Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Increasingly, consumers are vaping cannabinoids such as cannabidiol (CBD) or CBD-derived tetrahydrocannabinols (THCs), such as Delta-8-tetrahydrocannabinol (∆8-THC) and other THC isomers. Like in nicotine-containing e-liquids, flavoring chemicals are intentionally added to THC vaping liquids to make them more appealing for customers. In addition, metals, terpenes, pesticides, and microbial products have also been identified in commercially available THC vaping liquids. Chemical stability studies indicate that THCs can readily oxidize. Specifically, CBD and Δ8-THC have been shown to oxidize to their reactive quinone (CBDq and Δ8- THCq). Contaminant metals, such as Cu and Fe, catalyze the oxidation to Δ8-THCq. Similarly, flavoring chemicals like furanone compounds, providing a fruity flavor, have been shown to be pro-oxidants. However, the extent to which vaping liquid constituents, like metals and flavoring chemicals, oxidize THC isomers to reactive electrophilic quinones or other oxidation products and whether they pose a significant risk for lung health is completely unknown. Quinones, such as CBDq and Δ8-THCq, are Michael acceptors capable of covalently modifying biological molecules, especially proteins containing thiol groups. We hypothesize that 1) constituents like flavoring chemicals and metals, increase vaping-induced oxidation of THC and 2) the resulting quinone oxidation products cause airway epithelial cell toxicities through protein modification. Aim 1 will identify vaping- induced oxidation products and determine how vaping liquid constituents (metals, flavoring chemicals) affect the oxidation of THC isomers. Aim 2 will use our newly developed in vitro Vaping Product Exposure System (VaPES) to expose differentiated human bronchial epithelial cells (HBECs) to 1) commercial liquids, 2) lab-made liquids containing specific constituents, or 3) specific oxidation products. Aim 2 will link pro-oxidant constituents with protein adduction to cellular thiol groups and biological responses. Alkyne-tagged CBD and Δ8-THC analogues have been prepared for use in “click” cycloaddition to identify protein adduction of inhaled oxidant. In addition to specific targets, major proteins in the overall “adductome” will be identified, this uncovering novel cellular targets and biological pathways affected by inhalation of THC oxidation products. Aim 3 will collect nasal mucosal samples from non-vapers and frequent THC vapers and examined for a) tissue-level gene expression, b) untargeted metabolomic and proteomic profiles, and c) chemical biomarkers of exposure. Integrate multi-omic computational data analysis will be applied to uncover dysregulated immune pathways in the nasal mucosa of THC vapers. Data obtained from this grant will identify constituents of commercial THC vaping products impacting oxidation, toxicity, and normal functions of the airway mucosa in vitro and in vivo. To better understand the interaction between vaping-induced oxidation of THC products, signaling cascade initiation, and respiratory mucosal immune signaling, the translational and integrated multi-omic analysis proposed here, is critical for advancing the safety of THC vaping products.
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