Grantee Research Project Results
2010 Progress Report: Oxidative Stress Responses to PM Exposure in Elderly Individuals With Coronary Heart Disease
EPA Grant Number: R832413C004Subproject: this is subproject number 004 , established and managed by the Center Director under grant R832413
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for Comprehensive, optimaL, and Effective Abatement of Nutrients
Center Director: Arabi, Mazdak
Title: Oxidative Stress Responses to PM Exposure in Elderly Individuals With Coronary Heart Disease
Investigators: Delfino, Ralph , Vaziri, Nosratola D , Gillen, Dan , Staimer, Norbert , Neuhausen, Susan
Current Investigators: Delfino, Ralph , Vaziri, Nosratola D , Gillen, Dan , Staimer, Norbert , Neuhausen, Susan , Gastanaga, Victor
Institution: University of California - Irvine
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2012)
Project Period Covered by this Report: August 1, 2009 through July 31,2010
RFA: Particulate Matter Research Centers (2004) RFA Text | Recipients Lists
Research Category: Human Health , Air
Objective:
The overall goal of this study is to advance knowledge on the importance of particle size and composition to the induction of oxidative stress responses. Project 4 is a cohort panel study with repeated measures of outcomes and exposures in 60 elderly subjects with a history of coronary artery disease. We hypothesize that circulating biomarkers of systemic responses related to oxidative stress will be associated with exposure to indoor and outdoor home PM mass and total particle number concentration. Given the interplay between oxidative stress and inflammation, we anticipate this would support the view that PM leads to systemic inflammatory responses and adverse impacts on cardiovascular function. We further hypothesize that biomarkers will be more strongly associated with predicted indoor exposure to PM of outdoor origin (from source tracer analyses). We also will evaluate effects of exposure to specific metals, elemental and organic carbon, and specific organic components in PM that we used as source tracers and to characterize primary and secondary organic aerosol fractions of PM. We hypothesize that biomarker associations with ultrafine and fine PM will be better explained by chemical assays that measure reactive oxygen species and electrophilic activity. Individual susceptibility also will be assessed, including medication use and polymorphisms in genes coding for proteins involved in oxidative stress responses.
Progress Summary:
This report represents progress over the fifth year of funding. Additional laboratory work for the effects of air pollutants on a biomarker of antioxidant activity is planned.
Analysis of the relationship between biomarkers of antioxidant activity and air pollutants: In addition to a research focus on the varying effects of different particle size fractions on circulating biomarkers, we have continued work to evaluate relative differences in association between primary organic aerosols (POA) vs. secondary organic aerosols (SOA). We previously described our findings of inverse associations of air pollutants (especially ultrafine particles and markers of POA) with the activities of two critically important erythrocyte antioxidant enzymes [glutathione peroxidase-1 (GPx-1) and Cu,Zn-superoxide dismutase (Cu,Zn-SOD)] (Delfino, et al., 2008, 2009). Additional work this year has involved an analysis of GPx-1 and Cu,Zn-SOD in relation to exposures to chemical components in quasi-ultrafine particles (Delfino, et al., 2010). Briefly, weekly filters for PM < 0.25 μm in diameter (PM0.25 or quasi-ultrafine particles) were composited and extracted for chemical analyses in Dr. James Schauer’s laboratory.
As before (Delfino, et al., 2009), we again found that regression coefficients for air pollutants were largely negative suggesting inverse associations with erythrocyte antioxidant enzymes (CuZn-SOD and GPx-1), but most upper confidence limits crossed 1.0 (Delfino, et al., 2010). This exploratory analysis showed that among seven subjects previously identified as a “positive responder group” (Delfino, et al., 2009) we found largely positive associations of CuZn-SOD and GPx-1 with air pollutants, and lower confidence limits were >1.0 for outdoor PM0.25 mass and several other exposures. In the 53 subjects previously identified as a “negative responder group,” we found inverse associations of CuZn-SOD and GPx-1 with markers of exposures linked to primary combustion, including hopanes (vehicle emissions tracer), and indoor and outdoor total PAH as well as low, medium and high molecular weight PAH. Indoor water-soluble organic carbon was inversely (p < 0.07) associated with CuZn-SOD, but there were no other associations with SOA markers in the negative responder group, including n-alkanoic acids. Transition metals were not associated with either CuZn-SOD or GPx-1.
