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Multidimensional Exposure Architecture Shapes Vaping-Associated Transcriptomic Dysregulation in Oral Epithelium

ABSTRACT: Electronic cigarette (e-cig) use (vaping) has been associated with dysregulation of genes and molecular pathways in epithelial tissues. However, the relative contributions of dose and product characteristics to vaping-associated transcriptomic alterations have not been systematically evaluated. We performed RNA-sequencing of oral epithelial cells from e-cig users (vapers), cigarette smokers, and non-users. Differential gene expression was assessed using covariate-adjusted limma-voom modeling with false discovery rate control. We evaluated the extent to which exposure-specific dose metrics (including cumulative e-liquid, cumulative e-nicotine, years vaped, and plasma cotinine for vaping, and pack-years and plasma cotinine for smoking) explained transcriptional changes. Among vapers, we additionally examined whether device generation and flavor type contributed to variation in gene expression. Both vaping and smoking were associated with transcriptomic dysregulation relative to non-users, with partial overlap in differentially expressed genes (DEGs). Functional enrichment analyses revealed disruption of shared cancer- and signaling pathways, including RHO GTPase Cycle, as well as perturbation of pathways specific to vapers or smokers. Among vapers, 27.6% of DEGs showed concordant behavior across all dose metrics, indicating heterogeneous dose-response patterns for the remaining DEGs. Device generation and flavor type explained additional, largely non-overlapping components of gene expression variability. A much higher proportion of smoking-associated DEGs (54.1%) was consistently affected across dose metrics, reflecting more unified dose-dependent responses. These findings suggest that vaping-associated transcriptional dysregulation reflects combined influences of dose and product characteristics, highlighting structural differences in molecular perturbations between vaping and smoking. Incorporating multidimensional exposure metrics and product features into regulatory evaluation may better capture the biological complexity of e-cig exposure, thus informing clinical, public health practice, and regulatory decisions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330022 | GEO | 2026/06/24

REPOSITORIES: GEO

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Project description:Background: Adult vapers are likely to co-use electronic cigarettes (e-cigs) and combustible cigarettes or have a prior history of smoking. Teasing out the health consequences of vaping in adults, while accounting for the confounding effects of smoking, remains a research priority. Methods: We have segregated the biological effects of vaping from smoking by constructing the whole transcriptome in leukocytes of healthy adult vapers (with and without a history of smoking) and exclusive smokers in comparison to control nonsmokers non-vapers (n = 37, 22, 23, respectively). Results: Age- and sex-adjusted limmaVoom analysis of RNA-seq data showed significant dysregulation of key genes and molecular pathways in both vapers and smokers as compared to controls. The extent of transcriptomic effects, as reflected by the number of differentially expressed genes, was more pronounced in smokers than vapers (683 vs. 92). Computational modeling, combining primary and sensitivity analyses, revealed that e-cig use, but not past smoking, is significantly associated with gene dysregulation in vapers. Comparative analysis of the gene networks and canonical pathways impacted in vapers and smokers showed strikingly similar biological outcomes in the two groups, although the number of affected genes was several-fold higher in smokers than vapers. Of significance is the preferential targeting of mitochondrial genes in both vapers and smokers, consistent with impaired functional networks, which are known to drive mitochondrial DNA-related disorders. Equally remarkable is the dysregulation of immune response genes in both vapers and smokers, modulated by upstream cytokines, including members of the interleukin and interferon family, that play a crucial role in inflammation. Conclusions: The concurrent targeting of mitochondrial- and immune response genes in vapers and smokers suggests a consequential role for vaping and smoking in inflammation. Our findings accord with the growing evidence on the central role of mitochondria as signaling organelles that govern fundamentals of immunity and inflammatory response. In view of the widespread use of e-cigs among youth and young adults, these novel findings have significant implications for tobacco regulatory science and public health.

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Multidimensional Exposure Architecture Shapes Vaping-Associated Transcriptomic Dysregulation in Oral Epithelium

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