Air pollution, nanotoxicity and neurodegeneration; exploring the relationship between environmental metallic nanoparticles and human health

Hammond, Jessica and Allsop, David and Parkin, Edward (2023) Air pollution, nanotoxicity and neurodegeneration; exploring the relationship between environmental metallic nanoparticles and human health. PhD thesis, Lancaster University.

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Abstract

Air pollution and Alzheimer’s disease (AD) are two of the largest global health issues faced by society today; air pollution is a recognised risk factor for AD. Particulate matter (PM) is a major component of air pollution and refers to the solid and liquid particulates of varying sizes and compositions that are resuspended in the air. Of these particles, metallic particles in the nanometre range (ultrafine, UFPs; < 0.1 µm) are particularly hazardous due to their pervasiveness, ability to penetrate all major organs in the human body, and ability to generate both inflammatory and oxidative stress responses in humans. Magnetite (Fe3O4) nanoparticles (MNPs) and related iron oxides may be of relevance to neurodegeneration. MNPs are found within PM, typically in association with toxic metals, and have been found throughout the human brain, including in association with senile plaques (a key pathological hallmark of AD). MNPs have also been shown to accelerate amyloid beta (Aβ) toxicity and aggregation. MNPs have previously been quantified in a handful of studies to compare AD and control tissue, with mixed results. Improved understanding of the development of AD, the toxic effects of air pollution (especially magnetite and metals), and the relationship between these two phenomena would be highly beneficial to global health. In order to explore the potential causal link between air pollution and AD, two approaches were taken; metallic and magnetic quantification of post-mortem human brain tissue via superconducting quantum interference device (SQUID) magnetometry and inductively couple plasma mass spectrometry (ICP-MS), and exploration of the cytotoxic effects of ultrafine roadside dust particles (UF-RDPs) on human lung epithelial cells (Calu-3) using different in vitro assays. The concentration of magnetite (measured as magnetic remanence, SIRM) in human brain tissue was not statistically different when comparing AD cases to aged-matched controls. Similarly, there were no differences in metal content between the two groups. Principal component analysis grouped the metals into four components, which are potentially indicators of pollution sources: (1) traffic-related and crustal, (2) fuel oil combustion, (3) biological and tyre/brake wear, and (4) catalytic converters and dental alloys. The distributions of magnetite and metals were heterogenous across different individuals. Significantly lower concentrations of both MNPs and metals were reported in UK samples, compared topreviously reported Mexico City samples. Differences were also seen when comparing the in vitro response to UF-RDPs from three contrasting cities; Lancaster UF-RDPs increased cell viability, whilst Mexico City UF-RDPs were the most toxic and induced the highest amount of oxidative stress (ROS production), and Birmingham UF-RDPs were the most pro-inflammatory. These responses are not fully reflected in conventional mass metrics like PM10, as although the greatest cytotoxicity and ROS production was seen with Mexico City UF-RDPs (highest PM10 exposure), the strongest pro-inflammatory responses were seen in response to Birmingham UF-RDPs and a potentially tumorigenic or fibrosis related increase in cell viability was seen in response to Lancaster UF-RDPs despite the lower PM10 and PM2.5 exposures in the UK cities. There is a need for localised air pollution limits which use biologically relevant metrics that address particle size and cover non-exhaust emission sources of PM like road dust to minimize the health risks of air pollution exposure. Overall, this work demonstrates the presence of exogenous, pollution-derived metals and magnetic nanoparticles within the human brain. Highly reactive and toxic metals and MNPs may exert toxic effects in the brain and have been causally linked to neurodegeneration and AD. The geriatric blood-brain barrier is likely compromised allowing for universal incursion in both AD and age-matched controls, so the use of younger highly exposed individuals such as Mexico City urbanites is critical to identify any changes in metal/magnetic content in the brain decades prior to the presentation of AD. Clear differences were seen across geographical locations when looking at absolute concentrations of MNPs, as well as the composition and induced biological effects of UF-RDPs from different cities. It is thus important to focus on highly localised air pollution regulations to mitigate risk to human health.