Genotoxicity of tobacco smoke‐derived aromatic amines and bladder cancer: current state of knowledge and future research directions

Abstract

Bladder cancer is a significant public health problem, worldwide. In the United States, bladder cancer is the fourth most common cancer in men, and its recurrence rate is the highest among all malignancies. Tobacco smoking is the leading risk factor for bladder cancer. The risk of bladder cancer is directly related to the intensity and duration of smoking, while quitting smoking reduces this risk. The increased risk of smokers for developing bladder cancer is attributable to their exposure to aromatic amines, which constitute a family of known bladder carcinogens present in tobacco smoke. The underlying mechanism of action of aromatic amines in the genesis of bladder cancer is not, however, fully delineated. Research has identified a genotoxic mode of action, specifically DNA adduction and mutagenicity, for aromatic amines, which may account for their carcinogenicity. The present review summarizes our current knowledge on the DNA adduction and mutagenicity of aromatic amines in relation to smoking-associated bladder cancer. For illustrative purposes, representative results from published research on aromatic amine-induced DNA adduction and mutagenesis are discussed. The direction of future research on the underlying mechanisms of tobacco smoke-associated bladder carcinogenesis is also outlined. Understanding the molecular mechanisms of bladder carcinogenesis is essential for improving future strategies for prevention, early detection, treatment, and prognosis of this malignancy.

Alterations of DNA methylome in human bladder cancer

“…[89][90][91] Although the bladder-specific carcinogenicity of aromatic amines is well-established, the underlying mechanisms of action of these chemicals in the genesis and progression of bladder cancer are not fully delineated. 24 A genotoxic mode of action for aromatic amines has been demonstrated that involves the induction of DNA damage and mutations. [92][93][94][95] However, the genotoxicity of aromatic amines is not exclusive to the target organ of tumorigenesis.…”

“…[92][93][94][95] However, the genotoxicity of aromatic amines is not exclusive to the target organ of tumorigenesis. 24,[94][95][96][97][98] This suggests that an alternative mode of action (epigenetics) may also exist that singly or in combination with genotoxicity can explain the bladder-specific tumorigenicity of aromatic amines. 24 The concept of a chemical carcinogen exerting its biological effects through epigenetic changes is very novel, and has never been investigated comprehensively.…”

“…23 A requisite for alleviating the global burden of this disease is to understand the underlying mechanisms of the initiation and progression of this disease. 24 As the most miRNA Methylation and Human Bladder Cancer miRNAs are a class of short noncoding RNAs (~22 nt) that negatively regulate gene expression at the post-transcriptional level through sequence-specific targeting of mRNA. [105][106][107] The recognition of the target mRNA is based on complementarity of the seed sequence of the miRNA (i.e., 7-8 nt at the 5'-end) to a specific sequence motif within the 3'-untranslated region (3'-UTR) of the mRNA.…”

“…23 The quest for sensitive, specific, and non-invasive diagnostic, therapeutic, and prognostic tools for bladder cancer is a high priority research area, and can be achieved by understanding the molecular mechanisms underlying the initiation and progression of this malignancy. 24 Epigenetics is a fast growing field in cancer biology, and has enormous potential for clinical and translational research. [25][26][27] Cancer epigenetics refers to inheritable, yet reversible, changes associated with gene dysregulation, which manifest in a (pre) malignant phenotype where sequence of the genome is not altered [28][29][30] .…”

Bladder cancer prevention

“…Studies conducted in previous decades have confirmed their genotoxicity, showing that they are able to create DNA adducts and thus induce mutagenesis. Other (alternative or additional) carcinogenic effects of aromatic amines have also been proposed, including epigenetic mechanisms such as abnormal DNA methylation, chromatin remodeling, and histone modification [14].…”