World Trade Center Dust Derived Oxidative Stress at the Nasal-Neural Interface

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 DESCRIPTION (provided by applicant): Currently, there is an overall lack of scientific data with regard to effects of particulate matter (PM), more specifically World Trade Center (WTC) dust exposure, and its neuro-inflammatory potential. PM has been found to translocate across membrane barriers (air-blood, blood-brain), allowing for direct interaction with the brain and central nervous system. Due to the unique exposure scenario in which mouth breathing was prevalent, first responders were exposed to extremely high concentration of supercoarse alkaline corrosive PM (>20µm; pH 9.2-11.5). By this very nature, WTC particles may have a significant impact on the olfactory neurons of the olfactory bulb, eliciting injury to the oropharyngeal cavity, and potentially making subjects more vulnerable to subsequent PM exposure and more susceptible to develop neurological disorders. The goal of this study is to assess any potential inflammatory effects at the nasal-neural interface from intra-nasally administered WTC PM, collected near ground zero in Manhattan, New York 2 days after the WTC collapse event. In this study, we propose the use of C57Bl/6 and ApoE-/- mouse models to aid in identifying oxidative stress outcomes as well nasal epithelial integrity via inflammatory responses at the nasal-neural interface, as well as in neural tissues. We hypothesize that inflammation induced via intra-nasally administered WTC PM will lead to reactive oxygen species formation (ROS), potentially inciting a proinflammatory cascade linked to neuronal death in ApoE-/- models. These potential outcomes will be assessed by comparing inflammatory markers of oxidative stress and gene expression in both strains. Usage of ApoE-/- mice will aid in understanding mechanisms involved in microglial modulation and potential dopaminergic neurotoxicity. In doing so, WTC PM may elicit microglial activation, thus leading to the production of various pro-inflammatory markers such as TNFa, IL-1ß, IL-6, and the formation of reactive oxygen species (ROS) as seen previously with other PM exposure studies. Mechanistic cascades such as these have been evidenced in neuronal death in ApoE-/- mice. Intracellular oxidative stress induced by PM exposure has been systemically and neurologically linked to adverse health outcomes, including changes in histopathology, DNA damage, and resultant neurological disorders. More importantly, this system, as well as biological cascades within the system, could also be highly exploited and augmented in combination with other exposures resulting in co-exposure scenarios, thus further potentiating environmentally induced injuries brought about by repetitive insult from ambient pollutants. Following epithelial injury as well as barrier breaching due to subsequent cycles of PM exposure and insults, subjects then have the potential to become more vulnerable or predisposed to neurological disorders.