BACKGROUND-AIM:
The rapid increase in the use of electronic cigarettes (e-cigarettes) necessitates a comprehensive understanding of their long-term health consequences, particularly concerning carcinogenesis. Conventional cigarette smoking is the leading modifiable risk factor for bladder cancer, primarily due to the excretion of carcinogenic metabolites in the urine. This study investigates the presence of established and potential carcinogens in the urine of e-cigarette users and explores associated molecular alterations to assess the potential risk of developing bladder cancer.

METHODS:
A systematic literature review and synthesis of translational and basic science findings were conducted. The analysis focused on studies that quantified urinary biomarkers of exposure (BoEs) for carcinogens, including tobacco-specific nitrosamines (TSNAs), volatile organic compounds (VOCs), and polycyclic aromatic hydrocarbons (PAHs), in e-cigarette users compared to non-users and combustible cigarette smokers. Furthermore, studies exploring molecular alterations, such as DNA damage (e.g., adducts and 8-hydroxy-2’-deoxyguanosine (8−OHdG)), oxidative stress markers, and DNA methylation patterns in genitourinary tissues or cells (human and murine models), were included to elucidate mechanistic pathways of carcinogenesis.

RESULTS:
E-cigarette users exhibit significantly higher levels of several carcinogen biomarkers in their urine compared to non-users. Specifically, two aromatic amines that are established human bladder carcinogens, o-toluidine (found at a mean 2.3-fold higher concentration vs. controls) and 2-naphthylamine (mean 1.3-fold higher concentration), have been identified. Additionally, the genotoxic metabolite MNPB was found at significantly elevated levels. Furthermore, users show significantly elevated oxidative DNA damage, evidenced by urinary 8−OHdG levels often comparable to combustible cigarette smokers, with metal exposure such as zinc, potentially contributing to this effect. At the molecular level, e-cigarette exposure induces DNA damage and leads to shared DNA methylation changes between e-cigarette users and combustible cigarette smokers in epithelial cells, including loci associated with cancer-linked pathways including NOTCH1/RUNX3, indicating an epigenetic predisposition for carcinogenesis.

CONCLUSIONS:
The presence of established urinary carcinogens (aromatic amines), genotoxic biomarkers (MNPB), and significant evidence of oxidative DNA damage (8−OHdG), coupled with adverse epigenetic alterations, strongly suggests that electronic cigarette use places the user at an elevated, though likely lower than combustible cigarettes, risk for carcinogenesis and the potential development of bladder cancer. While the long-term clinical incidence requires decades of longitudinal follow-up, the current molecular and biomarker data provide a strong mechanistic rationale for concern regarding chronic urothelial exposure to these toxicants.