Abstract A19: Interactions between tobacco smoke chemicals in rodent tumor models
Authors: Peterson Lisa A. , Oram Marissa K. , Seabloom Donna E. , Smith William E. , Stornetta Alessia , Vevang Karin R. , Flavin Monica , Tabaran Alexandru F. , Cornax Ingrid , Gerard O’Sullivan M. , Upadhyaya Pramod , Zhang Lin , Hecht Stephen S. , Balbo Silvia , Wiedmann Timothy S. 
Published: June 2022

Tobacco is a complex chemical mixture, containing many toxicants and carcinogens. Most rodent risk assessment studies have focused on single chemicals or the complicated mixtures of tobacco smoke or its fractions. There are few studies evaluating how specific chemicals interact with one another to form the potent carcinogenic mixture of tobacco smoke. We hypothesized that tobacco smoke aldehydes like formaldehyde and acetaldehyde could enhance the carcinogenic properties of the tobacco-specific nitrosamines, N’-nitrosonornicotine (NNN) and 4-methylnitrosamine-1-(3-pyridyl)-1-butanone (NNK), through a variety of mechanisms. This hypothesis was tested in two established rodent tumor models, the NNN-induced rat esophageal tumor model and the NNK-induced A/J mouse lung tumor model. In the first model, rats were exposed to 0, 4, or 8 ppm NNN in the drinking water in the presence or absence of 3000 ppm acetaldehyde for up to 100 weeks. The number of esophageal papillomas per rat was doubled in animals receiving both acetaldehyde and 8 ppm NNN (0.5 versus 1.15 tumors/rat, respectively). Acetaldehyde alone did not cause esophageal tumors. DNA adduct levels were not affected by the combination of the two chemicals. In the second model, A/J mice were exposed to NNK (i.p, 0, 2.5, or 7.5 μmol in saline) in the presence or absence of acetaldehyde (0 or 360 ppmv) or formaldehyde (0 or 15 ppmv) for 3 hours in a nose-only inhalation chamber. Lung tumors were counted 16 weeks later. Neither aldehyde by itself induced lung tumors. However, mice receiving both NNK and acetaldehyde or formaldehyde had an increased number of adenomas with dysplasia or progression than those receiving only NNK, suggesting that aldehydes may increase dysplasia in tumors initiated by NNK. As in the rat study, DNA adduct levels were not affected by the coexposure. In a separate experiment, we tested the hypothesis that the elevated levels of carbon dioxide in tobacco smoke could affect the carcinogenic properties of NNK in the A/J mouse; tobacco smoke contains 12.5% carbon dioxide. Mice received a 3 h nose-only carbon dioxide (0, 5, 10, or 15%) coexposure of mice receiving NNK (i.p. in saline, 0, 2.5, or 7.5 μmol). The coexposure to carbon dioxide more than doubled the number of lung adenomas induced by 2.5 μmol NNK, with the maximal effect observed with 10% carbon dioxide (0%: 1.8 ± 1.9; 5%: 3.9 ± 2.8; 10%: 7.1 ± 3.5; 15%; 5.5 ± 2.9 lung adenomas/mouse). Lung adenomas were also significantly increased in mice receiving 7.5 μmol NNK, although to a lesser extent (0%: 11 ± 6.2; 5%: 13 ± 7.9; 10%: 18 ± 6.0; 15%; 12 ± 5.3 lung adenomas/mouse). This additive and synergistic effect of carbon dioxide was highly significant (p value = 1.0 × 10-14). The mechanism of this interaction is under investigation. Collectively, these studies support the hypothesis that the aldehydes and carbon dioxide present in the tobacco mixture interact to enhance the carcinogenic potency of the tobacco specific nitrosamines. (Funded by CA-184987.)

Citation Format: Lisa A. Peterson, Marissa K. Oram, Donna E. Seabloom, William E. Smith, Alessia Stornetta, Karin R. Vevang, Monica Flavin, Alexandru F. Tabaran, Ingrid Cornax, M. Gerard O’Sullivan, Pramod Upadhyaya, Lin Zhang, Stephen S. Hecht, Silvia Balbo, Timothy S. Wiedmann. Interactions between tobacco smoke chemicals in rodent tumor models [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A19.