Abstract Rationale Dual-use, the concurrent use of both e-cigarettes and traditional cigarettes, is prevalent with ∼30% of e-cigarette users engaging in dual-use. One distinction between exclusive e-cigarette use and dual-use is the patterns of toxicant exposures, potentially resulting in synergistic cardiopulmonary effects, creating a need for independent investigation. Hypothesis Dual-use results in increased heart and lung transcriptomic alterations providing a basis for early detection of cardiopulmonary toxicity in exclusive third- or fourth-generation e-cigarette users. Methods Adult male and female mice were exposed by inhalation for 4 months to either 1) air, 2) cigarette smoke plus third-generation e-cigarette aerosols (dual-use), 3) third-generation e-cigarette aerosols or 4) fourth-generation e-cigarette aerosols. All vaping products contained tobacco flavor and 30 mg/mL of either freebase nicotine (third-generation) or nicotine salt (fourth-generation). Exposure duration-dependent transcriptomic changes in the heart and lungs were evaluated at 2 and 4 months, plus following 1-month of recovery. Results In the heart, transcriptomic alterations were greater in male mice following dual-use, fourth-generation, and third-generation e-cigarette exposures, with 31, 22, and 16 genes dysregulated, respectively. Whereas in female mice, fewer changes in heart genes were noted, with dual-use, third-generation, and fourth-generation exposures dysregulating 19, 14, and 10 genes, respectively. The majority of the genes were down-regulated and Sfrp4, a gene involved in cardiac remodeling, plus Mmp-13, implicated in extracellular matrix remodeling, were commonly dysregulated in all groups. Further, genes encoding for collagen (Col) and atrial natriuretic peptide (Nppa, Nppb), associated with remodeling and cardiac stress, respectively, were down-regulated in both the dual-use and third-generation e-cigarette groups. In males, lung transcriptomic changes were robust, as evidenced by time-dependent gene dysregulation with dual-use (28, 101, and 106 genes at 2, 4 months, and following recovery, respectively) and fourth-generation e-cigarettes (70, 76, and 56 genes at 2, 4 months, and following recovery, respectively). In the third-generation e-cigarette group, transcriptomic patterns reflecting adaptative responses during exposures followed by tissue repair upon cessation were noted, with 292, 65 and 129 genes dysregulated at 2, 4 months, and following recovery, respectively. Common dysregulated gene-networks in all groups included innate immune response, circadian rhythm, and IL-17 signaling, which can lead to increased transcription of matrix metalloproteinases. Conclusion While transcriptomic alterations in the heart and lungs are dynamic during and after exposures, taken together, our data suggest that networks of dysregulated genes associated with cardiac and airway remodeling may have significant implications for cardiopulmonary toxicity induced by vaping products. This abstract is funded by: NIH National Heart, Lung, and Blood Institute
Noel et al. (Fri,) studied this question.