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1999 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, Terry , Leaman, Susan , McConnachie, Lisa , Rosenfeld, Michael
Institution: University of Washington
EPA Project Officer: Stacey Katz/Gail Robarge,
Project Period: June 1, 1999 through May 30, 2004 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 1999 through May 30, 2000
Project Amount: Refer to main center abstract for funding details.
RFA: Airborne Particulate Matter (PM) Centers (1999)
Research Category: Particulate Matter

Description:

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 main effort has been to develop the mouse animal model; in effect, to develop the surgical skills to successfully implant a radio-telemetry device manufactured by Data Sciences International (St. Paul, MN). This device is inserted in the abdominal aorta to monitor cardiovascular function (blood pressure, heart rate, body temperature and biopotentials, e.g., ECG). With such a device, a mouse can move freely, eliminating the need for jackets, restraints, tethers, and exteriorized catheters.

After getting the laboratory set up for surgery and obtaining the necessary equipment, working on the mice has entailed solving several technical problems. The first was the method of anesthesia. We found that the effects of injectable anesthetics was too variable. A standard dose (ketamine/xylazine, 85 & 7 :g/g body weight, respectively) would not keep some animals down while other animals would die during surgery. After a couple of months of this, we decided to spend $3,000 to purchase an inhalable system for administering the anesthetic. We now use 2 percent isofluorane in an oxygen stream from a nonrebreathing Gas Anesthetic Machine designed for rodents (Vasco, Veterinary Anesthesia Systems Co., Bend, OR).

Another problem was to obtain complete recovery of the animal after surgery. The process of inserting the catheter into the aorta is an intricate maneuver and needs to be performed quickly and efficiently to prevent ischemia-related hind-limb paralysis. With many attempts, Dr. Luchtel and a graduate student, Chunmei Fu, could only obtain a very low success ratio, about 5 percent. They consulted with the company and other researchers in the field and it became clear that the mouse strain we want to use, C57BL6, was not of sufficient size to do successful surgeries routinely. The company recommended using animals of 35-40 grams, as the animals on hand were in the 25-30 gram range.

A user group workshop sponsored by Data Sciences International was recently held at the Experimental Biology 2000 meeting in San Diego. Two researchers, Robin Davisson from the University of Iowa and Scott Carlson from the University of Alabama, have recently developed methods for implanting the radio-telemetry device in the carotid artery. They reported being able to do this routinely (90% success ratio) in smaller transgenic mouse strains. The catheter is implanted retrogradely in either the right or left carotid. Although one carotid artery is blocked, rodents have a robust circle of Willis circulation and the remaining carotid can supply blood to the brain and head without any apparent ill effect. We are now in the process of perfecting this surgical technique and expect to be collecting control physiological data within a month.

Future Activities:

During the next year, we will focus on perfecting the surgical technique of implanting the radio-telemetry device into the carotid artery of transgenic mice. Also, control physiological data will be collected.

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. , Air, Scientific Discipline, Health, Toxicology, Risk Assessments, Health Risk Assessment, Epidemiology, air toxics, Atmospheric Sciences, Biochemistry, particulate matter, Environmental Chemistry, aerosols, exposure assessment, exposure and effects, ambient air quality, cardiovascular disease, health effects, inhalation, mortality, hazardous air pollutants, atmospheric aerosols, cardiopulmonary responses, human health risk, particle exposure, mortality studies, air pollutants, human health effects, particulates, ambient particle health effects, air pollution, atmospheric chemistry, exposure, ambient aerosol, human exposure, morbidity, animal model
Relevant Websites:

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

Progress and Final Reports:
Original Abstract
2000 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

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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.

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