Respiratory health effects of aerosolized delta-8-THC and its oxidation products

项目概要/摘要 2018年大麻二酚（CBD）的合法化为有意将CBD化学转化为Δ8打开了大门- 四氢大麻酚（Δ8-THC），一种不受管制的精神活性大麻素。含有Δ8-THC的电子烟产品 从那以后，它们迅速受到消费者的欢迎;然而，人们对它们的呼吸系统健康知之甚少。 方面的影响.由于最近电子烟的爆发，迫切需要评估Δ8-THC的影响 电子烟产品相关肺损伤（EVALI）包括Δ8-THC电子烟产品使用者。此外，vaping- 诱导热氧化过程可以将Δ8-THC转化为反应性亲电体，包括Δ8-THC醌 和CBD醌（Δ8-THCq和CBDq），其可导致肺损伤。我们的长远目标是加强 通过向公众提供有关vaping Δ8-THC的准确安全信息， 对Δ8-THC和其他大麻素的监管决策。本提案的目的是了解 Δ8-THC如何改变正常肺细胞功能以及介导这些效应的机制。中央 假设是含有促氧化剂杂质的雾化Δ8-THC蒸汽烟液体产生反应性Δ8-THC， THCq和CBDq，它们加合蛋白巯基残基并损害人气道中的正常生物途径 上皮细胞我们的具体目标将确定（目标1）雾化Δ8-THC电子烟产品如何改变正常 气道上皮细胞功能，（目标2.1）包括金属和调味化学品在内的杂质如何影响 Δ8-THC氧化为醌Δ8-THCq和CBDq，并且（目的2.2）形成气道上皮细胞蛋白加合物 吸Δ8-四氢大麻酚这项建议的结果将是重要的，因为它们将首次确定 雾化的Δ8-THC对正常气道功能的影响以及蒸汽诱导的Δ8-THC“内收器”。这个项目是 创新地使用（1）一种新型的体外Vaping产品暴露系统（VaPES），以评估Δ8- THC气溶胶对在空气-液体界面生长的原代人支气管上皮细胞的作用和（2）炔基标记的 大麻素和点击化学方法，以揭示通过共价修饰的蛋白质的“内收体”， Δ8-THC氧化产物。本提案将提供技术技能培训机会，包括化学 分析vaped冷凝物，点击化学和蛋白质组学分析，这对我的发展至关重要 作为一个独立的科学家。最后，我将加强我在科学传播方面的培训， 通过将这项建议的结果转化为一个我将 在当地初中和高中实施。

PROJECT SUMMARY/ABSTRACT Legalization of cannabidiol (CBD) in 2018 opened the door to intentional chemical conversion of CBD to Δ8- tetrahydrocannabinol (Δ8-THC), an unregulated psychoactive cannabinoid. Vaping products containing Δ8-THC have since rapidly gained popularity with consumers; however, little is known about their respiratory health effects. There is an urgent need to evaluate the effects of vaping Δ8-THC as the recent outbreak of e-cigarette and vaping product associated lung injury (EVALI) included Δ8-THC vaping product users. Additionally, vaping- induced thermal oxidation processes can convert Δ8-THC into reactive electrophiles, including Δ8-THC quinone and CBD quinone (Δ8-THCq and CBDq), which may cause lung injury. Our long-term goal is to enhance the health of all individuals by providing the public with accurate safety information about vaping Δ8-THC and guiding regulatory decision making on Δ8-THC and other cannabinoids. The objective of this proposal is to understand how vaping Δ8-THC alters normal lung cell function and the mechanism mediating these effects. The central hypothesis is that aerosolized Δ8-THC vaping liquids containing pro-oxidant impurities generate reactive Δ8- THCq and CBDq, which adduct protein thiol residues and impair normal biological pathways in human airway epithelial cells. Our specific aims will determine (aim 1) how aerosolized Δ8-THC vaping products alter normal airway epithelial cell function, (aim 2.1) how impurities including metals and flavoring chemicals affect the oxidation of Δ8-THC to quinones Δ8-THCq and CBDq, and (aim 2.2) airway epithelial cell protein adducts formed from vaping Δ8-THC. The results of this proposal will be significant as they will identify for the first time the effects of aerosolized Δ8-THC on normal airway function and the vaping-induced Δ8-THC “adductome”. This project is innovative in its use of (1) a novel in vitro Vaping Product Exposure System (VaPES) to assess the effects of Δ8- THC aerosols on primary human bronchial epithelial cells grown at air-liquid interface and (2) alkynyl-tagged cannabinoids and click chemistry methodologies to uncover the “adductome” of proteins covalently modified by Δ8-THC oxidation products. This proposal will provide training opportunities in technical skills including chemical analysis of vaped condensates, click chemistry, and proteomic analysis, which will be critical for my development as an independent scientist. Finally, I will enhance my training in science communication and the impact of this work on the health of our community by translating the findings of this proposal into a lesson plan that I will implement at local middle and high schools.