Abstract
Changing the various properties of nanomaterials can result in amazing functionalities. However, it is often unknown how such changes may affect the ability of nanomaterials to cause adverse human health effects. The aim of the research described in this thesis is to investigate how several physicochemical properties of nanoparticles (NPs)
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influence their biodistribution, molecular pathways and toxicity after inhalation. The investigated physicochemical properties include redox activity (using zirconium(Zr)-doping of cerium dioxide (CeO2) and iron(Fe)-doping of cobalt oxide (Co3O4) NPs), dissolution (using silver (Ag) and zinc oxice (ZnO) NPs), chemical composition and particle size. The following aspects were investigated: in vivo lung deposition, biodistribution and inflammation, in vitro multi-omics responses in alveolar epithelial cells, in vivo adjuvant activity, in vitro inflammasome activation and in vitro dendritic cell maturation.
The influence of the redox activity (the tendency to acquire or lose electrons) of Zr-doping of CeO2 NPs and Fe-doping of Co3O4 NPs on the investigated biological responses was very limited and did not follow a consequent trend of either an increase or a decrease with increasing redox activity. However, the influence of the redox activity on the various biological responses was difficult to evaluate, because the redox activity of NPs may change over time due to the interaction of the NPs with their surrounding environment within the various toxicity assays.
The results of the in vitro and in vivo assays described in the this thesis indicate that other properties of the tested NPs, including particle size, dissolution and chemical composition, are more important determinants of the investigated biological responses than redox activity. Comparison of the results of our inhalation study with other inhalation studies suggested that species, particle size and other properties of the NPs are more important determinants of the inflammatory responses observed after inhalation of CeO2 NPs than redox activity. Furthermore, chemical composition and dissolution were more important drivers of the molecular responses observed in A549 cells than redox activity as indicated by the results of our in vitro multi-omics study. Finally, the results of the in vivo study on the adjuvant activity and the in vitro studies on inflammasome activation and dendritic cell maturation indicated that chemical composition has more influence on the type of immune responses than redox activity.
Also the particle size, dissolution and chemical composition of the NPs may change over time depending on their surrounding environment. Although it is not always possible to measure these changes in NP properties throughout the whole toxicity assay, it is important to know which properties may change throughout each assay and how this may influence the outcome of the assay. The research presented in this thesis provides more insight how some physicochemical properties and environmental conditions may influence various biological responses after exposure to NPs in the lung. The challenge for future research is to fill the remaining knowledge gaps on how the various physicochemical properties, environmental conditions and underlying mechanistic pathways are connected to each other.
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