2000 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. , Ladiges, Warren , Larson, Timothy V. , Lewtas, Joellen
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, 2000 through May 30, 2001
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 toxicology project uses transgenic mouse strains, initially those selected for cardiovascular disease, as animal model(s) for exploring the mechanisms of PM-related acute morbidity and mortality. This model will be used to test the hypotheses that in compromised individuals (age, disease status), inhaled PM initiate production by cells in the lung of inflammatory mediators and oxidants, that then become blood-borne and target the cardiovascular system, leading to acute morbidity and mortality. Apart from use in validating and mechanistic studies, a susceptible mouse model will be useful in assessing relative potency of different ambient PM mixtures, leading to new hypotheses regarding causative agents. We hypothesize that inhaled PM causes release of inflammatory mediators from cells in the lung that become blood-borne and target the cardiovascular system, particularly the heart. In compromised individuals (age, diet, disease status), the cascade of mediators released from the lung acts on the cardiovascular system and causes acute morbidity and mortality. We will use transgenic mouse strains with specific cardiovascular genetic alterations to address the research need to identify potential health conditions that enhance susceptibility to adverse PM health effects. The nature of such health conditions should then provide insight into the biological mechanisms by which PM mediates acute and chronic health effects.

Progress Summary:

The objective of the studies carried out this past year was to determine whether heart rate and blood pressure were altered after exposure to PM. The first year was spent getting the mouse animal model up and running. Two groups of animals were compared: (1) control normal C57/BL6 male mice without preexisting cardiovascular disease; and (2) transgenic ApoE knockout (-/-) male mice that spontaneously accumulate cholesterol and thus serve as a model of atherosclerosis. The PM source was a U.S. Environmental Protection Agency (USEPA) reference sample dust from Washington, DC. The method of exposure was oropharyngeal instillation of the PM.

The study involved telemetric monitoring of cardiovascular function in freely moving, nontethered mice. The monitoring was done via an implanted radio transmitter. A catheter attached to the transmitter was inserted into the left carotid, while the transmitter was positioned between the skin and body wall on the right side of the body trunk. After surgery, the animals were allowed to recover for 7 to 10 days. A 1-day baseline recording was followed by a vehicle (pyrogen-free saline, 50 L/mouse) exposure and 3-day recording. After recovery for another 7 to 10 days, mice were then exposed to a dose of 125 g PM/50 L saline/mouse followed by a 3-day recording of cardiovascular parameters. Results were analyzed using a one-way ANOVA test with Bonferroni correction.

PM exposure caused a significant change in the heart rate of control as well as ApoE-/- mice as compared to baseline and saline exposure. A significant decrease in heart rate occurred on days 1 and 2 after exposure in the control mice. ApoE -/- mice also exhibited a significant decrease in heart rate on days 1 and 2 after exposure. This decrease in heart rate remained significant through day 3 after exposure. This prolonged effect indicates increased susceptibility of the mice predisposed to atherosclerosis.

Future Activities:

Our plans for the coming year include the following:

  1. Comparing the effects of an EPA reference dust from St. Louis to results obtained with the USEPA reference dust from Washington, DC.

  2. With a different type of implanted radio transmitter, studying ECG parameters of control and ApoE -/- mice after exposure to EPA reference dusts.

  3. Begin studying the possible cardiovascular effects of Seattle ambient PM collected from the central monitoring site (Beacon Hill) in Seattle.

Journal Articles:

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

Supplemental Keywords:

particulate matter, PM, human health effects, asthma, COPD, heart disease, Seattle, Spokane, Washington, WA, exposure, air pollution., 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 EPA icon

Progress and Final Reports:

Original Abstract
  • 1999 Progress Report
  • 2001 Progress Report
  • 2002 Progress Report
  • 2003 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