Differentiating the biological effects of vaping from smoking by analyzing the methylome and transcriptome

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Responsiveness to NOT-OD-22-022: This proposal will segregate the biological effects of electronic cigarette (e-cig) use (‘vaping’) from smoking by measuring the epigenetic and transcriptomic changes linked to risk of disease in cells and tissues of healthy adult vapers and/or cigarette smokers as compared to controls (non-users of either product). Furthermore, it will determine whether these molecular alterations are modulated by the intensity and duration of vaping/smoking and the characteristics of tobacco product(s) used, including e-cig device features and e-liquid ingredients, and cigarette brand, type, and chemical constituents. By elucidating the molecular mechanisms underlying the biological effects of vaping vs. smoking, we will develop novel biomarkers of exposure and effects, which will have significant utility for assessing the health risks or potential benefits of vaping relative to smoking. Rationale: Adult e-cig users are likely to have a prior history of smoking or co-use e-cigs and combustible cigarettes (i.e., dual users). To investigate the biological effects of e-cig use in adults, it is imperative to tease out the consequences of vaping, while accounting for the confounding effects of ‘past’ or ‘present’ smoking. Premise: Many toxicants and carcinogens present in e-cig vapor and cigarette smoke exert their biological effects through epigenetic effects, such as aberrant DNA methylation, and/or transcriptomic alterations that can lead to dysregulation of disease-related genes. Project outline: Leveraging the banked specimens from our recently completed NIDCR- and TRDRP-funded studies, we will differentiate the biological consequences of e-cig use from those of smoking by analyzing the whole methylome and transcriptome in oral- and blood cells of healthy adult ‘exclusive’ vapers, dual users, ‘exclusive’ cigarette smokers, and controls. We will use a novel approach, combining primary analysis of the whole methylome (Aim 1) and transcriptome (Aim 2) and ordinal sensitivity analysis of various models built on vaping/smoking dose and tobacco product characteristics (Aim 3). Integrative analysis of data from Aims 1 and 2 will determine the methylome and transcriptome changes that regulate disease-specific genes, thus identifying novel biomarkers of exposure and effects for vaping, dual use, and smoking. We will validate the identified biomarkers in patient populations using highly curated and quality-controlled ‘omics’ datasets processed from public sources. This will verify the utility of the identified biomarkers for assessing disease risk in exclusive’ e-cig users, dual users, and ‘exclusive’ smokers. The detailed computational modeling and sensitivity analysis in Aim 3 will determine the impact of vaping/smoking dose and product characteristics on the alterations of the methylome & transcriptome in vapers, dual users, and smokers. These data will inform the FDA’s regulation of tobacco products to protect public health. Innovation: We will investigate the effects of e-cig aerosol and cigarette smoke on cells and tissues of vapers and/or smokers using genome-wide sequencing of the methylome & transcriptome and integrative bioinformatic analysis & computational modeling, accounting for vaping/smoking dose and product characteristics.