Grantee Research Project Results
Final Report: Coronary Effects of Combustion-Source Particulate Matter
EPA Grant Number: R830839Title: Coronary Effects of Combustion-Source Particulate Matter
Investigators: Campen, Matthew J. , McDonald, Jacob D. , Reed, Matthew D.
Institution: Lovelace Biomedical & Environmental Research Institute
EPA Project Officer: Chung, Serena
Project Period: April 21, 2003 through April 20, 2006 (Extended to March 31, 2007)
Project Amount: $1,018,920
RFA: Airborne Particulate Matter Health Effects: Cardiovascular Mechanisms (2002) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air , Human Health
Objective:
We proposed to investigate indices of risk for vasospastic sudden cardiac death and alterations in coronary artery physiology incurred by exposure to combustion-source (diesel and gasoline exhaust) particles and associated gaseous copollutants in a murine model of coronary vascular disease. Among these markers were changes in electrocardiographic (ECG) morphology, serum markers (endothelin-1) and tissue markers (endothelin-1 and heme oxygenase-1). The original project was expanded to incorporate a chronic exposure to take advantage of the animal model of hyperlipidemia and atherosclerosis. Overall, the project was able to incorporate several additional studies, in terms of the comparative research with resuspended road dust and gasoline engine emissions. In Specific Aim 1, ApoE-/- and their genetic background, C57BL/6J, mice were exposed acutely to diesel engine exhaust (DE). Various proposed mechanisms of cardiac effects were examined in vivo during and after PM exposure, including electrocardiographic changes (measured by telemetry) to assess myocardial repolarization anomalies. In Specific Aim 2, we assessed the effects of bioavailable PM on coronary artery physiology using state-of-the-art in vitro video microscopic edge-detection myography. Vessels from exposed and naïve mice were used to compare the relative pathophysiologic contributions of bioavailable PM versus endogenous circulating mediators. Lastly, in Specific Aim 3, we implemented a novel inhalation exposure system that enables separation of DE PM and gaseous phase components to identify putative toxic drivers of cardiac responses. Mice were exposed as in specific aim 1 to gaseous and particulate phases to determine respective health impacts of either portion. In addition to these Aims, we also implemented exposures to gasoline emissions and road dust, and included a longer-term exposure to examine the impact of gasoline emissions on vascular transcriptional changes.
Summary/Accomplishments (Outputs/Outcomes):
Study 1: Whole-body Exposures to Diesel Emissions in C57BL/6 and ApoE-/- Mice
The initial observation of the susceptibility conferred by hypercholestermia in the Apolipoprotein E-null mouse model was shown acutely by electrocardiographic changes. We conducted diesel exposures in C57BL/6J mice and ApoE-/- mice on either low fat or high fat diets. Diesel concentrations were 0.5 and 3.5 mg/m3 for 6 h/day x 3 days. The ApoE-/- mice displayed diesel-induced decreases in HR compared to filtered air mice. Effects were seen at the lowest concentration. Also, significant changes in the T-wave morphology, possibly indicative of an ischemic effect, were observed in the ApoE-/- mice. Despite the clear sensitivity of the ApoE-/- mouse to cardiac effects, pulmonary inflammation, as assessed by lavage cell differentials, was not significantly different between the C57BL/6J mice and ApoE-/- mice. Furthermore, we were able to document that the soluble components of diesel exhaust, including aldehydes and alkanes, were able to alter coronary vascular physiology in an ex vivo assay system. These data correlate with the in vivo data suggesting that diesel inhalation may impair coronary function and place the heart at risk of an ischemic event due to insufficient perfusion.
Study 2: Comparison of Cardiac Effects of Exposure to Gasoline Exhaust Emissions and Resuspended Road Dust in the ApoE-/- Mouse Model
Next, we used the ApoE-/- mouse model to further test the role of particulates, specifically those freshly generated from engine emissions, by conducting a comparative study of gasoline engine exhaust with and without particles filtered. As an additional comparison, we conducted studies of high concentrations of resuspended paved road dust PM, which contributes to roadside exposures and has been previously correlated with in vivo cardiovascular effects. The results of this study implicate fresh gasoline exhaust PM in driving acute cardiovascular events. We clearly demonstrated alterations in T-wave morphology caused by gasoline engine emissions, with no significant effects from resuspended road dust, even at magnitudes greater concentrations. These effects occurred in the absence of measurable pulmonary or systemic inflammation. Whole gasoline emissions were able to increase circulating endothelin-1, a potent vasoconstrictor, in a concentration-dependent manner. We conclude that the acute electrocardiographic findings were related primarily to inhalation of freshly-generated gasoline particles.
Study 3: Cardiac Effects of Diesel Engines Operating on a Partial Load versus a High Load
To further explore the importance of exhaust composition on cardiovascular toxicity, we tested the hypothesis that the non- and partially-combusted portions of exhaust were more toxic by comparing the cardiac toxicity of emissions from a diesel engine operating under partial versus a high load. The load was adjusted by altering the number of flood lights connected in series to the diesel generator (and thus altering the electrical current pulled from the system). Our characterization of the chemical differences revealed high compositional ratios of organic:elemental carbon in the particulate phase of the partial load emission, and much higher output of alkanes and other SVOCs in the gas phase. The results in terms of biological effects were dramatic, with nearly immediate bradycardia observed in the mice exposed to the partial load emissions, while cardiac effects from high load emissions were decidedly more gradual, despite equivalent mass concentrations of PM. Moreover, while the high load exposures elicited a slight but significant alteration in T-wave area, the effects from the partial load exposure were dramatic. Consistent with the previous diesel study, these results indicate that the emissions composition has a strong impact on the biological response.
