Population-based Genetic Model for Diisocyanate-induced Asthma

摘要 接触二异氰酸酯(DI)是职业性哮喘的主要原因，估计有28万名工人暴露在 仅在美国就有异氰酸酯。使用含DI产品的工人暴露在单体和聚合物DIS中 10%的≈发生DI诱发的哮喘(DA)。在人类中，DA与皮肤和吸入DIS有关， 豚鼠，还有老鼠。聚合二异氰酸酯在这两个方面的增感能力都比单体大。 人类和动物。此外，聚合物DI暴露在DI暴露的总暴露中占绝大多数 工人们。DA可能是由暴露水平和遗传基因变异的个体间差异引起的。 因此，确定单体和聚合物之间的相对效力和剂量关系是至关重要的 DA的发展。我们的目标是更好地了解DA易感性的遗传和机制基础。由于 DIS强大的敏化能力及其在消费产品中的潜在存在，敏化研究使用 人类志愿者是不道德的。因此，我们建议使用遗传多样性的合作杂交重组自交系 LINES(CC RIL)，一种实验小鼠模型，以研究DA的敏感性。为了实现我们的目标，我们将确定 1，6-六亚甲基二异氰酸酯(HDI)的个体(品系)差异及剂量-反应关系 单体及其齐聚物HDI异氰尿酸酯，已被证明会导致DA的模型化学品，对 纯合子近交系BALB/CJ和CC RIL小鼠的过敏性呼吸道炎症反应。临床前动物毒性 对DI过敏性的研究大多在纯合近交系BALB/CJ小鼠中进行。中国生物多样性研究进展 单个或有限数量的近交系小鼠，如BALB/CJ，可能会限制对人类DA易感性的研究结果的翻译。抄送 RIL小鼠具有与人类相似的遗传多样性(≥4500万全基因组遗传标记)和基因组结构 群体，但具有12%的平衡次要等位基因频率，这极大地增加了识别基因的能力 使用全基因组关联研究的变种。通过定义个体间的差异和一种 通过对职业暴露应激源的基准反应，我们可以指导人群暴露和风险评估。 这项研究的范围是一致的，并扩大了NIOSH的目标，使两个NIOSH Nora部门(服务和 制造)，新的Nora免疫、传染病和皮肤病预防跨部门目标，以及NIOSH R2P 减少和预防职业病的倡议。这项研究的产出和结果可以概括为 如下：这个实验模型将是(1)体内预测模型发展的重要一步 发现因果变异，(2)确定与人类有关的暴露生物标记物，(3)确定 基准剂量反应，(4)DI皮肤-呼吸道系统水平不良结果路径的确定 呼吸道迟发性免疫的致敏和激发，(5)估计方差，为设计未来的基因。 环境互作作图研究以确定与抗病或感病相关的遗传基因座 皮肤致敏后的呼吸道炎症，以及(6)建立DA基准剂量模型的遗传学基础 风险评估。

ABSTRACT Diisocyanate (DI) exposure is a prominent cause of occupational asthma and an estimated 280,000 workers are exposed to isocyanates in the US alone. Workers who use products containing DI are exposed to both monomeric and polymeric DIs and ≈10% develop DI-induced asthma (DA). DA has been linked to skin and inhalation exposure to DIs in humans, guinea pigs, and mice. The sensitization capacity of polymeric DIs has been shown to be greater than monomers in both humans and animals. Further, polymeric DI exposure encompasses the vast majority of the total exposure in DI-exposed workers. DA is likely caused by inter-individual differences in levels of exposure and inherited genetic variants. Therefore, it is critical to determine the relative potency and dose-relationships between monomeric and polymeric DIs on the development of DA. Our goal is to better understand the genetic and mechanistic basis for DA susceptibility. Due to the strong sensitization capacity of DIs and their potential presence in consumer products, sensitization studies using human volunteers is unethical. Thus, we propose to use the genetically diverse Collaborative Cross recombinant inbred lines (CC RIL), an experimental mouse model, to investigate DA susceptibility. To accomplish our goal, we will identify inter-individual (strain) differences and the dose-response relationships between 1,6-hexamethylene diisocyanate (HDI) monomer and its oligomer HDI isocyanurate, model chemicals that have been shown to cause DA, on the development of allergic airway inflammation response in homozygous inbred BALB/cJ and CC RIL mice. Preclinical animal toxicity studies of DI allergenicity have been performed mostly in homozygous inbred BALB/cJ mice. Genetic diversity in a single or limited number of inbred mice, like BALB/cJ, may limit translation of findings to human DA susceptibility. CC RIL mice have a genetic diversity (≥45 million genome-wide genetic markers) and genomic architecture similar to human populations but with a balanced minor allele frequency of 12%, which greatly increases power for identification of genetic variants using genome-wide association studies. By defining inter-individual differences and a mechanistic basis for a benchmark response to occupational exposure stressors, we can guide exposure and risk assessment in human populations. The scope of this research is consistent and amplifies NIOSH goals benefitting two NIOSH NORA sectors (Services and Manufacturing), the new NORA Immune, Infectious and Dermal Disease Prevention Cross-Sector goals, and NIOSH r2p initiative to reduce and prevent occupational diseases. The Outputs and Outcomes from this study can be summarized as follows: this experimental model will be a significant step forward in the (1) development of predictive in vivo models to discover causal variants, (2) identification of biomarkers of exposure relevant to humans, (3) determination of a benchmark-dose response, (4) determination of the systems-level adverse outcome pathways for DI skin-airway sensitization and elicitation of delayed-type immunity in the airways, (5) estimating variance for designing future gene- environment interaction mapping studies to identify genetic loci associated with either resistance or susceptibility to airway inflammation following skin sensitization, and (6) establishing a genetic basis for DA benchmark-dose models for risk assessment.