Exposure to aromatic amines via smoking or the environment is a significant risk factor for bladder cancer (BC) and renal cancer. Epidemiological studies suggest that genotoxic heterocyclic aromatic amines (HAAs) found in well-done cooked meats also may contribute to BC. 4-Aminobiphenyl (4-ABP) is a tobacco smoke carcinogen that forms DNA adducts in human bladder. However, the identities of other chemicals that contribute to the etiology of BC are mainly unknown. We examined the ability of 4-ABP, 2-naphthylamine (2-NA), and 2-amino-9H-pyrido[2,3-b]indole (AαC), carcinogens present in tobacco smoke; 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, carcinogens formed in cooked meats, and 8-methoxy-6-nitrophenanthro[3,4-d]-1,3-dioxole-5-carboxylic acid (AA-I), a potent urothelial carcinogen present in herbal remedies, to form DNA adducts in bladder, kidney and liver tissues, using a male mouse model. Carcinogens mixed in the drinking water (100 ppm) were administered to mice for four consecutive days. The levels of DNA adducts in bladder, liver, and kidney were monitored by mass spectrometry after one and 33 days post-dosing. 4-ABP produced the highest adduct levels in bladder and liver among all carcinogens tested. On day 33, &gt;50% of the adducts persisted in the bladder, and 90% were present in liver and kidney at day 33. AA-I formed the highest levels of DNA adducts in the kidney. The AA-I adduct level in the bladder was 50-fold lower than 4-ABP. AA-I adducts persisted in renal tissue, but 90% were removed from the bladder by day 33. The AαC-DNA adduct formed in the bladder occurred at 50-fold lower levels than for 4-ABP, and more than 95% of the adducts were removed by day 33. DNA adducts of the other carcinogens formed in bladder, kidney, and liver at 200- 5000-fold lower levels than 4-ABP adducts and were efficiently removed from all three organs by day 33. Our data demonstrate that 4-ABP and AA-I are potent DNA-damaging carcinogens in the mouse urinary system, and their adducts persist in these tissues over time. Our goal is to develop a noninvasive method to detect DNA-adducts of bladder carcinogens in humans using exfoliated urinary cells. The male mouse model is a promising approach to develop this screening technology.

Kinetics of formation and removal of DNA adducts in mice exposed to tobacco and meat carcinogens by UPLC-mass spectrometry

2019 Fall National Meeting

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