In situ quantification of diverse titanium dioxide nanoparticles unveils selective endoplasmic reticulum stress-dependent toxicity

Abstract

Although titanium dioxide nanoparticles (TiO₂ NPs) have been extensively studied, their possible impact on health due to their specific properties supported by their size and geometry, remains to be fully characterized to support risk assessment. To further document NPs biological effects, we investigated the impact of TiO₂ NPs morphology on biological outcomes. To this end, TiO₂ NPs were synthesized as nanoneedles (NNs), titanate scrolled nanosheets (TNs), gel-sol-based isotropic nanoparticles (INPs) and tested for perturbation of cellular homeostasis (cellular ion content, cell proliferation, stress pathways) in three cell types and compared to the P25. We showed that TiO₂ NPs were internalized at various degrees and their toxicity depended on both titanium content and NPs shape, which impacted on intracellular calcium homeostasis thereby leading to endoplasmic reticulum stress. Finally, we showed that a minimal intracellular content of TiO₂ NPs was mandatory to induce toxicity enlightening once more the crucial notion of internalized dose threshold beside the well-recognized dose of exposure.

Keywords:

• Titanium dioxide nanoparticles
• morphology-dependant toxicology
• ER stress
• calcium homeostasis
• in situ quantification

Acknowledgements

This research was undertaken on the high-resolution microbeam line at the AIFIRA facility (“Applications Interdisciplinaires des Faisceaux d’Ions en Région Aquitaine”). We also wish to thank the technical staff members of the AIFIRA facility (Ph. Alfaurt, S. Sorieul), the Bordeaux Imaging Center (TEM facility, E. Gontier and M. Petrel). The Région Aquitaine supported financially the AIFIRA facility and the technical development of the microbeam line. The authors acknowledge the Evonik (Degussa) Company (Düsseldorf, Germany) for their generous gift (P25 TiO₂ NPs). This work has been partly supported by the European Community as an Integrating Activity “Support of Public and Industrial Research Using Ion Beam Technology” (SPIRIT) under the EC contract n° 227012 and as an “Integrating Activity Supporting Postgraduate Research with Internships in Industry and Training Excellence” (SPRITE) under EC contract no. 317169. The CNRS, the French National Research Agency (ANR CES2010, n° CESA 009 01, TITANIUMS) and the Région Aquitaine (TOX-NANO n° 20111201003/POPRA n° 14006636-034) support the research program and the funding of QLT, GS, GM, MS.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work has been partly supported by the European Commission as an Integrating Activity “Support of Public and Industrial Research Using Ion Beam Technology” (SPIRIT) under the EC contract n° 227012 and as an “Integrating Activity Supporting Postgraduate Research with Internships in Industry and Training Excellence” (SPRITE) under EC contract no. 317169. The CNRS, the Agence Nationale de la Recherche (ANR CES2010, n° CESA 009 01, TITANIUMS) and the SGAR, Etat en Région Aquitaine (TOX-NANO n° 20111201003/POPRA n° 14006636-034) support the research program and the funding of QLT, GS, GM, MS.