Genetic linkage analysis of susceptibility to particle exposure in mice

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 particu late exposure. This study was designed to identify susceptibility loci for alveolar macrophage (AM) immune dysfunction induced by inhalation of sulfat e-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 hypothesi zed to be an important factor in particle-induced respiratory morbidity. Th e quantitative phenotype for these studies was Fc receptor-mediated phagocy tic function, an index of AM integrity. Analyses of macrophage dysfunction phenotypes of segregant and non-segregant populations derived from these tw o strains indicate that two unlinked genes control susceptibility. A genome -wide linkage analysis of an intercross (F-2) cohort identified significant and suggestive quantitative trait loci (QTLs) on chromosomes 17 and 11, re spectively Candidate susceptibility genes were identified for mice and huma ns by comparative mapping. Importantly, both QTLs overlap previously identi fied QTLs for susceptibility to another common pollutant, ozone. This is th e first demonstration that genetic background is an important determinant o f responsiveness to particle-induced immune dysfunction, and it has importa nt implications for understanding the epidemiologic associations between pa rticulates and morbidity and mortality.