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Urinary mutagenicity and bladder cancer risk in northern New England
Citation:
Wong, J., A. Fischer, D. Baris, L. Beane-Freeman, M. Karagas, M. Schwenn, A. Johnson, P. Matthews, A. Swank, M. Hosain, S. Koutros, D. Silverman, D. DeMarini, AND N. Rothman. Urinary mutagenicity and bladder cancer risk in northern New England. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, 65(1-2):47-54, (2024). https://doi.org/10.1002/em.22588
Impact/Purpose:
Bladder cancer is a significant health burden in the U.S., with an estimated ~80,000 new cases each year, resulting in ~17,000 deaths annually. Although ~85% of bladder cancer is associated with cigarette smoking, ~15% of cases occur in non-smokers. This study was part of a large bladder cancer case-control epidemiology study performed in New England by the U.S. National Cancer Institute that was designed to investigate the causes of bladder cancer, especially among non-smokers. Exposure to agents that cause mutations in DNA is a primary mechanism by which environmental agents, such as cigarette smoke, cause cancer. Next to lung cancer, bladder cancer is the second-most frequent cancer associated with cigarette smoking, and essentially all cigarette smokers have mutagenic urine. Because of this observation, the present study evaluated for the first time the urinary mutagenicity of people without (268 controls) and people with bladder cancer (203 cases), focusing on bladder cancer cases that were not smokers so see if they also had mutagenic urine. Urinary mutagenicity was assessed by extracting the organic compounds from the urine and testing them for their ability to cause mutations in special strains of bacteria in a Petri dish (the Salmonella or Ames mutagenicity assay). The presence of mutagens in the urine would put the bladder epithelial cells at risk for mutation, leading to bladder cancer. The study found that non-smokers who had mutagenic urine had a 3.8-fold increased risk for bladder cancer compared to non-smokers who did not have mutagenic urine. This study also found that urinary mutagenicity among non-smoking bladder cancer subjects was associated with the recent use of wood-burning fireplaces/stoves and occupational exposure to mineral oil. This is the first clinical study of urinary mutagenicity as a risk factor for bladder cancer among non-smokers. The long-term importance of this finding is that urinary mutagenicity can now be considered a risk factor for bladder cancer even among non-smokers. This study is of interest to both the Air and Drinking Water Program Offices. Recently, the International Agency for Research on Cancer (IARC) evaluated firefighting as a known carcinogen to firefighters, causing lung mesothelioma and bladder cancer (P.A. Demers et al., Lancet Oncology 23(8):985, 2022). Non-smoking firefighters have mutagenic urine, and the present study provides mechanistic support for a role for mutagenic urine in the increased risk of firefighters for bladder cancer—likely due to exposure to polycyclic aromatic hydrocarbons (PAHs) from combustion emissions (smoke) from the fires (D.M. DeMarini and W.P. Linak, Environmental and Molecular Mutagenesis 63:135, 2022). Bladder cancer is the primary cancer associated with exposure (primarily via dermal/inhalation) to trihalomethanes, particularly brominated trihalomethanes, in disinfected water, such as chlorinated drinking water or swimming pool/hot tub water. Dermal/inhalation exposure to high levels of brominated trihalomethanes cause mutagenic urine (D.M. DeMarini, Environ Mol Mutagen 61:588, 2020). The U.S. EPA Office of Water has recently shown that ~10% of bladder cancer cases in the U.S. are associated with exposure to such disinfection by-products in drinking water (R.J. Weisman et al., Environ Health Perspectives 130(8):87002, 2022). This first clinical study of urinary mutagenicity and bladder cancer provides mechanistic support for the finding of increased risk for bladder cancer among firefighters and people exposed dermally or via inhalation to high levels of trihalomethanes, especially brominated trihalomethanes, in drinking water.
Description:
The etiology of bladder cancer among never smokers without occupational or environmental exposure to established urothelial carcinogens remains unclear. Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. Here, we investigated its potential association with bladder cancer in rural northern New England. We analyzed 156 bladder cancer cases and 247 cancer-free controls from a large population-based case–control study conducted in Maine, New Hampshire, and Vermont. Overnight urine samples were deconjugated enzymatically and the extracted organics were assessed for mutagenicity using the plate-incorporation Ames assay with the Salmonella frameshift strain YG1041 + S9. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer in relation to having mutagenic versus nonmutagenic urine, adjusted for age, sex, and state, and stratified by smoking status (never, former, and current). We found evidence for an association between having mutagenic urine and increased bladder cancer risk among never smokers (OR = 3.8, 95% CI: 1.3–11.2) but not among former or current smokers. Risk could not be estimated among current smokers because nearly all cases and controls had mutagenic urine. Urinary mutagenicity among never-smoking controls could not be explained by recent exposure to established occupational and environmental mutagenic bladder carcinogens evaluated in our study. Our findings suggest that among never smokers, urinary mutagenicity potentially reflects genotoxic exposure profiles relevant to bladder carcinogenesis. Future studies are needed to replicate our findings and identify compounds and their sources that influence bladder cancer risk.
URLs/Downloads:
DOI: Urinary mutagenicity and bladder cancer risk in northern New England
https://pubmed.ncbi.nlm.nih.gov/38465801/