Sapienza, Silvia (2024) Neurotoxic effect of ultrafine carbonaceus components of air pollution in the central nervous system: UFPs putative mechanisms in neurodegenerative diseases. [Tesi di dottorato]

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Abstract

Ninety-nine percent of the global population has been estimated to be exposed to polluted air and indeed, air pollution is believed to be by many researchers one of the greatest scourges of our era, for its inevitable impact on our world. Besides having an active role in affecting the environment and ecosystem, it affects our society and most importantly, our health and life- expectancy. Among all air pollutants, particulate matter (PM) is a heterogeneous class consisting of particles of different sizes, which has the infamous highest burden of disease globally. The small size of these particles makes them especially harmful and, in fact, smaller particles are associated to greater adverse health outcomes than larger ones. In particular, the smallest fraction of PM, ultrafine particulate matter (UFP), has been shown to be able to penetrate virtually all human barriers: the skin, the alveolar-capillary, placental and blood brain barrier. Not surprisingly, UFPs have been associated to different nervous system pathologies, such as amyotrophic lateral sclerosis (ALS); yet the mechanisms underlying are still mysterious and the knowledge on the effects of UFPs is lacking. Moreover, current world regulations do not include UFPs, as data are not sufficient to provide recommendations, but only good practice statements. Despite this, UFPs represent the dominant fraction of aerosols dispersed into the air and human exposure to it will increase drastically in the next decades. Therefore, the main purpose of the present doctoral study was to evaluate the toxicity driven by the finest fraction of particulate matter in in vitro and in vivo models. More precisely, this doctoral study focused, in vitro, on finding the cellular mechanisms through which UFPs exert their detrimental effects on the nervous tissue, specifically on motor neurons. Secondly, it aimed at establishing such mechanisms as pathological pathways shared with the neurodegenerative disease ALS - a motor neuronal disease in which the role of environmental etiology has been extensively addressed. Whilst in vivo, the aim was to explore the toxicity of UFPs in a more complex organism. To this scope, UFPs were produced in a lab-scale manner, to yield nanoparticles having high similarities in size and microscopic structures with particles emitted by diesel exhaust combustion (PM0.1 < 100 nm and NP20 < 20 nm); thus providing a model for anthropogenic diesel exhaust emissions. Taken together, results show that the ultrafine fraction of PM, namely PM0.1 and NP20, exerts neurotoxicity through several mechanisms targeting different cellular components and compartments, such as the plasma membrane, mitochondria, lysosomes and ER: in all cases, UFPs were able to impair organelles functionality and eventually to have a detrimental effect on cellular homeostasis. Furthermore, the present study indicated that UFP- driven toxicity shares several pathomechanisms with neurodegenerative diseases, in particular with ALS. PM0.1 and NP20 were also able to yield toxic effects on the reproduction, growth and lifespan of more complex organisms. Lastly, this doctoral research provided evidence for smaller sub-fractions of PM (i.e. NP20) being more toxic than larger UFPs (i.e. PM0.1).

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