The erythrocyte antioxidant enzymes also were inversely associated with circulating biomarkers of inflammation and platelet activation. Therefore, pollutant associations with antioxidant enzymes may at least in part be related to our findings of significantly increased markers of vascular hypercoagulability and inflammation in relation to exposures to combustion-related air pollutants (e.g., elemental carbon and primary organic carbon) (Delfino, et al., 2008, 2009, 2010, in press). The importance of combustion-related chemicals is supported by our finding that associations of plasma IL-6 and TNF-RII with PM0.25 mass were completely confounded by the PAH fraction of PM0.25, and these cytokine biomarkers were not associated with chemical tracers of SOA (Delfino, et al., 2010). Our chemical mass balance model results using source tracers showed that a majority of the PAH came from vehicular sources (Arhami, et al., 2010; Delfino, et al., 2010). This suggests that chemical components from traffic are responsible for blood biomarker associations with uncharacterized quasi-ultrafine particle mass.
Relationship of biomarkers of inflammation to ROS production by PM using in vitro bioassays of aqueous particle extracts collected at indoor and outdoor retirement community sites: We evaluated the relation of airway and systemic inflammatory responses to the potential of aqueous extracts of the weekly PM0.25 filters to induce cellular production of ROS (Delfino, et al., in press). As one marker of PM oxidative potential, ROS production was measured by exposing rat alveolar macrophages (NR8383) in vitro to the aqueous extracts of PM0.25 collected outdoors at the subjects’ retirement community. Health outcomes included 12 weekly measurements of both plasma IL-6 (a biomarker of systemic inflammation) and offline fractional exhaled NO (a biomarker of airway inflammation) in the 60 elderly subjects studied previously (Delfino, et al., 2009, 2010). Both exhaled NO and IL-6 were positively associated with levels of macrophage ROS generation. Results from regression models including both PM0.25 mass with ROS production showed that oxidative potential explained most of the association of IL-6 with PM0.25 mass. The association of exhaled NO with ROS activity was not reflected by PM0.25 mass concentration at all. We concluded that the ability of particles to induce ROS generation by macrophages is associated with both systemic and airway biomarkers of inflammation and that this association is nominally reflected by particle mass concentration.
Analysis of cardiovascular function: We analyzed the relation of air pollutant exposures to both hourly blood pressure (BP) and ST depression ≥1 mm (indicative of cardiac ischemia). Both outcomes were collected using ambulatory monitors over a 10-day period in each of the study subjects. Results established coherence with the blood biomarker data by estimating relative effects from particle size fractions and from POA vs. SOA markers and related criteria pollutant gases. Briefly, we found significant positive associations of systolic and diastolic BP with air pollutants (Delfino, et al., 2010). The strongest associations were with PM2.5 organic carbon (OC) as compared with PM2.5 black carbon (BC) or PM2.5 mass. Associations also strengthened with longer multi-day averaging time to 9 days. Effect estimates were clinically relevant. For example, an interquartile range increase (25th to 75th percentile) in 5-day average OC (5.2 µg/m3) was associated with 6.0 mm Hg higher mean systolic BP (95% CI: 1.0, 11) and 4.6 mm Hg higher mean diastolic BP (95% CI: 1.9, 7.2). An analysis of the OC fraction showed that primary OC was more strongly associated with BP than secondary OC as we found for the circulating biomarkers. These results suggest that exposure to primary organic components of fossil fuel combustion near the home are strongly associated with increased ambulatory blood pressure in a population at potential risk of myocardial infarction. Results also showed that SOA is associated with BP, perhaps through an effect on airways.
While wearing the ambulatory blood pressure monitor, each subject also was followed for 10 days with 24-hr ambulatory electrocardiograph (ECG) monitors (Holter monitors). Generalized estimating equations were used to estimate the odds of ST segment depression ≥1 mm (indicative of possible ischemia) from hourly exposure to air pollution controlling for temperature, community, and season. We found significant positive associations of ST segment depression events with markers of primary combustion aerosols, including primary OC and BC, but not SOC. Associations were stronger for multiday averages and for the 92 percent of time subjects were at home near air monitors.
Overall, our results show that biomarkers of systemic inflammation (Delfino, et al., 2009, 2008, 2010, in press), ambulatory blood pressure (Delfino, et al., 2010), and electrocardiographic ST segment depression ≥1 mm (Delfino, et al., submitted) are more strongly associated with POA than SOA exposure markers (and related chemical components). Findings indicate that traffic-related pollutants, the predominant source of POA in many urban areas, have adverse cardiovascular effects that could include cardiac ischemia. This is in contrast with our finding that a biomarker of airway inflammation (fractional exhaled NO) was much more strongly associated with SOA and ozone, than with POA or combustion-related gases (CO or NOx) (Delfino, et al., in press). It is possible that many hydrophilic and highly oxidized SOA chemical components have immediate pro-oxidant effects on the airways, whereas many POA components (e.g., PAH), are hydrophobic and require biotransformation to pro-oxidant species after systemic distribution via the circulation. A commonly assumed pathway to the systemic inflammatory effects of particulate air pollution is the activation of leukocytes in the lungs, followed by the release of pro-inflammatory mediators.
