Mitochondrial-mediated Lung Injury mechanisms of QACs in vivo

QACs 体内线粒体介导的肺损伤机制

基本信息

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
项目类别：
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

项目摘要

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：体内 QAC 线粒体介导的肺损伤机制项目概要/摘要季铵盐 (QAC)，例如苯扎氯铵 (BAC) 和二甲基二癸基氯化铵（DDAC）广泛用于许多消毒剂和清洁剂中，很可能有超过100万美国人接触过每天发送至 BAC/DDAC。尽管 QAC 被认为是安全的，并且被“祖父”纳入美国监管机构 20 世纪 60 年代的系统中，我们最近的试点人体暴露数据表明，BAC/DDAC 等 QAC 存在于人体中 1/3 样本群体中的血浆浓度范围为 10-150 nM，高于美国环境保护局机构内部风险的“可采取行动”水平。我们的人体暴露试验研究进一步表明 QAC 的存在人类血液中的线粒体与白细胞中最大线粒体呼吸的降低密切相关。我们之前和正在进行的体外研究表明，QAC（例如 BAC）可抑制线粒体功能并抑制 100 体内的雌激素信号传导 10,000 nM (0.000004% - 0.0004% w/w) 范围，该浓度范围与 QAC 的 10-150 nM 血浆水平重叠在人类中表现出线粒体毒性。根据我们的研究，加州公共卫生部将 QAC 列为用于生物监测目的的优先化学品。当前新冠肺炎疫情期间，基于 QAC 的消毒剂的使用增加了许多倍，并且大多数消毒剂是通过雾化器和喷雾剂施用的，这表明潜在的人类的雾化吸入暴露。尽管临床研究表明接触 QAC 会导致支气管收缩和肺损伤的细胞靶点和分子机制目前尚不清楚。这应用探索了动物模型中通过吸入的全身吸收，建立了剂量依赖性体内线粒体抑制并阐明 QAC 诱导的肺损伤的分子机制和细胞靶点。目标 1 是体内系统性 BAC/DDAC 线粒体抑制的浓度-反应研究，并阐明肺损伤的分子机制。目标 2 将评估 QAC 引起的肺毒性的严重程度并阐明体内的细胞靶标。目标 3 将开发一种可靠的方法来检测生物基质中的 QAC 并测量吸入剂量动物组织中的 BAC/DDAC 水平。这些研究的完成将决定 BAC/DDAC 是否可以通过吸入被系统吸收，是体内的线粒体毒素，线粒体是否 BAC/DDAC 的抑制特性导致其肺部毒性所有这些最终都可以支持更多就人类可能安全的 QAC 暴露相对范围做出明智的决策。