People who vape regularly show altered activity in 3,124 genes across the genome compared with people who do not smoke or vape. While some of those changes (28.8%) relate to how often or how much people vape, a much greater portion (66.6%) is linked to the type of flavors and devices they use. The findings, just published in the journal Frontiers in Oncology , underscore the role of flavor and device type in the biological effects of vaping and could have regulatory implications as the Food and Drug Administration (FDA) moves to approve marketing of flavored vapes.
Because vapes, or e-cigarettes, are relatively new, their long-term health risks remain unclear. While chronic diseases take decades to emerge, changes in expression of disease-related genes can provide early clues about the potential harms of vaping. Past research has already shown that vaping, similar to smoking, is linked to changes in gene expression involved in the development of cancer, as well as certain heart and lung diseases.
"One major question still remains: What is driving these changes? Is it the act of vaping itself—or is it the intensity and duration of vaping, the characteristics of the products used, or some combination of these?" said Ahmad Besaratinia, PhD , professor of research population and public health sciences at the Keck School of Medicine of USC and senior author of the study, which was funded in part by the National Institutes of Health.
To answer that question, Besaratinia and his colleagues compared changes in gene expression among 83 people, including vapers, smokers and non-users. They found that two-thirds of changes in gene activity could be explained by vape flavor and device type, suggesting the chemical makeup of vaping products and the design and configuration of devices play a major role in their biological effects. Among vapers, those who used fruit flavors or multiple flavors, as well as advanced refillable devices (often called "mods"), showed more changes in gene expression compared with other groups.
"The implication is that each flavor has unique attributes that produce different biological effects," Besaratinia said. "This is something regulators should carefully consider when evaluating the health risks or potential benefits of each flavored e-cigarette product."
Comparing gene expression
For the study, researchers recruited 35 vapers, 24 smokers and 24 non-users, including both men and women. Participants were healthy young adults and researchers used statistical methods to account for differences in age and sex when they analyzed data on gene expression.
The researchers collected oral cell samples from the inside of each participant's cheek. Using RNA sequencing, the researchers examined activity across thousands of genes at the same time, including how changes in one gene may affect other genes or the network of genes.
Compared with people who did not smoke or vape, vapers had altered expression in 3,124 genes. Vapers showed more variable patterns of gene activity than smokers—and drilling down into product details helps explain why.
The analysis showed that different vape flavors produced different changes in gene regulation. Sweet flavors were linked to changes in 2.9% of affected genes; mint/menthol flavors to changes in 0.9% of affected genes; fruit flavors to changes in 31% of affected genes; and multiple flavors to changes in 64.3% of affected genes. In addition, higher-generation devices such as mods were associated with the strongest and most consistent changes in gene regulation.
"These product differences explained more of the variation in gene regulation than how much or how often people vaped," Besaratinia said.
The researchers also conducted a sophisticated bioinformatics analysis to identify the molecular processes, biological pathways and diseases linked to the gene expression changes they observed. Among vapers, cancer was linked to the highest number of gene expression changes, followed by endocrine disorders, gastrointestinal diseases and neurological diseases.
Minimizing harm
The new findings have particular relevance as the FDA finalizes guidance on flavored e-cigarette products.
"Regulators have been tasked with verifying that the benefits of using e-cigarettes for adults outweigh the risks posed to youth," Besaratinia said. "But we show here that vaping flavored products is associated with disease-related molecular changes, regardless of the user's age."
The researchers recommend regulators evaluate products in a more granular way, with greater attention to flavors and device characteristics. Mods and other newer devices can deliver higher nicotine levels than earlier-generation vapes. Many also contain potentially toxic additives designed to make vaping smoother and more appealing.
Besaratinia and his colleagues are now conducting a follow-up study of the chemicals used in vaping liquid to determine which compounds are linked to changes in gene expression.
"Once we identify these chemicals, policymakers could instruct manufacturers to either eliminate these chemicals or reduce their level in e-cigarette products to minimize potential harm," he said.
About this research
In addition to Besaratinia, the study's other authors are Jessica George, Niccolo Pabustan, Daria M. Kessler and Zairah L. Thomas from the Department of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California; and Stella Tommasi, Lourdes Baezconde-Garbanati and Kimberly D. Siegmund from the USC Norris Comprehensive Cancer Center and the Department of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California.
This work was supported by the National Institute of Dental and Craniofacial Research and National Institute on Drug Abuse of the National Institutes of Health [R01DE031863, R21DA058342] and the University of California Tobacco-Related Disease Research Program [T31IR1839, T32IR5144, T33IR6680].