Our epidemiologic findings do not support this as a major mechanism, but experimental work as well as additional studies in human populations are needed to evaluate this.
In vitro assay of antioxidant enzyme inactivation: To follow up on the findings in the panel cohort, we are developing a high-throughput assay for investigating the inhibitory properties of electrophilic compounds and other components (present in air and air particulate suspensions) on the antioxidant enzyme GPx-1. This work is showing good promise as an in vitro test aimed at providing a biomonitoring tool for in vivo studies. We have developed a rapid assay that has shown positive results using a number of electrophilic compounds (including acrolein, crotonaldehyde, and benzoquinone) with immobilized erythrocyte GPx-1 as a probe. The immobilization of GPx to the wells of a microtiter plate enables us to remove the reactive compounds simply by washing before adding the substrate mixture. We also used this assay to preliminarily test aqueous extracts of particles from filter samples as well as diesel exhaust particles. Using air samples collected at a heavily trafficked urban area of Los Angeles, we found a direct inhibitory effect of aqueous particle filter extracts on the activity of GPx-1. Similar effects were found for diesel exhaust particles suggesting that traffic-related air pollutants have the potential to generate oxidative stress by electrophile-derived covalent modifications of enzymes involved in the cytosolic defense against reactive oxygen and nitrogen species.
Future Activities:
To substantiate these findings, in the coming year we will evaluate gene-environment interactions from GSTM1 null genotype across all outcomes measured in the panel study. We also will incorporate data related to antioxidant/oxidative stress responses from Project 4 to better understand potential differences in responses between individuals. Because oxidative stress is important in blood pressure, we will evaluate effect modification of associations between air pollutants and blood pressure by erythrocyte GPx-1 and Cu,Zn-SOD activities, and by plasma myeloperoxidase concentrations. Additional work on the high throughput GPx-1 assay also is planned.
Journal Articles on this Report : 14 Displayed | Download in RIS Format
Other subproject views: | All 35 publications | 15 publications in selected types | All 15 journal articles |
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Other center views: | All 241 publications | 157 publications in selected types | All 157 journal articles |
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Arhami M, Polidori A, Delfino RJ, Tjoa T, Sioutas C. Associations between personal, indoor, and residential outdoor pollutant concentrations:implications for exposure assessment to size-fractionated particulate matter. Journal of the Air & Waste Management Association 2009;59(4):392-404. |
R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C004 (2009) R832413C004 (2010) R832413C004 (Final) |
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Arhami M, Minguillon MC, Polidori A, Schauer JJ, Delfino RJ, Sioutas C. Organic compound characterization and source apportionment of indoor and outdoor quasi-ultrafine particulate matter in retirement homes of the Los Angeles Basin. Indoor Air 2010;20(1):17-30. |
R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C004 (2009) R832413C004 (2010) R832413C004 (Final) |
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Delfino RJ, Staimer N, Tjoa T, Polidori A, Arhami M, Gillen DL, Kleinman MT, Vaziri ND, Longhurst J, Zaldivar F, Sioutas C. Circulating biomarkers of inflammation, antioxidant activity, and platelet activation are associated with primary combustion aerosols in subjects with coronary artery disease. Environmental Health Perspectives 2008;116(7):898-906. |
R832413 (2007) R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2007) R832413C001 (2008) R832413C001 (Final) R832413C004 (2007) R832413C004 (2008) R832413C004 (2009) R832413C004 (2010) R832413C004 (Final) |
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Delfino RJ, Staimer N, Tjoa T, Gillen DL, Polidori A, Arhami M, Kleinman MT, Vaziri ND, Longhurst J, Sioutas C. Air pollution exposures and circulating biomarkers of effect in a susceptible population: clues to potential causal component mixtures and mechanisms. Environmental Health Perspectives 2009;117(8):1232-1238. |
R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C004 (2009) R832413C004 (2010) R832413C004 (Final) |
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Delfino RJ, Staimer N, Tjoa T, Arhami M, Polidori A, Gillen DL, Kleinman MT, Schauer JJ, Sioutas C. Association of biomarkers of systemic inflammation with organic components and source tracers in quasi-ultrafine particles. Environmental Health Perspectives 2010;118(6):756-762. |
R832413 (Final) R832413C001 (2010) R832413C001 (Final) R832413C004 (2010) R832413C004 (Final) |
