79 - Investigating the Redox Toxicology of Ambient Air Pollutants

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Ambient air pollution is a leading global cause of morbidity and mortality. Millions of Americans live in areas in which levels of tropospheric ozone exceed air quality standards, while exposure to particulate matter (PM2.5) alone results in 3.2 million excess deaths annually worldwide. Evidence from epidemiological and clinical studies points to a link between inhalation of air pollutants and adverse cardiovascular and pulmonary outcomes. Laboratory studies support an inflammatory basis for these effects, as exposure to a wide variety of environmental agents leads to inflammatory signaling and gene expression in human lung cells. Investigations aimed at elucidating the mechanisms of signaling activation in cells exposed to broadly disparate ambient air contaminants converge on protein sulfenylation and a loss of protein tyrosine phosphatase activity as key initiating events that are dependent on an accompanying elevation in intracellular concentrations of H2O2. Interventions with ectopic expression of catalase and metabolic inhibitors implicate both mitochondrial respiration and redox cycling as potential sources of the H2O2 response. Studies using various model particles show that in addition to bearing adsorbed electrophiles, surface moieties on carbonaceous particles can directly present radical and non-radical oxidative stress to cells. Investigating the redox toxicology of environmental electrophiles (e.g., ozone, metal ions, quinones) presents unique pitfalls and potential artifacts that can confound methodological approaches, including fluorogenic live-cell imaging and extracellular flux analyses. Nonetheless, an increasing body of evidence points to oxidative dysregulation of intracellular signaling in the initiation of the inflammatory effects of air pollution inhalation. This abstract of a proposed presentation does not necessarily reflect EPA policy.