Superfund sites typically contain complex mixtures of pollutants including chlorinated hydrocarbons, metals, and other toxic organic and inorganic compounds. Remediation of these sites results in some exposure of the surrounding population to airborne soil dust contaminated with hazardous substances or PM emitted from the treatment devices. Our researchers have shown EPFRs are present in at least some contaminated Superfund soils and formed in high concentration during incineration and thermal treatment of hazardous substances. These PM-associated EPFRs exist for days in the atmosphere and may continually form in contaminated soils. Once inhaled, they initiate and participate in catalytic chain cycles generating ROS and persist in biological media long enough to lead to pulmonary and cardiovascular damage. Since our discovery of EPFRs associated with Superfund sites is relatively recent, little is known about their mechanisms of toxicity. The toxic responses are thought to be mediated through the generation of reactive oxygen species (ROS), with several studies implicating the P450 system in this process. The goal of this study is to examine the roles of the P450 and HO-1 systems in the response to EPFR exposure within an organism. The hypothesis being addressed is that EPFRs associated with ultrafine particles (1) directly inhibit cytochrome P450-mediated activities, (2) decrease the expression of several P450 enzymes and increase the expression of ROS-protective enzymes (such as HO-1), and (3) alter P450-dependent ROS production. We will determine if decrease in P450 expression is the result of a ROS-mediated alteration in NFkB expression, where NFkB activation leads to decreases in P450 and increases in HO-1 expression that serve to limit oxidative damage in exposed tissues. Taken together, these studies are expected to provide novel information regarding how the P450 and HO-1 systems respond to EPFR exposure and affect EPFR-mediated toxicity.
Significant correlations between pulmonary and cardiovascular toxicity are associated with increased levels of airborne PM. Contaminated Superfund soils and PM emissions from thermal treatment of hazardous substance are especially toxic because they contain EPFRs of aromatic chlorinated hydrocarbons capable of generating reactive oxygen species. The goal of this study is to determine how drug and pollutant metabolism is affected by EPFR exposure, and to determine the mechanism of toxicity by these substances.
|Huang, Huaqiong; Saravia, Jordy; You, Dahui et al. (2015) Impaired gamma delta T cell-derived IL-17A and inflammasome activation during early respiratory syncytial virus infection in infants. Immunol Cell Biol 93:126-35|
|Park, Ji Won; Reed, James R; Brignac-Huber, Lauren M et al. (2014) Cytochrome P450 system proteins reside in different regions of the endoplasmic reticulum. Biochem J 464:241-9|
|Cormier, Stephania A; Shrestha, Bishwas; Saravia, Jordy et al. (2014) Limited type I interferons and plasmacytoid dendritic cells during neonatal respiratory syncytial virus infection permit immunopathogenesis upon reinfection. J Virol 88:9350-60|
|Lee, Greg I; Saravia, Jordy; You, Dahui et al. (2014) Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection. Part Fibre Toxicol 11:57|
|Saravia, J; You, D; Thevenot, P et al. (2014) Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression. Mucosal Immunol 7:694-704|
|Gehling, William; Khachatryan, Lavrent; Dellinger, Barry (2014) Hydroxyl radical generation from environmentally persistent free radicals (EPFRs) in PM2.5. Environ Sci Technol 48:4266-72|
|Kiruri, Lucy W; Khachatryan, Lavrent; Dellinger, Barry et al. (2014) Effect of copper oxide concentration on the formation and persistency of environmentally persistent free radicals (EPFRs) in particulates. Environ Sci Technol 48:2212-7|
|Schwingshackl, Andreas; Teng, Bin; Makena, Patrudu et al. (2014) Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury. Crit Care Med 42:e692-701|
|dela Cruz, Albert Leo N; Cook, Robert L; Dellinger, Barry et al. (2014) Assessment of environmentally persistent free radicals in soils and sediments from three Superfund sites. Environ Sci Process Impacts 16:44-52|
|Hettiarachchi, Suraj U; Prasai, Bijeta; McCarley, Robin L (2014) Detection and cellular imaging of human cancer enzyme using a turn-on, wavelength-shiftable, self-immolative profluorophore. J Am Chem Soc 136:7575-8|
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