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 (CeO 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 CeO NPs with varying amounts of Zr-doping (0%, 27% or 78% Zr), or clean air, over a four-week period (4 mg/m for 3 h/day, 5 days/week). Effects were assessed four weeks post-exposure. In all three mouse models CeO 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 CeO 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 CeO NPs. These findings show that subacute inhalation of CeO NPs causes minimal pulmonary and cardiovascular effect four weeks post-exposure and that Zr-doping of CeO 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.

Evaluation of neurological effects of cerium dioxide nanoparticles doped with different amounts of zirconium following inhalation exposure in mouse models of Alzheimer's and vascular disease

“…Detailed characteristics of NPs and their particle size distributions, mass and number exposure concentrations as well as lung deposited dose estimations for the inhalations are described in detail elsewhere ( Dekkers et al 2017 , 2018 ). Briefly, the different CeO 2 particles had a primary particle size of 4.7 ± 1.4 nm.…”

“…Female ApoE -/- mice (n = 32) were obtained from Taconic, Denmark at age 10–12 weeks at the beginning of the study. The four-week inhalation exposure protocol in the ApoE -/- mice was integrated into an 8-week high-fat (Western diet) feeding regime (Purified Diet Western 4021.06, ABdiets, Woerden, The Netherlands), which has been shown to generate complex atherosclerotic plaques with many of the hallmarks of the human disease in specific arterial locations ( Cassee et al 2012 ; Miller et al 2013 ; Dekkers et al 2017 ). All mice were barrier maintained and housed in a single room in macrolon cages.…”

“…Production and detailed characterization of CeO 2 NPs doped with different amounts of ZrO 2 (ZrO 2 contents in the doped NPs were 0 mol%, 27 mol% and 78 mol%) is described elsewhere ( Dekkers et al 2017 ). Approximately one week before the four-week exposure period, 20 samples of each NP (one for each day) were prepared at a concentration of 1 mg/mL from the stock dispersions (20, 20 or 29 mg/mL for 0%, 27% and 78% ZrO 2 -doped CeO 2 NPs, respectively) by diluting with ultrapure water.…”

“…Before use, stock and sample dispersions were sonicated for 5 min in an ultrasonic bath (Branson CPX2800, 40 kHz, 110W) before use to re-disperse any possible agglomerates. Aerosols of NPs were freshly generated using a spray nozzle technique, diluted with pressurized, clean and particle-free air, and heated to 24–25 °C (for detailed description see ( Dekkers et al 2017 ). Control animals were exposed to 3-h filtered air under the same exposure conditions (i.e.…”

“…The aim of the current study was to evaluate the potential neurotoxic and neurodegenerative effects of CeO 2 NPs in mice following a four-week inhalation exposure and to assess the influence of redox activity by the concurrent evaluation of CeO 2 NPs with different Zr-doping grades. The investigations formed part of a large study conducted in to explore the (patho)physiological effects of NP exposure on multiple organ systems in various mouse models ( Dekkers et al 2017 , 2018 ).…”