Mitochondrial-mediated Lung Injury mechanisms of QACs in vivo

QACs 体内线粒体介导的肺损伤机制

• 批准号: 10467271
• 负责人: Gino A Cortopassi
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467271
• 关键词: Affect; American; Ammonium; Animal Model; Animals; Asthma; Atomizer; Benzalkonium Chloride; Biological; Biological Monitoring; Blood; Bronchoconstriction; COVID-19 pandemic; California; Cations; Cells; Chemicals; Chlorides; Clinical Research; Complex; Culture Media; Cytosol; Data; Decision Making; Detection; Development; Disinfectants; Dose; Drug or chemical Tissue Distribution; Estrogens; Exposure to; Future; Household; Human; Human body; In Vitro; Inflammatory; Inhalation; Inhalation Exposure; Lead; Liquid substance; Liver; Lung; Measures; Mediating; Methods; Mitochondria; Molecular; Monitor; Mus; Muscle; Muscle Cells; Names; Pattern; Phase; Pilot Projects; Plasma; Population; Property; Public Health; Pulmonary Inflammation; Reaction; Respiration; Safety; Salts; Sampling; Signal Transduction; Specimen; Stable Isotope Labeling; System; Toxic effect; Toxicology; Toxin; United States Environmental Protection Agency; Urine; absorption; aerosolized; analytical method; animal tissue; base; cell type; cellular targeting; chemical property; cytotoxicity; detection limit; detection method; eosinophil; experimental study; exposed human population; in vivo; inhibitor; instrument; irritation; lung injury; mass spectrometer; minimal risk; neutrophil; pandemic disease; quaternary ammonium compound; response; rho; tandem mass spectrometry

Title: Mitochondrial-mediated Lung Injury mechanisms of QACs in vivo Project Summary/Abstract Quaternary ammonium salts (QACs) such as benzalkonium chloride (BAC) and dimethyldidecylammonium chloride (DDAC) are widely used in many disinfectants and cleaners, and it is likely that more than 1 million Americans get exposed to BAC/DDAC on a daily basis. Although QACs have been considered safe, and were 'grandfathered' into US regulatory system in 1960s, our recent pilot human exposure data demonstrate that QACs such as BAC/DDAC are present in human plasma in 1/3rd of sample population at the range of 10-150 nM which is greater than the US Environmental Protection agency's `actionable' level for internal exposure. Our pilot human exposure study further shows that the presence of QACs in human blood strongly correlates with decreased maximal mitochondrial respiration in WBCs. Our previous and ongoing in vitro studies show that QACs such as BACs inhibit mitochondrial function and suppress estrogen signaling in the 100 - 10,000 nM (0.000004% - 0.0004% w/w) range, and this concentration range overlaps the 10-150 nM plasma levels of QACs in humans showing mitochondrial toxicity. Based on our studies California Department of Public Health has listed QACs as priority chemicals for biomonitoring purposes. During the current COVID19 pandemic, usage of QAC-based disinfectants has increased many fold and most of these disinfectants are applied through atomizers and sprays suggesting a potential aerosolized inhalation exposure to humans. Although clinical studies have demonstrated that exposure to QACs can cause bronchoconstriction and lung injury, the cellular targets and the molecular mechanisms are currently unknown. This application explores the systemic absorption through inhalation in an animal model, establishes a dose-dependent mitochondrial inhibition in vivo and elucidate the molecular mechanism and cellular targets for QAC-induced lung injury. Aim 1 is a concentration-response study of systemic BAC/DDAC mitochondrial inhibition in vivo and elucidation of molecular mechanism of lung injury. Aim 2 will evaluate the magnitude of QAC-induced pulmonary toxicity and elucidate the cellular targets in vivo. Aim 3 will develop a reliable method to detect QACs in biological matrices and measure BAC/DDAC levels in inhalation-dosed animal tissues. The completion of these studies will determine whether BAC/DDAC can get absorbed systematically through inhalation and are mitochondrial toxins in vivo, and whether mitochondrial inhibitory property of BAC/DDAC is responsible for their pulmonary toxicity All of these could ultimately support more educated decision making about the relative range of QAC exposure that may be safe in humans.

标题：QAC在体内的线粒体介导的肺损伤机制 项目摘要/摘要 第四纪铵盐（QAC），例如氯化苯甲酸盐（BAC）和二甲基二甲基氯铵 （DDAC）在许多消毒剂和清洁剂中广泛使用，并且可能有超过100万的美国人暴露 每天进行BAC/DDAC。尽管QAC被认为是安全的，并且被“祖父”进入美国监管 1960年代的系统，我们最近的试验人类暴露数据表明，诸如BAC/DDAC之类的QAC存在于人类中 在10-150 nm范围内1/3的样本人群中的等离子体大于美国环境保护 代理商的“可行”水平用于内部暴露。我们的飞行员人类暴露研究进一步表明QAC的存在 在人类血液中，WBC中的最大线粒体呼吸密切相关。我们以前的和正在进行的 体外研究表明，诸如BAC之类的QAC抑制线粒体功能并抑制100-中的雌激素信号传导。 10,000 nm（0.000004％-0.0004％w/w）范围，此浓度范围与10-150 nm血浆QAC的水平重叠 在人类中显示线粒体毒性。根据我们的研究，加利福尼亚公共卫生部已将QACS列为 用于生物监测目的的优先化学品。在当前的Covid19大流行期间，使用基于QAC的消毒剂 已经增加了许多折叠，大多数这些消毒剂都是通过雾化器和喷雾来应用的 吸入吸入对人的接触。尽管临床研究表明，暴露于QAC会导致 当前未知细胞收缩和肺损伤，细胞靶标和分子机制。这 应用通过在动物模型中吸入探索系统吸收，建立剂量依赖性 线粒体在体内抑制，并阐明了QAC诱导的肺损伤的分子机制和细胞靶标。 AIM 1是全身性BAC/DDAC线粒体抑制体内的浓度反应研究和阐明 肺损伤的分子机制。 AIM 2将评估QAC诱导的肺毒性的大小并阐明 体内细胞靶标。 AIM 3将开发一种可靠的方法来检测生物矩阵中的QAC并测量 吸入剂量的动物组织中的BAC/DDAC水平。这些研究的完成将确定BAC/DDAC是否 可以通过吸入系统地吸收，并且是体内线粒体毒素，以及是否线粒体 BAC/DDAC的抑制特性负责其肺毒性，所有这些最终都可以支持更多 关于人类可能安全的QAC暴露范围的有根据的决策。