Mitochondrial-mediated Lung Injury mechanisms of QACs in vivo

QACs体内线粒体介导的肺损伤机制 项目摘要/摘要 季铵盐(QAC)，如苯扎氯铵(BAC)和二甲基二癸基氯化铵(DMDAC) (DdAC)被广泛用于许多消毒剂和清洁剂，很可能有100多万美国人接触到 每天向BAC/DDAC发送数据。尽管QAC一直被认为是安全的，并被纳入美国监管机构 系统在20世纪60年代，我们最近的试点人体暴露数据表明，QAC，如BAC/DDAC存在于人类中 1/3样本人群在10-150 nm范围内的血浆浓度大于美国环保局 机构内部风险暴露的“可起诉”水平。我们的试验性人体暴露研究进一步表明，QAC的存在 人血中线粒体的最大呼吸与WBC中线粒体最大呼吸量的降低密切相关。我们之前和正在进行的 体外研究表明，BAC等QAC抑制了100-10h的线粒体功能和雌激素信号转导。 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 在表现出线粒体毒性的人类身上。根据我们的研究，加州公共卫生部已将QAC列为 用于生物监测的优先化学品。在目前的COVID19大流行期间，使用基于QAC的消毒剂 已经增加了许多倍，大多数这些消毒剂是通过雾化器和喷雾来使用的，这表明 对人体的雾化吸入暴露。尽管临床研究表明暴露在QAC中会导致 支气管收缩和肺损伤，其细胞靶点和分子机制目前尚不清楚。这 在动物模型中通过吸入探索全身吸收，建立了剂量依赖关系 体内线粒体抑制，阐明QAC致肺损伤的分子机制和细胞靶点。 目的1是体内全身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引起的肺毒性的大小并阐明 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 吸入剂量的动物组织中的BAC/DDAC水平。这些研究的完成将决定BAC/DDAC是否 能否通过吸入全身吸收和体内线粒体毒素，以及线粒体是否 BAC/DDAC的抑制性是其肺部毒性的原因，所有这些最终都可能支持更多 关于QAC暴露在人体内可能是安全的相对范围的明智决策。

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.