Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. Previous studies have identified AgNP toxicity in airway epithelial cells, but no in vitro studies to date have used organotypic cultures as a high-content in vitro model of the conducting airway to characterize the effects of interactions between host genetic and acquired factors, or gene × phenotype interactions (G × P), on AgNP toxicity. In the present study, we derived organotypic cultures from primary murine tracheal epithelial cells (MTEC) to characterize nominal and dosimetric dose-response relationships for AgNPs with a gold core on barrier dysfunction, glutathione (GSH) depletion, reactive oxygen species (ROS) production, lipid peroxidation, and cytotoxicity across two genotypes (A/J and C57BL/6J mice), two phenotypes (‘Normal’ and ‘Type 2 [T2]-Skewed’), and two exposures (an acute exposure of 24 h and a subacute exposure of 4 h, every other day, over 5 days [5 × 4 h]). We characterized the ‘T2-Skewed’ phenotype as an in vitro model of chronic respiratory diseases, which was marked by increased sensitivity to AgNP-induced barrier dysfunction, GSH depletion, ROS production, lipid peroxidation, and cytotoxicity, suggesting that asthmatics are a sensitive population to AgNP exposures in occupational settings. This also suggests that exposure limits, which should be based upon the most sensitive population, should be derived using in vitro and in vivo models of chronic respiratory diseases. This study highlights the importance of considering dosimetry as well as G × P effects when screening and prioritizing potential respiratory toxicants. Such in vitro studies can be used to inform regulatory policy aimed at special protections for all populations.

银纳米颗粒 (AgNP) 有多种应用，但主要用于抗菌产品的制造。先前的研究已经确定了 AgNP 对气道上皮细胞的毒性，但迄今为止还没有体外研究使用器官型培养物作为传导气道的高含量体外模型来表征宿主遗传因素和获得性因素或基因×之间相互作用的影响。表型相互作用 (G × P)，对 AgNP 毒性的影响。在本研究中，我们从原代小鼠气管上皮细胞 (MTEC) 中获得器官型培养物，以表征金核 AgNP 对屏障功能障碍、谷胱甘肽 (GSH) 消耗、活性氧 (ROS) 产生的名义和剂量剂量反应关系两种基因型（A/J 和 C57BL/6J 小鼠）、两种表型（“正常”和“2 型 [T2]-偏斜”）和两次暴露（急性暴露 24 小时和亚急性暴露 4 小时，每隔一天，持续 5 天 [5 × 4 小时]）。我们将“T2-Skewed”表型描述为慢性呼吸道疾病的体外模型，其特点是对 AgNP 诱导的屏障功能障碍、GSH 耗竭、ROS 产生、脂质过氧化和细胞毒性的敏感性增加，这表明哮喘患者是一种敏感的慢性呼吸道疾病。职业环境中暴露于 AgNP 的人群。这也表明暴露限值应基于最敏感人群，并应使用慢性呼吸道疾病的体外和体内模型得出。这项研究强调了在筛选和优先考虑潜在呼吸道毒物时考虑剂量测定以及 G × P 效应的重要性。此类体外研究可用于为旨在为所有人群提供特殊保护的监管政策提供信息。