Particle-induced Cardiopulmonary Injury In Mice: Genetic

Environmental Health Sciences

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Abstract

Because of the impact that particle-gas exposures may have on public health, identification of host factors that influence susceptibility to airborne pollutants remains an important issue. Particular concern has arisen about potentially sensitive sub-groups such as children, asthmatics, and the elderly. Individuals with cardiopulmonary disease are at particular risk to the effects of exposure. Recent evidence has suggested that some individuals may be genetically predisposed to environmental stressors, including oxidants and particles. Epidemiological studies have also suggested that PM may produce significant changes in cardiovascular function in addition to its pulmonary effects. In ongoing studies, we have began to test the hypothesis that genetic background is an important host factor that contributes to interindividual responsivity to particulate-induced immune dysfunction (an indicator of morbidity) and decreased heart rate variability (HRV). [unreadable] [unreadable] We initially designed a study to identify susceptibility loci for alveolar macrophage (AM) immune dysfunction induced by inhalation of sulfate-associated carbon black (CB) particles in differentially susceptible B6 and C3 inbred mice. AMs were chosen for study because they represent in important component of host defense, and compromised host defense has been hypothesized to be an important factor in particle-induced respiratory morbidity. B6 and C3 mice were chosen for investigation because a strain screen identified them as the most differentially susceptible to CBA/SO2-induced phagocytic dysfunction among eight strains studied. A B6C3F2 cohort was genotyped at 147 SSLP markers and a QTL on chromosome 17 exceeded the threshold value for statistically significant linkage as determined empirically by permutation test. A QTL on chromosome 11 exceeded the threshold for suggestive linkage. Candidate susceptibility genes in the chromosome 17 QTL were identified by comparative mapping and included Tnf, Lta, and Ccl2 (monocyte chemoattractant protein 1). Importantly, both QTLs overlap previously identified susceptibility QTLs for lung injury induced by the common pollutant ozone, as well as bleomycin and radiation. This may suggest common regulatory loci for injury and inflammation in the lung.[unreadable] [unreadable] We have also initiated a study to investigate the mechanisms of susceptibility to chronic bronchitis phenotypes induced by exposure to the metal vanadium which is known to be an important component of particulates in industrialized cities. We have identified significant variation among inbred strains of mice in the lung phenotypes induced by exposure to vanadium, and have initiated linkage analyses to identify the genes responsible for this variation. [unreadable] [unreadable] A link between changes in heart rate variability (HRV) and cardiovascular disease has been established. Recent studies have suggested a genetic component to heart rate variability. However, a full assessment of possible differences in heart rate (HR) and HRV using inbred mouse strains has not been studied. Furthermore, the heritability of HR and HRV has not been assessed using inbred mice. We have begun to investigate the genetic contribution and the heritability of HR and HRV using a wide range of inbred mouse strains. We anticipate our investigations will provide valuable insight to the genetic determinants of HR and HRV, and the mechanisms through which these genes interact in host response to environmental particulates.