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

项目摘要/摘要 2018年大麻二酚合法化开启了故意将大麻二酚化学转化为Δ8的大门-- 四氢大麻酚(Δ8-THC)，一种未受监管的精神活性大麻素。含有Δ8-THC的蒸发产品 自那以后迅速受到消费者的欢迎；然而，人们对它们的呼吸道健康知之甚少 效果。随着最近电子烟的爆发，迫切需要评估蒸发Δ8-THC的效果 蒸发产品相关肺损伤包括Δ8-THC蒸发产品使用者。此外，蒸发- 诱导热氧化过程可以将Δ8-THC转化为活性亲电体，包括Δ8-THC的苯二酚 和CBDQ(Δ-8-THCq和CBDq)，可能引起肺损伤。我们的长远目标是加强 通过向公众提供有关VapingΔ8-THC和引导的准确安全信息，保护所有个人的健康 关于Δ8-THC和其他大麻素的监管决策。这项建议的目标是理解 蒸发Δ8-THC如何改变正常肺细胞功能及其调节机制。中环 假设含有促氧化剂杂质的雾化Δ8-THC蒸发液体产生活性Δ8- THCq和CBDq，它们加成了蛋白质硫醇残基，损害了人呼吸道的正常生物途径 上皮细胞。我们的具体目标将决定(目标1)雾化Δ8-THC蒸发产品如何改变正常 呼吸道上皮细胞功能，(目标2.1)包括金属和调味品在内的杂质如何影响 Δ8-Thc氧化为对苯二酚Δ8-Thcq和CBDq，并(Aim 2.2)形成呼吸道上皮细胞蛋白加合物 来自VapingΔ8-THC。这项提议的结果将是重大的，因为它们将第一次确定影响 雾化吸入Δ8-Thc对正常气道功能和蒸发诱导的Δ8-Thc“内收环”的影响。这个项目是 创新性地使用(1)一种新的体外蒸发产品暴露系统(VAPES)来评估Δ8- 气溶胶对气液界面原代培养的人支气管上皮细胞的作用及(2)炔基标记 大麻素和点击化学方法发现共价修饰的蛋白质的加合物组 Δ8-THC氧化产物。这项提议将提供包括化学品在内的技术技能培训机会。 分析蒸发的冷凝物，点击化学，和蛋白质组分析，这对我的发展至关重要 作为一名独立科学家。最后，我将加强我在科学传播和这方面的影响方面的培训 通过将这项建议的结果转化为我将 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.