E-cigarette use and the risk of bladder cancer

(UroToday.com) The 2024 SUO Annual Meeting included a session on smoking cessation, vaping and e-cigarettes with a presentation by Dr. Marc Bjurlin on the use of e-cigarettes and the risk of bladder cancer.

The most common causes of bladder cancer include (i) smoking and other tobacco use, (ii) radiation exposure, (iii) chronic cystitis, (iv) exposure to chemicals, especially at work, and (v) parasitic infections. However, it is not always clear what causes bladder cancer, and some people may be diagnosed without having been exposed to any of the causes listed above. A cigarette contains many chemicals that are believed to cause bladder cancer, as shown in the following image:

In particular, nitrosamines, aromatic amines and polycyclic aromatic hydrocarbons are absorbed by the kidney and bladder cells, resulting in DNA damage. The research question for Dr. Bjurlin’s talk is: Are there carcinogens in the urine of e-cigarette users (e.g. those who smoke combustible cigarettes) that are linked to bladder cancer?

In 2021, Dr. Bjurlin and colleagues conducted a systematic literature review to characterize and summarize known carcinogenic urinary biomarkers in e-cigarette users in relation to the risk of developing bladder cancer.¹ Among the 22 studies that met the inclusion criteria, these studies reported 40 different parent compounds and four metals found in the urine of e-cigarette users. Because each parent compound can be metabolized in different ways, 63 unique toxic or carcinogenic metabolite biomarkers have been identified, six of which are closely associated with bladder cancer:
Dr. Bjurlin emphasized that metabolomics can be used to characterize the urinary landscape of e-cigarette users. There are different approaches to testing metabolomics:

• Targeted metabolomics

  • Hypothesis testing strategy
  • Low number of metabolites examined
  • The identity of the metabolites is known a priori
  • Absolute quantification of metabolites

• Untargeted metabolomics

  • Hypothesis generation/discovery strategy
  • High number of metabolites examined (typically 100–1000)
  • The identity of the metabolites is unknown a priori
  • Relative quantification of metabolites

To better understand the metabolic landscape and possible health consequences of e-cigarettes, Drs. Bjurlin and colleagues used liquid chromatography and mass spectrometry-based non-targeted metabolomics to analyze compounds in the urine of e-cigarette users (n = 34), cigarette smokers (n = 38), and non-users (n = 45).² The following figure illustrates the workflow used and exploratory data analysis:

This study showed that all six identified nicotine metabolites did not differ between smokers and e-cigarette users, and both groups experienced increases compared to unexposed controls. Several non-nicotine alkaloids have also been detected:

They also observed a total of 21 altered types of fatty acids, esters and amides, six of which were elevated in both smokers and e-cigarette users compared to controls:

In the non-targeted chemical analysis of urine samples, Dr. Bjurlin and colleagues also identified three potential flavoring compounds that had higher concentrations in e-cigarette users than in smokers and controls: ethyl levulinate, delta-decalactone, and gamma-heptalactone:

Additionally, e-cigarette users had the highest diethyl phthalate urine levels among the three groups, while smokers also had elevated urine levels:

Regarding the presence of carcinogens and cancer-related biomarkers, they found that Me-Fapy (whose monitoring suggests the extent of alkylating DNA damage) showed a significant increase in the urine samples of smokers compared to the control, while z-cigarette users there was a weak statistical trend. However, there were significantly higher MNPB levels in the urine of e-cigarette users with a 1.2-fold change (p = 0.02) compared to controls:

Taken together, these results suggest that some cancer induction is caused by e-cigarette and e-cigarette use.

Dr. Bjurlin emphasized that DNA methylation occurs at CpG sites and patterns can regulate gene expression differently. CpG methylation can accurately identify current and former smokers, and methylated CpG patterns have been linked to the effects of smoking on bladder cancer. It is noteworthy that traditional cigarette consumption and e-cigarettes have different methylation patterns. Dr. Bjurlin wanted to find out whether exposure to e-cigarettes leads to changes in DNA methylation in the urothelium of the mouse bladder. They found that exposure to e-cigarettes led to a shift in global methylation patterns, which may play a role in triggering the development of bladder cancer:

Dr. Bjurlin concluded his talk on e-cigarette use and the risk of bladder cancer with the following take-home messages:

• The long-term effects of chronic urothelial exposure to urinary carcinogens in e-cigarette users are unknown and require long-term follow-up
• E-cigarette users appear to have carcinogens in their urine, some of which are linked to bladder cancer
• There are increased cancer-related biomarkers in the urine of e-cigarette users due to higher lipid peroxidation, radical-producing aroma, and higher levels of specific notrosamines

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 Society of Urologic Oncology (SUO) 2024 Annual Meeting, Dallas, TX, Tuesday, December 3 – Fri, December 6, 2024.

References:

1. Bjurlin MA, Matulewicz RS, Roberts TR, et al. Carcinogenic biomarkers in the urine of e-cigarette users and effects on the development of bladder cancer: A systematic review. Eur Urol Oncol. 2021 Oct;4(5):766-783.
2. Hsiao YC, Matulewicz RS, Sherman SE, et al. Untargeted metabolomics to characterize the chemical landscape in the urine of e-cigarette users. Chem Res Toxicol. 2023 April 17;36(4):630-642.