Genetic linkage analysis of susceptibility to particle exposure in mice

Yoshinori Ohtsuka, Kiana J. Brunson, Anne E. Jedlicka, Wayne Mitzner, Robert W. Clarke, Liu Yi Zhang, Scott M. Eleff, Steven R. Kleeberger

Research output: Contribution to journalArticlepeer-review

Abstract

Particle-induced increases in respiratory morbidity and mortality have been observed worldwide in industrialized cities but the toxicologic mechanisms have not been elucidated. It is hypothesized that subpopulations including the elderly and individuals with cardiopulmonary disease are particularly at risk to the effects of exposure. Genetic background is another important host factor that may contribute to interindividual responsivity to particulate exposure. This study was designed to identify susceptibility loci for alveolar macrophage (AM) immune dysfunction induced by inhalation of sulfate-associated carbon particles in susceptible C57BL/6J and resistant C3H/HeJ inbred mice. AMs were chosen for study because they represent an important component of host defense, and compromised host defense has been hypothesized to be an important factor in particle-induced respiratory morbidity. The quantitative phenotype for these studies was Fc receptor-mediated phagocytic function, an index of AM integrity. Analyses of macrophage dysfunction phenotypes of segregant and non-segregant populations derived from these two strains indicate that two unlinked genes control susceptibility. A genome-wide linkage analysis of an intercross (F2) cohort identified significant and suggestive quantitative trait loci (QTLs) on chromosomes 17 and 11, respectively. Candidate susceptibility genes were identified for mice and humans by comparative mapping. Importantly, both QTLs overlap previously identified QTLs for susceptibility to another common pollutant, ozone. This is the first demonstration that genetic background is an important determinant of responsiveness to particle-induced immune dysfunction, and it has important implications for understanding the epidemiologic associations between particulates and morbidity and mortality.

Original languageEnglish (US)
Pages (from-to)574-581
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume22
Issue number5
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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