Study 4: Subchronic Effects of Gasoline Engine Emissions Exposure of Markers of Vascular Remodeling
Epidemiological evidence indicates that environmental air pollutants are positively associated with the development of chronic vascular disease; however, the mechanisms involved have not been fully elucidated. In Study 4 we examined molecular pathways associated with chronic vascular disease in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice, including markers of vascular remodeling and oxidative stress, in response to exposure to the ubiquitous environmental pollutant, gasoline engine emissions. ApoE-/- mice, on a high-fat diet, were exposed by inhalation to either filtered air; 8, 40, or 60 µg/m3 particulate matter whole exhaust, or filtered exhaust with gases matching the 60 µg/m3 concentration, for 7 wk. Aortas and plasma were collected and assayed for changes in histochemical markers, real time RT-PCR, and indicators of oxidative damage. Inhalational exposure to gasoline engine emissions resulted in increased aortic mRNA expression of matrix metalloproteinase-3, -7, and -9, tissue inhibitor of metalloproteinases-2, endothelin-1 and heme oxygenase-1 in ApoE-/- mice; increased aortic MMP-9 protein levels were confirmed through immunohistochemistry. Elevated ROS were also observed in arteries from exposed animals, despite absence of plasma markers. Similar findings were also observed in the aortas of ApoE-/- mice exposed to particle-filtered atmosphere, implicating the gaseous components of the whole exhaust in mediating the expression of markers associated with the vasculopathy. These findings demonstrate that exposure to gasoline engine emissions results in the transcriptional upregulation of factors associated with vascular remodeling, as well as increased markers of vascular oxidative stress, which may contribute to the progression of atherosclerosis and reduced stability of vulnerable plaques.
Conclusions:
The cardiovascular impact of whole emissions is clearly more complicated than simple exposure to particles. Other gases, especially those generated during partial load engine operation, seem to have strong effects on cardiovascular function. Moreover, the effects are not limited to acute changes in physiology. Subchronic increases in markers of vascular remodeling suggest that the gaseous copollutants may have a significant role in the promotion of atherosclerosis.
Journal Articles on this Report : 5 Displayed | Download in RIS Format
Other project views: | All 22 publications | 6 publications in selected types | All 6 journal articles |
---|
Type | Citation | ||
---|---|---|---|
|
Campen MJ, Babu NS, Helms GA, Pett S, Wernly J, Mehran R, McDonald JD. Nonparticulate components of diesel exhaust promote constriction in coronary arteries from ApoE-/-mice. Toxicological Sciences 2005;88(1):95-102. |
R830839 (2004) R830839 (2005) R830839 (Final) |
Exit Exit |
|
Campen MJ, McDonald JD, Reed MD, Seagrave JC. Fresh gasoline emissions, not paved road dust, alter cardiac repolarization in ApoE-/- mice. Cardiovascular Toxicology 2006;6(3-4):199-209. |
R830839 (2005) R830839 (Final) CR831455 (Final) |
Exit |
|
Lund AK, Knuckles TL, Akata CO, Shohet R, McDonald JD, Gigliotti A, Seagrave JC, Campen MJ. Gasoline exhaust emissions induce vascular remodeling pathways involved in atherosclerosis. Toxicological Sciences 2007;95(2):485-494. |
R830839 (2005) R830839 (Final) CR831455 (Final) R831860 (2007) R831860 (Final) |
Exit Exit Exit |
|
Lund AK, Lucero J, Lucas S, Madden MC, McDonald JD, Seagrave J-C, Knuckles TL, Campen MJ. Vehicular emissions induce vascular MMP-9 expression and activity associated with endothelin-1–mediated pathways. Arteriosclerosis, Thrombosis, and Vascular Biology 2009;29(4):511-517. |
R830839 (2005) R830839 (Final) CR831455 (Final) |
Exit Exit Exit |
|
Rowan III WH, Campen MJ, Wichers LB, Watkinson WP. Heart rate variability in rodents: uses and caveats in toxicological studies. Cardiovascular Toxicology 2007;7(1):28-51. |
R830839 (2005) R830839 (Final) CR831455 (Final) |
Exit |
Supplemental Keywords:
Atherosclerosis, coronary artery disease, carbon monoxide, gasoline engine emissions, road dust, air pollution, nitrogen dioxide, RFA, Scientific Discipline, Health, Air, TREATMENT/CONTROL, particulate matter, Air Pollution Control, Health Risk Assessment, air toxics, Risk Assessments, Incineration/Combustion, copollutant exposures, elderly adults, health effects, atmospheric particulate matter, airway epithelial cells, cardiopulmonary responses, fine particles, combustion-related pollutants, stratospheric ozone, acute cardiovascular effects, acute lung injury, vascoconstriction, combustion emissions, air pollution, susceptible subpopulations, cardiac arrest, chronic health effects, lung inflammation, oxidant gas, particulate exposure, cardiopulmonary effects, Acute health effects, inhaled, cardiovascular morbifity, cardiopulmonary, cardiotoxicity, concentrated particulate matter, acute exposure, airborne urban contaminants, cardiovascular disease, exposure assessmentProgress and Final Reports:
Original AbstractThe 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.