Mitochondrial-mediated Lung Injury mechanisms of QACs in vivo

标题：体内QAC的线粒体介导的肺损伤机制 项目概要/摘要 季铵盐（QAC），如苯扎氯铵（BAC）和二甲基二癸基氯化铵 （DDAC）被广泛用于许多消毒剂和清洁剂，可能有超过100万美国人接触到DDAC。 BAC/DDAC每天尽管QAC被认为是安全的，并且被“祖父”纳入美国监管机构， 我们最近的试验性人体暴露数据表明，人体中存在BAC/DDAC等QAC 1/3样品群体中血浆浓度在10-150 nM范围内，高于美国环境保护署 机构内部暴露的“可采取行动”水平。我们的初步人体暴露研究进一步表明，QAC的存在 与WBC中最大线粒体呼吸降低密切相关。我们以前和正在进行的 体外研究表明，QAC如BAC抑制线粒体功能，并抑制100 - 2000个细胞中的雌激素信号传导。 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 表现出线粒体毒性根据我们的研究，加州公共卫生部已将QAC列为 用于生物监测目的的优先化学品。在当前的COVID 19大流行期间，使用QAC消毒剂 增加了许多倍，这些消毒剂中的大多数是通过雾化器和喷雾器应用的，这表明潜在的 人体吸入气雾剂。尽管临床研究表明接触QAC可导致 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 本申请在动物模型中探索了通过吸入的全身吸收， 线粒体抑制，阐明QAC诱导的肺损伤的分子机制和细胞靶点。 目的1是在体内进行全身性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的2将评价QAC诱导的肺毒性的程度，并阐明 体内的细胞靶点。目的3建立一种可靠的检测生物基质中QAC的方法， 吸入给药动物组织中的BAC/DDAC水平。这些研究的完成将决定BAC/DDAC是否 可以通过吸入系统吸收，在体内是线粒体毒素， BAC/DDAC的抑制特性是其肺毒性的原因。所有这些最终可能支持更多 就QAC暴露的相对范围做出有教育意义的决策，这可能对人类安全。

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.