The effect of zirconium doping of cerium dioxide nanoparticles on pulmonary and cardiovascular toxicity and biodistribution in mice after inhalation

Abstract

Development and manufacture of nanomaterials is growing at an exponential rate, despite an incomplete understanding of how their physicochemical characteristics affect their potential toxicity. Redox activity has been suggested to be an important physicochemical property of nanomaterials to predict their biological activity. This study assessed the influence of redox activity by modification of cerium dioxide nanoparticles (CeO₂ NPs) via zirconium (Zr) doping on the biodistribution, pulmonary and cardiovascular effects in mice following inhalation. Healthy mice (C57BL/6 J), mice prone to cardiovascular disease (ApoE^−/−, western-diet fed) and a mouse model of neurological disease (5 × FAD) were exposed via nose-only inhalation to CeO₂ NPs with varying amounts of Zr-doping (0%, 27% or 78% Zr), or clean air, over a four-week period (4 mg/m³ for 3 h/day, 5 days/week). Effects were assessed four weeks post-exposure. In all three mouse models CeO₂ NP exposure had no major toxicological effects apart from some modest inflammatory histopathology in the lung, which was not related to the amount of Zr-doping. In ApoE^−/− mice CeO₂ did not change the size of atherosclerotic plaques, but there was a trend towards increased inflammatory cell content in relation to the Zr content of the CeO₂ NPs. These findings show that subacute inhalation of CeO₂ NPs causes minimal pulmonary and cardiovascular effect four weeks post-exposure and that Zr-doping of CeO₂ NPs has limited effect on these responses. Further studies with nanomaterials with a higher inherent toxicity or a broader range of redox activities are needed to fully assess the influence of redox activity on the toxicity of nanomaterials.

Keywords:

• Nanomaterials
• cerium dioxide
• redox activity
• inhalation
• cardiovascular

Acknowledgements

The authors would like to thank Paul H.B. Fokkens, Daan L.A.C. Leseman, Liset J.J. de la Fonteyne, Piet K. Beekhof, Christine M.R. Soputan, Hans J.C. Strootman, Jolanda Rigters, Ron F. Vlug, Karin M.P. van den Hurk, Julia Kolling, Geert B. van der Horst, Rory Verhagen, Dirk J. Elberts, Pieter W. Dissel and Angéla Gomersbach-de Ridder for their help during the conduction of the animal experiment and valuable technical assistance. In addition, Geert B. van de Horst is acknowledged for his contribution to the generation of the cytotoxicity in A549 cells and Joost Lensen of Will Research for the histopathology.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The work leading to these results has received funding from the European Union Seventh Framework Programme for research, technology development and demonstration under grant agreement n° 310451 (NanoMILE) and the Netherlands Food and Consumer Product Safety Authority (NVWA).