2003 Progress Report: Mechanisms of Toxicity of Particulate Matter Using Transgenic Mouse Strains

EPA Grant Number: R827355C005
Subproject: this is subproject number 005 , established and managed by the Center Director under grant R827355
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Airborne PM - Northwest Research Center for Particulate Air Pollution and Health
Center Director: Koenig, Jane Q.
Title: Mechanisms of Toxicity of Particulate Matter Using Transgenic Mouse Strains
Investigators: Luchtel, Daniel L. , Baker, Coralie , Feigl, Eric , Kavanagh, Terrance J , Larson, Timothy V. , Rosenfeld, Michael
Current Investigators: Luchtel, Daniel L. , Baker, Coralie , Ceballos, Diana , Kavanagh, Terrance J , Leaman, Susan , McConnachie, Lisa , Rosenfeld, Michael
Institution: University of Washington
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 30, 2004 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 2003 through May 30, 2004
Project Amount: Refer to main center abstract for funding details.
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air

Objective:

The objective of this research project is to test the hypothesis that inhaled particulate matter (PM) causes release of inflammatory mediators from cells in the lung that become bloodborne and target the cardiovascular system, particularly the heart. The project is using transgenic mouse strains with specific cardiovascular genetic alterations to address the need to identify potential health conditions that enhance susceptibility to adverse PM health effects.

Progress Summary:

Reanalysis of Previous Work on U.S. Environmental Protection Agency (EPA) Reference Dusts

We completed reanalysis of data (previous results based on 24-hour averages) from studies on Washington, DC (standard reference material [SRM] 1649) and St. Louis (SRM 1648) dusts (manuscript ready for submission, 2004). A pollution-related change from baseline for heart rate (HR), systolic blood pressure, diastolic blood pressure, and activity was seen in 6-hour segments.

We also tested St. Louis dust for endotoxin (ET) content: the dust was negative for ET when pH-adjusted from acidic to neutral (test kit pH range) by diluting the sample in ET-free water.

Analyses of Studies Done on Seattle PM

A dose-response study of aged male ApoE-/- and C57BL/6J mice was conducted using oropharyngeal exposure. Mice were exposed to 0, 50, 150, or 400 mg of Seattle PM collected from three different fixed-site monitors. The health outcomes measured were signs of inflammation in lung lavage specimens and electrocardiographic (ECG) changes. A significant difference in ECG effects in mice was seen between PM from the central Beacon Hill site and that from a residential site impacted by wood burning.

  • Lung Lavage Study (manuscript near submission)
    • Beacon Hill Seattle PM
    • Lake Forest Park Seattle PM
    • Georgetown Seattle PM
  • ECG Study (manuscript ready for submission to the Journal of Toxicology and Environmental Health)
    • Oropharyngeal exposure to silica, titanium and Beacon Hill Seattle PM
    • Nasal exposure to silica, titanium, and Beacon Hill Seattle PM
      • HR and activity in an approximately 12-hour circadian cycle (data matched based on activity)
      • Time/domain analyses (24-hour averages over 4 days)
      • Frequency domain analyses (2-minute data segments that are matched based on activity)
        • Total, high, low, and very low frequency
        • Normalized high, low, and very low frequency

Significant decreases in HR variability were associated with exposure to silica or PM, suggesting a decrease in parasympathetic tone, which may lead to cardiac arrhythmia and mortality.

  • Microarray Study (manuscript in preparation).
    • Beacon Hill Seattle PM. The microarray data show different patterns of gene expression for PM-exposed versus saline-exposed mice. We are attempting to determine whether these data shed light on the different metabolic pathways involved.

Review of Telemetry

Manuscript in preparation (2004) reviews the telemetry literature and its application in studies on mechanisms of PM toxicity.

Cell Culture Studies (Characterization of Transgenic Macrophage Cell Line With Susan Leaman in Terry Kavanagh’s Laboratry)

We set up and harvested dose-response and time-course experiments using RAW 264.7 (mouse macrophage) cells exposed to St. Louis dust (SRM 1648) for later analysis of lactose dehydrogenase release as well as protein for Westerns and RNA for PCR of glutamate-cysteine ligase subunits, glutamate-cysteine catalytic subunit (GCLC) and a modifier subunit (GCLM). Results are pending.

