1150. Nanoparticulate Matter Produces White Matter Damage through Oxidative Stress and Mitochondrial Damage

Authors: Krista Lamorie-Foote; Michelle Connor; Kristina Shkirkova; Arati Patel; Qinghai Liu; Todd Morgan; Constantinos Sioutas; Caleb Finch; William Mack (Calabasas, CA)

Introduction: Exposure to particulate matter (PM), a neurotoxic component of traffic related air pollution, results in white matter ischemic injury and neurocognitive deficits. PM is a potent source of oxidative stress, which may contribute significantly to the PM-generated white matter injury. The aim of the present study is to quantify markers of oxidative stress and mitochondrial dysfunction following particulate matter exposure in a murine model. Methods: Nanoscale particulate matter (nPM, <200nm) collected from near an urban Los Angeles freeway was transferred to an aqueous suspension, and reaeorsolized for exposure. Mice were exposed to filtered air (n=15) or nPM (n=18) for five hours/day, three-days/week for 10 weeks (150 total exposure hours). Following exposure, mice were sacrificed. Immunohistochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress, was performed in the corpus callosum and cerebral cortex. Nitric Oxide (NO) concentration was assessed through nitrate quantification. Following whole brain mitochondrial isolation, JC-1 and Cytochrome C assays were performed to assess mitochondrial inner and outer membrane integrity, respectively. Results: 8-OHdG integrated density was significantly increased in the corpus callosum (p<0.01) and cortex (p<0.05) of nPM mice when compared to filtered air controls. Nitrate concentrations (µM) were increased in nPM mice when compared to filtered air controls, (p<0.05). Inner mitochondrial membrane integrity, assessed with the JC-1 590/530 fluorescence ratio, decreased (p<0.01) following nPM exposure, suggesting mitochondrial injury. The percent of mitochondria with damaged outer membranes was increased in nPM-exposed mice (p<0.01). Conclusion: Nanoparticulate matter exposure increases reactive oxygen and nitrogen species in the brain and damages mitochondrial inner and outer membranes. Increased oxidative stress and mitochondrial dysfunction may contribute to air pollution-mediated neurotoxicity.