Abstract
Aromatic amines are a widespread class of environmental contaminants present in various occupational settings and tobacco smoke. Exposure to aromatic amines is a major risk factor for bladder cancer development. The etiologic involvement of aromatic amines in the genesis of bladder cancer is attributable to their ability to form DNA adducts, which upon eluding repair and causing mispairing during replication, may initiate mutagenesis. We have investigated the induction of DNA adducts in relation to mutagenesis in bladder and various nontarget organs of transgenic Big Blue mice treated weekly (i.p.) with a representative aromatic amine compound, 4-aminobiphenyl (4-ABP), for six weeks, followed by a six-week recovery period. We show an organ-specificity of 4-ABP in inducing repair-resistant DNA adducts in bladder, kidney, and liver of carcinogen-treated animals, which accords with the bioactivation pathway of this chemical in the respective organs. In confirmation, we show a predominant and sustained mutagenic effect of 4-ABP in bladder, and much weaker but significant mutagenicity of 4-ABP in the kidney and liver of carcinogen-treated mice, as reflected by the elevation of background cII mutant frequency in the respective organs. The spectrum of mutations produced in bladder of 4-ABP-treated mice matches the known mutagenic properties of 4-ABP-DNA adducts, as verified by the preponderance of induced mutations occurring at G:C base pairs (82.9%), with the vast majority being G:C→T:A transversions (47.1%). Our data support a possible etiologic role of 4-ABP in bladder carcinogenesis and provide a mechanistic view on how DNA adduct-driven mutagenesis, specifically targeted to bladder urothelium, may account for organ-specific tumorigenicity of this chemical.
Highlights
Aromatic amines and bladder cancer have been a primary focus of research since the early years of chemical carcinogenesis [1]
No experimental study has investigated the formation and kinetics of repair of 4-ABP–DNA adducts in relation to mutagenesis in target and nontarget organs of 4-ABP– induced carcinogenesis in vivo
The etiologic role of aromatic amines in bladder carcinogenesis revolves around their ability to form covalently bound DNA adducts, which upon eluding repair and causing mispairing during replication, may initiate mutagenesis [15, 16]
Summary
Aromatic amines and bladder cancer have been a primary focus of research since the early years of chemical carcinogenesis [1]. Subsequent epidemiologic studies confirmed an association between exposure to chemicals of the family of aromatic amines, including 2-naphthylamine, benzidine, and 4-aminobiphenyl (4-ABP), and the incidence of urinary bladder cancer [4]. These observational findings were substantiated by animal experiments in which exposure of dogs, rabbits, hamster, rats, and mice to prototype aromatic amines. The elevated risk of bladder cancer in smokers is ascribed to their exposure to aromatic amines, with smokers of black (air cured) tobacco being at higher risk than smokers of blond (flue cured) tobacco [12,13,14]. The latter finding accords with the richer content of aromatic amines in black tobacco products than blond tobacco products [10]
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