Diesel Pilot Study (With Mike Rosenfeld and Terry Kavanagh)

  • Young male ApoE-/- exposed 6 hours to either air or diesel and sacrificed at 24-hours postexposure.
  • Older female ApoE-/- exposed 6 hours to either air or diesel for and sacrificed at 24-hours postexposure.
  • Older female ApoE-/- exposed 6 hours to either air or diesel for 3 consecutive days and sacrificed at 72-hours postexposure.

Endpoints:

  • Collect plasma to be analyzed for cytokine, cholesterol, triglyceride, lipoprotein, and F2 isoprostane profiles
  • Freeze bronchoalveolar lavage for cytokine analysis
  • Fix lung, heart, spleen, liver, aorta, carotid artery, and innominate/brachiocephalic artery for histopathology
  • Perform cell counts and cell differentials. This work will be completed during Year 6 of the project.

Future Activities:

We will continue with exposures of ApoE-/- mice to diesel using the University of Washington/EPA diesel generating facility and using the health endpoints described above. We are attempting to measure comparable endpoints in mice and humans to aid extrapolation and interpretation.

Journal Articles:

No journal articles submitted with this report: View all 8 publications for this subproject

Supplemental Keywords:

ambient particles, fine particles, combustion, health, exposure, biostatistics, susceptibility, human susceptibility, sensitive populations, air toxics, genetic susceptibility, indoor air, indoor air quality, indoor environment, tropospheric ozone, California, CA, polyaromatic hydrocarbons, PAHs, hydrocarbons, acute cardiovascular effects, aerosols, air pollutants, air pollution, air quality, airborne pollutants, airway disease, airway inflammation, allergen, ambient aerosol, ambient aerosol particles, ambient air, ambient air quality, ambient particle health effects, animal model, assessment of exposure, asthma, atmospheric aerosols, atmospheric chemistry, biological markers, biological response, cardiopulmonary response, cardiovascular disease, children, children’s vulnerability, combustion, combustion contaminants, combustion emissions, epidemiology, exposure, exposure and effects, exposure assessment, harmful environmental agents, hazardous air pollutants, health effects, health risks, human exposure, human health effects, human health risk, incineration, inhalation, lead, morbidity, mortality, mortality studies, particle exposure, particle transport, particulates, particulate matter, risk assessment,, Health, Scientific Discipline, Air, particulate matter, Toxicology, air toxics, Environmental Chemistry, Health Risk Assessment, Epidemiology, Risk Assessments, Biochemistry, Atmospheric Sciences, ambient aerosol, ambient air quality, health effects, particulates, air pollutants, cardiopulmonary responses, human health effects, morbidity, exposure and effects, exposure, hazardous air pollutants, animal model, air pollution, particle exposure, human exposure, inhalation, atmospheric aerosols, ambient particle health effects, mortality studies, mortality, aerosols, atmospheric chemistry, cardiovascular disease, exposure assessment, human health risk

Relevant Websites:

http://depts.washington.edu/pmcenter/ Exit

Progress and Final Reports:

Original Abstract
  • 1999 Progress Report
  • 2000 Progress Report
  • 2001 Progress Report
  • 2002 Progress Report
  • 2004 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R827355    Airborne PM - Northwest Research Center for Particulate Air Pollution and Health

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R827355C001 Epidemiologic Study of Particulate Matter and Cardiopulmonary Mortality
    R827355C002 Health Effects
    R827355C003 Personal PM Exposure Assessment
    R827355C004 Characterization of Fine Particulate Matter
    R827355C005 Mechanisms of Toxicity of Particulate Matter Using Transgenic Mouse Strains
    R827355C006 Toxicology Project -- Controlled Exposure Facility
    R827355C007 Health Effects Research Core
    R827355C008 Exposure Core
    R827355C009 Statistics and Data Core
    R827355C010 Biomarker Core
    R827355C011 Oxidation Stress Makers