Cellular crosstalk in environmental neurotoxicology : unraveling the inflammatory mechanisms along the lung-brain axis.

Amidst rapid urbanization, ambient air pollution emerges as a complex environmental threat, encompassing a diverse group of compounds-- classified as "criteria pollutants". Among the designated criteria pollutants, fine particulate matter, and airborne heavy metals, have the potential to trigger systemic inflammatory responses. The lung, continuously exposed to environmental contaminants and intricately connected to the brain's extensive neural network, positions the lung-brain axis as a pivotal focal point for assessing human health. The lung-brain axis is characterized by bidirectional communication between the respiratory and nervous systems. This integrated system offers insights into the intricate mechanisms that govern the physiological responses to environmental pollutants and the implications for neurological health. Operating through three distinct modes of communication—neural, humoral, and cellular—the lung-brain axis is fundamentally driven by the immune system. To unravel the dynamic processes of the lung-brain axis, the primary pathways investigated were neuroinflammation, oxidative stress, and microglia activation. The work in this dissertation focuses on understanding cellular crosstalk along the lung-brain axis after pulmonary exposure to chemicals, with an emphasis on cytokine signaling. In this study, the interconnected mechanism by which the lung and brain communicate were identified, this was via 1. vagal nerve transmission, 2. cytokine mediation, 3. neuroendocrine signaling, and 4. microbial metabolite diffusion. The key discovery from this review indicated that immune signaling, triggered by the inhalation of environmental irritants, served as the driving force behind these modes of communication. To contextualize immune signaling in the environmental etiology of neurodegeneration, a cellular model for Parkinson's disease was employed to compare genetic and idiopathic (metal-induced) Parkinson's. The findings of this investigation established that dopamine, oxidative stress, and DNA damage were the key determinants of metal-induced neurodegeneration. We developed a novel, high-throughput in vitro model to assess microglia activation after pulmonary exposure via cytokine diffusion. This determined that cytokine signaling is more potent and specific in inducing neuroinflammation. Finally, the biomarkers identified in metal-induced neurodegeneration were applied to assess the impact of neuroinflammation on degenerative pathogenesis, using a neuro-glia co-culture model. This study employed various bioanalytical techniques and toxicological principles in cellular communication and simulated environmental exposure to showcase, in an in vitro model, the contributory role of immune signaling in the pathogenesis linked to the environmental origins of neurodegeneration.