Effect of Inhaled Acid-Coated Particles on Alveolar Macrophage Function: Genetic Susceptibility

EPA Grant Number: R825815
Title: Effect of Inhaled Acid-Coated Particles on Alveolar Macrophage Function: Genetic Susceptibility
Investigators: Kleeberger, Steven R. , Jakab, George J.
Institution: The Johns Hopkins University
EPA Project Officer: Saint, Chris
Project Period: October 1, 1997 through September 30, 2000
Project Amount: $561,577
RFA: Issues in Human Health Risk Assessment (1997) RFA Text |  Recipients Lists
Research Category: Human Health , Health Effects , Human Health Risk Assessment , Health

Description:

Epidemiology studies have associated exposures to high particle and sulfur dioxide (SO2) concentrations with increased mortality and morbidity in urban cities throughout the U.S. and other industrialized countries. Particular concern has arisen about sensitive sub-groups such as children, asthmatics, and individuals with genetic predisposition to environmental stressors. Understanding the genetic basis for inter-individual variation in response to air pollutant exposure will clarify the mechanism(s) of host response, and provide a means to identify genetically susceptible individuals who may be at risk. The primary objective of this project is to define the mode of inheritance of susceptibility to the pulmonary response to inhaled acid-coated particles in the mouse, and to identify and map the susceptibility genes.

Approach:

We have developed a model of genetic predisposition to the toxic effects of acid coated particles on alveolar macrophage function (an indicator of immunologic health status). We will use this model to address three specific aims. Initially, we will characterize the kinetics of alveolar macrophage dysfunction and inflammation induced in SUSCEPTIBLE B6 and RESISTANT C3 mice by exposure to a mixture of carbon black aerosol (CBA) and SO2 at high humidity. These studies will provide the optimal phenotype to determine the mode of inheritance of susceptibility to the effects of CBA/ SO2 mixture. Segregant populations derived from B6 and C3 mice will be phenotyped for inflammation and macrophage dysfunction after exposure to CBA/ SO2, and inheritance patterns will be determined by formal segregation analyses. Finally, we will determine the chromosomal location(s) of quantitative trait loci (QTL) that control susceptibility to CBA/ SO2. Segregant animals phenotyped for particle susceptibility will be genotyped for PCR-based polymorphic simple sequence repeat markers (SSR) distributed throughout the mouse genome. A genome-wide search for linkage between the phenotypic responses to particle inhalation and the chromosomal markers will identify candidate genes (QTL) and will ultimately define the molecular mechanisms that determine susceptibility in the inbred mouse.

Expected Results:

Identification of host factors that influence susceptibility to particle-gas exposures remains an important issue. We believe that the proposed studies will lead to the identification and location of loci that determine differential susceptibility to alveolar macrophage dysfunction induced by acid-coated particles. Because of the extensive genetic linkage homology (synteny) between mouse and human, the proposed studies have important public health implications. That is, because of the recent associations between particle exposure and increased morbidity, including lower respiratory tract infection, an understanding of the mechanistic/genetic basis for susceptibility to alveolar macrophage dysfunction may lead to the identification of sensitive individuals who are "at risk" for particle exposure and intervention strategies. Together with our on-going work on oxidant susceptibility, these studies will contribute to our understanding of inter-individual variation in pulmonary/immunologic responses to environmental pollutants.

Publications and Presentations:

Publications have been submitted on this project: View all 5 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 2 journal articles for this project

Supplemental Keywords:

inter-individual variation; susceptible populations; risk; linkage analysis; segregation analysis; breeding studies; inbred strains of mice; synteny; homology; quantitative trait locus; QTL; lung inflammation; immune defense; immune dysfunction; carbon black; sulfur dioxide; aerosol., RFA, Health, Scientific Discipline, Toxicology, Genetics, Environmental Chemistry, Chemistry, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Children's Health, genetic susceptability, breeding studies, pulmonary immunotoxicity, asthma, sensitive populations, inhaled pollutants, Quantitative Trait Loci, airway disease, exposure, genetic predisposition, air pollution, acid coated particles, children, acidic particulate matter, human exposure, carbon black aerosol, inhalation, lung inflamation, inter-individual variation, human susceptibility, alveolar macrophage function, mortality, urban environment, inhaled particles, genetic susceptibility, air contaminant exposure, environmental hazard exposures

Progress and Final Reports:

Final Report