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Delfino RJ, Tjoa T, Gillen DL, Staimer N, Polidori A, Arhami M, Jamner L, Sioutas C, Longhurst J. Traffic-related air pollution and blood pressure in elderly subjects with coronary artery disease. Epidemiology 2010;21(3):396-404. |
R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (2010) R832413C001 (Final) R832413C004 (2010) R832413C004 (Final) |
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Delfino RJ, Staimer N, Tjoa T, Arhami M, Polidori A, Gillen DL, George SC, Shafer MM, Schauer JJ, Sioutas C. Associations of primary and secondary organic aerosols with airway and systemic inflammation in an elderly panel cohort. Epidemiology 2010;21(6):892-902. |
R832413 (Final) R832413C001 (2010) R832413C001 (Final) R832413C004 (2010) R832413C004 (Final) |
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Delfino RJ, Gillen DL, Tjoa T, Staimer N, Polidori A, Arhami M, Sioutas C, Longhurst J. Electrocardiographic ST-segment depression and exposure to traffic-related aerosols in elderly subjects with coronary artery disease. Environmental Health Perspectives 2011;119(2):196-202. |
R832413 (Final) R832413C001 (2010) R832413C001 (Final) R832413C004 (2010) R832413C004 (Final) |
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Delfino RJ, Staimer N, Vaziri ND. Air pollution and circulating biomarkers of oxidative stress. Air Quality, Atmosphere & Health 2011;4(1):37-52. |
R832413 (Final) R832413C004 (2010) R832413C004 (Final) |
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DiStefano E, Eiguren-Fernandez A, Delfino RJ, Sioutas C, Froines JR, Cho AK. Determination of metal-based hydroxyl radical generating capacity of ambient and diesel exhaust particles. Inhalation Toxicology 2009;21(9):731-738. |
R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C003 (2009) R832413C003 (2010) R832413C004 (2010) |
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Gorham KA, Sulbaek Andersen MP, Meinardi S, Delfino RJ, Staimer N, Tjoa T, Rowland FS, Blake DR. Ethane and n-pentane in exhaled breath are biomarkers of exposure not effect. Biomarkers 2009;14(1):17-25. |
R832413 (Final) R832413C004 (2009) R832413C004 (2010) R832413C004 (Final) |
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Polidori A, Cheung KL, Arhami M, Delfino RJ, Schauer JJ, Sioutas C. Relationships between size-fractionated indoor and outdoor trace elements at four retirement communities in southern California. Atmospheric Chemistry and Physics 2009;9(14):4521-4536. |
R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C004 (2009) R832413C004 (2010) R832413C004 (Final) R833743 (Final) |
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Shinyashiki M, Rodriguez CE, Di Stefano EW, Sioutas C, Delfino RJ, Kumagai Y, Froines JR, Cho AK. On the interaction between glyceraldehyde-3-phosphate dehydrogenase and airborne particles:evidence for electrophilic species. Atmospheric Environment 2008;42(3):517-529. |
R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2008) R832413C001 (Final) R832413C003 (2007) R832413C003 (2008) R832413C003 (2010) R832413C003 (Final) R832413C004 (2009) R832413C004 (2010) |
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Shinyashiki M, Eiguren-Fernandez A, Schmitz DA, Di Stefano E, Li N, Linak WP, Cho S-H, Froines JR, Cho AK. Electrophilic and redox properties of diesel exhaust particles. Environmental Research 2009;109(3):239-244. |
R832413 (2008) R832413 (Final) R832413C003 (2009) R832413C003 (2010) R832413C003 (Final) R832413C004 (2010) |
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Supplemental Keywords:
Health Effects, human health, sensitive populations, dose-response, enzymes, particulates, epidemiology, environmental chemistry, modeling., RFA, Health, Scientific Discipline, Air, particulate matter, Health Risk Assessment, Risk Assessments, Biochemistry, Ecology and Ecosystems, atmospheric particulate matter, particulates, elderly adults, human health effects, PM 2.5, airway disease, airborne particulate matter, cardiovascular vulnerability, air pollution, human exposure, vascular dysfunction, cardiovascular disease, human health riskProgress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R832413 Center for Comprehensive, optimaL, and Effective Abatement of Nutrients Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832413C001 Contribution of Primary and Secondary PM Sources to Exposure & Evaluation of Their Relative Toxicity
R832413C002 Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
R832413C003 The Chemical Properties of PM and their Toxicological Implications
R832413C004 Oxidative Stress Responses to PM Exposure in Elderly Individuals With Coronary Heart Disease
R832413C005 Ultrafine Particles on and Near Freeways
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2011
- 2009 Progress Report
- 2008 Progress Report
- 2007 Progress Report
- 2006 Progress Report
- Original Abstract
15 journal articles for this subproject
Main Center: R832413
241 publications for this center
157 journal articles for this center