(UroToday.com) The 2024 SUO annual meeting included a session on smoking cessation, vaping, and e-cigarettes, featuring a presentation by Dr. Marc Bjurlin discussing e-cigarette use and the risk of bladder cancer.
The most common causes of bladder cancer include (i) smoking and other tobacco use, (ii) post radiation exposure, (iii) chronic bladder inflammation, (iv) exposure to chemicals, especially at work, and (v) parasitic infections. However, it is not always clear what causes bladder cancer, and some people can be diagnosed without having had exposure to any of the above listed causes. There are many chemicals in a cigarette that is thought to cause bladder cancer as highlighted in the following figure:
Specifically, nitrosamines, aromatic amines, and polycyclic aromatic hydrocarbons are absorbed by the kidney and bladder cells leading to DNA damage. The research question for Dr. Bjurlin’s talk is: are there carcinogens in the urine of e-cigarette users (like that of those who smoke combustible cigarettes) that are linked to bladder cancer?
In 2021, Dr. Bjurlin and colleagues performed a systematic review of the literature to characterize and summarize known urinary carcinogenic biomarkers in e-cigarette users as they relate to the risk of developing bladder cancer.1 Among 22 studies which met inclusion criteria, these studies described 40 different parent compounds and four metals found in the urine of e-cigarette users. Since each parent compound can be metabolized several different ways, 63 unique toxicant or carcinogenic metabolite biomarkers were identified, six of which are strongly linked to bladder cancer:
Dr. Bjurlin emphasized that metabolomics may be used to characterize the urinary landscape of e-cigarette users. There are several approaches to testing metabolomics:
- Targeted metabolomics
- Hypothesis testing strategy
- Low number of metabolites studied
- Identity of metabolites is known a priori
- Absolute quantification of metabolites
- Untargeted metabolomics
- Hypothesis generating/discovery strategy
- High number of metabolites studied (typically 100-1000s)
- Identity of metabolites are unknown a priori
- Relative quantification of metabolites
To better understand the metabolic landscape and potential health consequences of e-cigarettes, Dr. Bjurlin and colleagues applied liquid chromatography-mass spectrometry based non-targeted metabolomics to analyze compounds in the urine of e-cigarette users (n = 34), cigarette smokers (n = 38), and nonusers (n = 45).2 The following figure highlights the workflow and exploratory data analysis used:
This study showed that all six identified nicotine metabolites did not differ between smokers and e-cigarette users, and both of these groups resulted in elevations compared to the non-exposed controls. Several non-nicotine alkaloids were also detected:
They also observed a total of 21 altered species of the fatty acids, esters, and amides, with six of them elevated in both smokers and e-cigarette users compared to the controls:
In the non-targeted chemical analysis of urinary samples, Dr. Bjurlin and colleagues also characterized three potential flavoring compounds that showed higher levels in e-cigarette users than in smokers and controls: ethyl levulinate, delta-decalactone, and gamma-heptalactone:
In addition, e-cigarette users had the highest urinary level of diethylphthalate among the three groups, while smokers also showed elevated exposure in their urine:
With regards to the presence of carcinogens and cancer-related biomarkers, they found that Me-Fapy (the monitoring of which may imply the level of alkylating DNA damage) showed a significant elevated in the urine samples of smokers compared to control, whereas for e-cigarette users there was a weak statistical trend. However, there were significantly higher levels of MNPB in the urine of e-cigarette users with a 1.2 fold change (p = 0.02) compared to the controls:
Taken together, these results suggest some cancer induction effected by e-cigarette use and vaping.
Dr. Bjurlin emphasized that DNA methylation occurs at CpG sites and patterns can differentially regulate gene expression. CpG methylation can accurately identify current and former smokers, and methylated CpG patterns have been linked to the effects of smoking on bladder cancer. Of note, tradition cigarette use and e-cigarettes have differing patterns of methylation. Dr. Bjurlin aimed to determine if e-cigarette exposure results in alterations of DNA methylation in the mouse bladder urothelium. They found that e-cigarette exposure resulted in a shift of global methylation patterns, which may play a role in precipitating the development of bladder cancer:
Dr. Bjurlin concluded his presentation discussing e-cigarette use and the risk of bladder cancer with the following take home messages:
- Long term implications of chronic urothelial exposure to urinary carcinogens of e-cigarette users are unknown and will require long-term follow-up
- E-cigarette users appear to have carcinogens in the urine, some of which are linked to bladder cancer
- With higher lipid peroxidatation, radical-forming flavoring, and higher levels of specific notrosamines, there is elevated cancer-related biomarkers in the urine of e-cigarette users
Presented by: Marc Bjurlin, DO, MSc, FACOS, University of North Carolina, Chapel Hill, NC
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Society of Urologic Oncology (SUO) Annual Meeting, Dallas, TX, Tues, Dec 3 – Fri, Dec 6, 2024.
References:
- Bjurlin MA, Matulewicz RS, Roberts TR, et al. Carcinogen biomarkers in the urine of electronic cigarette users and implications for the development of bladder cancer: A systematic review. Eur Urol Oncol. 2021 Oct;4(5):766-783.
- Hsiao YC, Matulewicz RS, Sherman SE, et al. Untargeted metabolomics to characterize the urinary chemical landscape of e-cigarette users. Chem Res Toxicol. 2023 Apr 17;36(4):630-642.