In vitro and In vivo toxicity assessment of metal oxide nanomaterials

Nanomaterials (NMs) are defined as having at least one dimension in the nanoscale, which commonly ranges from 1 nm to 100 nm. Their small size and large surface area to volume ratio increase the activity of the materials and results in them possessing novel properties; therefore, they have attracted high interest in scientific research and industry. Growth in production of NMs in the past few decades has raised concerns as to their toxicity and has led to the development of various in vivo and in vitro experimental models in order to understand their possible adverse effects and their fate inside the human body. As the most unintentional route of exposure to NMs is by inhalation, toxicity assessment of inhaled NMs was performed in this dissertation.

The first section of this dissertation provided the approaches to screen the toxicity of nine inhaled metal oxide NMs and showed that copper oxide (CuO) NMs and zinc oxide (ZnO) NMs possessed the highest toxicity. CuO NMs were the candidate for the study of pulmonary inflammation changes over time during and after inhalation exposure as well as distribution of CuO NMs from lung into other organs. We found that inhaled CuO NMs were mainly located in the lung tissue and could be found in the blood and heart, indicating that inhaled CuO NMs can travel to these sites. Two organs, the kidneys and spleen, elicited noticeable changes in organ weight and the balance of trace elements, which indicate potential adverse effects of CuO NMs on these organs.

The following section was to establish a house dust mite (HDM)-induced lung inflammation model and develop a vaccine protecting against HDM-induced lung inflammation and then to use them as a tool to study the effects on the immune response of inhaled CuO NMs. The model of HDM-induced lung inflammation was successfully created and was used to test the efficacy of the vaccine. The vaccine did not help reduce primary outcomes that indicated lung inflammation; however, it promoted an increase in a type of antibody that could help relieve the lung inflammation. The last section was to study the immune response under different health conditions in mice, comprising healthy, asthmatic, and allergen immunotherapy (AIT)-treated asthmatic mice after inhalation exposure to CuO NMs. CuO NMs-exposed healthy mice showed increases in certain immune cell types indicating the persistence of lung inflammation 40 days after the completion of the exposure period. CuO NMs-exposed asthmatic mice showed the most noticeable changes in the balance of immune cells, especially T lymphocytes, which supported the findings that CuO NM exposure caused a trend toward reducing lung sensitivity in the asthmatic mice. CuO NM exposure did not cause major changes in the levels of immune cells in the AIT-treated asthmatic mice, but did show a trend toward lower lung sensitivity, similar to the asthmatic mouse model.

In conclusion, this dissertation addressed the potential impact of inhaled NMs on human health by screening for their toxic effects using simple techniques. The fate of inhaled CuO NMs as well as their potential adverse effects on distal organs were investigated. In addition, this research investigated the effect of inhaled CuO NMs on immune responses using mouse models representing different health paradigms.