IMPACTS OF DIETARY N-3 PUFA INTERVENTIONS IN THE PREVENTION OF AGRICULTURAL DUST-INDUCED NEUROINFLAMMATION

Abstract

Neuroinflammation is a central feature of neurodegenerative diseases, includingAlzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Chronic activation of microglia and astrocytes leads to sustained cytokine and chemokine production, oxidative stress, and blood–brain barrier (BBB) dysfunction, establishing a positive feedback loop that exacerbates neuronal injury. Peripheral immune cells also further contribute to CNS inflammation and neurodegeneration. Environmental exposures, particularly inhaled particulate matter (PM) and organic dusts common in agricultural settings, act as potent triggers of systemic and central immune activation. PM₂.₅ can reach the CNS through olfactory, hematogenous, or immune cell-mediated routes, promoting protein aggregation, oxidative stress, and glial reactivity. Organic dust has been shown to increase pro-inflammatory cytokines, microglial activation, and neuroinflammation in animal models, while interventions with omega- 3 fatty acid metabolites, such as aspirin-triggered resolvin D1 (AT-RvD1), attenuate these responses. Omega-3 and omega-6 polyunsaturated fatty acids serve as precursors to bioactive lipid mediators that regulate the balance between pro- and anti-inflammatory signaling. Dysregulation of this balance can prolong neuroinflammation, whereas omega-3–derived specialized pro-resolving mediators (SPMs) actively resolve inflammation. Understanding the iv interplay between environmental exposures, glial activation, peripheral immunity, and lipid- mediated inflammation is essential for developing therapeutic strategies that mitigate neuroinflammation and slow the progression of neurodegenerative disease. The studies presented in this dissertation demonstrate that inhaled agricultural organic dust rapidly initiates neuroinflammatory responses within the olfactory bulb and hippocampus, characterized by early microglial and astrocyte activation that precedes overt neuronal loss. Furthermore, chronic dust exposure promoted inflammatory astrocyte polarization and region-specific neurodegeneration, while endogenous enrichment of omega-3 polyunsaturated fatty acids modified glial responses, attenuated inflammatory astrocyte phenotypes, and preserved neuronal integrity. Collectively, these findings establish the central nervous system as an early target of agricultural dust exposure, support a temporal progression from neuroinflammation to neurodegeneration, and identify endogenous omega-3 fatty acids as a promising strategy for mitigating the neurological consequences of chronic occupational inhalant exposures.