E-cigarette advocates — as well as regulators like the FDA — are fond of pointing out that nicotine is not a carcinogen (chemical that causes cancer) and noting that because they do not involve combustion, e-cigarettes do not deliver many carcinogenic chemicals produced by burning cigarettes. A new paper by Stella Tommasi , Ahmad Besaratinia and their colleagues at USC just published Epigenomic Dysregulation in Youth Vapers: Implications for Disease Risk Assessment that provides a much more complete — and troubling — look at the genetic impacts of vaping and smoking that shows substantial risks associated with e-cigarette use.
They completed the first genome-wide comparison of young adult (21-27) exclusive vapers, exclusive smokers and people who did not use either product and found, among other things, similar DNA changes linked to disease risk, including damage to a key tumor-suppressor gene.
Tumor suppressor genes sense when a cell is dividing abnormally and instruct the cell to commit suicide. Disabling tumor suppressor genes is a crucial step in the development of cancer.
Comparing DNA methylation
Tommasi and colleagues measured DNA methylation, a chemical modification of DNA that can effectively turn genes “on” or “off,” in cheek cells. (Cheek cells turn over quickly, which means that the effects of any past smoking would be long gone.) DNA methylation is vital to normal cellular processes but if it goes awry it can lead to cancer and other diseases. They analyzed virtually the entire genome in the cells of study participants, compared to previous studies that analyzed just two to three percent of genetic regions in vapers or smokers.
They used a high-resolution sequencing technique to study more than 25 million sites across the genome. They searched for differentially methylated regions (DMRs), or areas in the genome that were more or less methylated in one group of participants compared to the others. They found 831 DMRs in vapers and 2,863 in smokers.
Next, they looked for DMRs that were shared between smokers and vapers, finding 346 (46% of all DMR-associated genes in vapers) that overlapped between the two groups. These methylated regions were on gene sites known to regulate important biological signaling pathways that drive disease development. This indicates that DNA methylation in vapers, much like in smokers, can contribute to the development of diseases such as cancer.
As noted above, a key finding was that the most significant DMR most shared between vapers and smokers was located within HIC1, a tumor-suppressor gene named Hypermethylated In Cancer 1 because of the extensive research base linking it with various cancers, including those linked to tobacco use.
HIC1 is altered by methylation at a very early stage in cancer development. Methylation of HIC1 has also been found in blood samples of smokers who are at high risk of cancer and other chronic diseases. This means it may be useful as a predictive biomarker to help identify people who need to be monitored closely so cancer can be diagnosed early on when it is easiest to treat.
Significantly, more than half of the DMRs found in vapers were not detected in smokers. That finding is consistent with the fact that e-cigarettes produce a wide range of harmful or potentially harmful chemicals, some of which are not found in tobacco cigarettes. It also means that, contrary to another widely made assumption by e-cigarette advocates (and the FDA) e-cigarettes do not just expose users to a subset of toxicants produced by a cigarettes; they are produce a different toxic load.
Implications for FDA
An important implication of this work is that the FDA needs to update its list of Harmful and Potentially Harmful Compounds (HPHC) that it uses to judge e-cigarettes and other new tobacco products. The current HPHC list, adopted in 2012, is based on the worst things in cigarette smoke. FDA proposed updating the HPHC list five years ago in 2019 to include important chemicals in e-cigarettes, but never completed the process. This new paper adds even more urgency to finish the job.
This new paper shows that there are much better biomarkers of disease than the crude biomarkers that the tobacco industry and others have been promoting for decades. While actual evidence of disease is best, these genetic assessments also provide direct estimates to harm, especially for diseases like cancer that take a long time to develop. If FDA wants to rely on biomarkers, they should be modern about how they do it.
Here is the abstract:
Despite the ongoing epidemic of youth vaping, the long-term health consequences of electronic cigarette use are largely unknown. We report the effects of vaping versus smoking on the oral cell methylome of healthy young vapers and smokers relative to non-users. Whereas vapers and smokers differ in number of differentially methylated regions (DMRs) (831 vs 2,863), they share striking similarities in the distribution and patterns of DNA methylation, chromatin states, transcription factor binding motifs, and pathways. There is substantial overlap in DMR-associated genes between vapers and smokers, with the shared subset of genes enriched for transcriptional regulation, signaling, tobacco use disorders, and cancer-related pathways. Of significance is the identification of a common hypermethylated DMR at the promoter of “Hypermethylated In Cancer 1” (HIC1), a tumor suppressor gene frequently silenced in smoking-related cancers. Our data support a potential link between epigenomic dysregulation in youth vapers and disease risk. These novel findings have significant implications for public health and tobacco product regulation.
The full citation is: Tommasi S, Brocchieri L, Tornaletti S, Besaratinia A. Epigenomic Dysregulation in Youth Vapers: Implications for Disease Risk Assessment. Am J Respir Cell Mol Biol. 2024 Aug 12. doi: 10.1165/rcmb.2024-0207OC. Epub ahead of print. PMID: 39133188. It is available here.
Note: I drew some of this blog post from the USC press release on the paper.
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