Genetic linkage analysis of susceptibility to particle exposure in mice
Genetic linkage analysis of susceptibility to particle exposure in mice
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DOI：
10.1165/ajrcmb.22.5.3895
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发表时间：
2000-05-01
影响因子：
6.4
通讯作者：
Kleeberger, SR
中科院分区：
文献类型：
--
作者：
Ohtsuka, Y;Brunson, KJ;Kleeberger, SR
颗粒引起的呼吸系统发病率和死亡率的增加已在世界范围内的工业化城市中观察到，但毒理学机制尚未阐明。据推测，包括老年人和患有心肺疾病的个体在内的亚人群特别容易受到暴露的影响。遗传背景是另一个重要的宿主因素，可能有助于个体间对颗粒暴露的反应。本研究旨在确定易感C57BL/6J和耐药C3H/HeJ自交系小鼠吸入硫酸盐相关碳颗粒诱导的肺泡巨噬细胞（AM）免疫功能障碍的易感位点。之所以选择AMs进行研究，是因为它们是宿主防御的重要组成部分，而宿主防御受损被认为是颗粒引起呼吸道疾病的重要因素。这些研究的定量表型是Fc受体介导的吞噬功能，这是AM完整性的一个指标。对这两种菌株分离群体和非分离群体巨噬细胞功能障碍表型的分析表明，两个非连锁基因控制着易感性。通过对一个交叉（F-2）队列的全基因组连锁分析，分别在17号染色体和11号染色体上发现了显著的和暗示性的数量性状位点（qtl），并通过比较定位确定了小鼠和人类的候选易感基因。重要的是，这两个qtl重叠之前确定的对另一种常见污染物臭氧易感性的qtl。这是第一次证明遗传背景是对颗粒诱导的免疫功能障碍的反应性的重要决定因素，它对理解颗粒与发病率和死亡率之间的流行病学关联具有重要意义。
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 (F-2) 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.