopique Environnementale (GIS) / Université de Nîmes
7 IRSN/PRP-ENV/SERIS/LECO - Laboratoire d'écotoxicologie des radionucléides

Background: The mechanisms of toxicity of metal oxide particles towards lung cells are far from being understood. In particular, the relative contribution of intracellular particulate versus solubilized fractions is rarely considered as it is very challenging to assess, especially for low-solubility particles such as cobalt oxide (Co 3 O 4). Methods: This study was possible owing to two highly sensitive, independent, analytical techniques, based on single-cell analysis, using ion beam microanalysis, and on bulk analysis of cell lysates, using mass spectrometry. Results: Our study shows that cobalt oxide particles, of very low solubility in the culture medium, are readily incorporated by BEAS-2B human lung cells through endocytosis via the clathrin-dependent pathway. They are partially solubilized at low pH within lysosomes, leading to cobalt ions release. Solubilized cobalt was detected within the cytoplasm and the nucleus. As expected from these low-solubility particles, the intracellular solubilized cobalt content is small compared with the intracellular particulate cobalt content, in the parts-per-thousand range or below. However, we were able to demonstrate that this minute fraction of intracellular solubilized cobalt is responsible for the overall toxicity. Conclusions: Cobalt oxide particles are readily internalized by pulmonary cells via the endo-lysosomal pathway and can lead, through a Trojan-horse mechanism, to intracellular release of toxic metal ions over long periods of time, involving specific toxicity.

Mots clés: Toxicity; Lung cells; Cobalt oxide; Particles; Endocytosis; Lysosome; Intracellular solubilization; PIXE; ICP-MS

Domaines: Toxicologie

Richard Ortega, Carole Bresson, Carine Darolles, Celine C. Gautier, Stéphane Roudeau, et al.. Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells. Particle and Fibre Toxicology, 2014, 11 (1), pp.14. ⟨10.1186/1743-8977-11-14⟩. ⟨hal-02899990⟩