Transcriptomic and functional responses of human airway cells to vaped ∆8-THC and its oxidation product ∆8-THCQ

Abstract

Δ8-tetrahydrocannabinol (Δ8-THC) products have expanded rapidly since the 2018 Farm Bill, yet they remain largely unregulated despite containing high cannabinoid levels, additives, and contaminants, and growing evidence of respiratory risks. We identify the reactive electrophile Δ8-THC quinone (Δ8-THCQ, HU-336) as a major constituent of commercial Δ8-THC distillates and disposable vape products, with concentrations increasing substantially after vaping. Across high-potency products, Δ8-THCQ rose an average of 3.67-fold, reaching millimolar levels. While Δ8-THC alone did not elicit a statistically distinct transcriptomic signature from the vehicle control in a bronchial epithelial cell line, Δ8-THCQ caused marked gene-expression changes, activating cilia-related, stress-response, xenobiotic-metabolism, and inflammatory pathways. Using primary differentiated human bronchial epithelial cells and the UNC Vaping Product Exposure System (VaPES), we found that aerosols from commercial Δ8-THC mixtures rapidly induced immediate-early stress genes, suppressed ribosomal and mitochondrial programs, and activated fibrosis-linked signaling. In contrast, Δ8-THC-containing “juice” products had milder effects, mainly upregulating cell-cycle and proliferation pathways. Computational analyses linked the chemical composition of Δ8-THC aerosols to distinct transcriptional responses, identifying clusters of compounds driving specific airway effects. Functionally, distillate and disposable aerosols impaired motile-cilia activity. Collectively, these findings indicate that vaping generates substantial Δ8-THCQ and suggest that repeated inhalation may disrupt mucociliary defense and raise concern for chronic airway injury warranting further investigation.