Particle Translocation as a Mechanism of Toxicity of Inhaled Particulates in the Central Nervous System

Saturday, 15 February 2014
Crystal Ballroom A (Hyatt Regency Chicago)
Alison Elder , University of Rochester , Rochester, NY
The consistent findings that particulate matter exposure is causally associated with the adverse cardiopulmonary health effects of ambient air pollution have prompted a number of mechanistic explanations, including the generation of inflammatory mediators by lung tissue that then travel to other organ systems, the activation of autonomic nervous system responses, and the delivery of respiratory tract-deposited material to other tissues via solid particle (translocation) or solute transport.  The deposition of inhaled particles is dependent upon size, but nanoscale particles (<100 nm in diameter, also ultrafine particles) deposit with high efficiency in all regions of the respiratory tract.  Studies with very poorly-soluble nanoscale particles demonstrated translocation to distal tissues (e.g., liver, brain) and a dependence on particle size, with smaller particles accumulating to a greater extent, albeit at a small fraction of applied dose. It was hypothesized that brain accumulation could be explained by solid particle transported via the olfactory nerve.  A reasonable question, though, is whether or not there are adverse consequences of such accumulation, such as local inflammation or the induction or exacerbation of neurodegenerative processes.  Using poorly-soluble nanoscale Mn oxide particles, it was found that markers of oxidative stress and inflammatory cell activation (tumor necrosis factor (TNF)-a) were elevated in the same regions of the brain where Mn accumulated following whole-body inhalation exposure in rats (olfactory bulb, frontal cortex, striatum).  Using a mouse model of Alzheimer’s disease (AD), it was also demonstrated that exposure led to an increased expression of microglial and astrocyte activation markers in the hippocampus and that effects persisted for two months post-exposure.  In addition, there were marked elevations in amyloid b-42 protein and decreases in synaptophysin staining.  Similar studies were done using concentrated ambient ultrafine particles.  These studies showed that TNF gene expression was elevated in brain in response to inhaled ambient ultrafine particles and that such elevation was more pronounced in the transgenic AD mice as compared to non-transgenic mice.  Furthermore, when TNF receptor bioactivity was blocked, microglial activation was dampened.  Taken collectively, the findings from these studies suggest that inhaled particles can be transported to the central nervous system and that they can elicit tissue responses that could contribute to the progression of pathology in those regions where accumulation occurs.  Given the growing literature that links ambient air pollution to oxidative stress, inflammation, neuronal loss, and behavioral and cognitive changes, it is critical to gain a better understanding of the mechanisms by which the changes occur, the specific components of pollutant mixtures that contribute to response, and strategies to mitigate adverse outcomes.