Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung

Lisa A. Peterson, Marissa K. Oram, Monica Flavin, Donna Seabloom, William E. Smith, M. Gerard O'Sullivan, Karin R. Vevang, Pramod Upadhyaya, Alessia Stornetta, Andrew C. Floeder, Yen Yi Ho, Lin Zhang, Stephen S. Hecht, Silvia Balbo, Timothy S. Wiedmann

Research output: Contribution to journalArticlepeer-review

Abstract

Tobacco smoke is a complex mixture of chemicals, many of which are toxic and carcinogenic. Hazard assessments of tobacco smoke exposure have predominantly focused on either single chemical exposures or the more complex mixtures of tobacco smoke or its fractions. There are fewer studies exploring interactions between specific tobacco smoke chemicals. Aldehydes such as formaldehyde and acetaldehyde were hypothesized to enhance the carcinogenic properties of the human carcinogen, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) through a variety of mechanisms. This hypothesis was tested in the established NNK-induced A/J mouse lung tumor model. A/J mice were exposed to NNK (intraperitoneal injection, 0, 2.5, or 7.5 μmol in saline) in the presence or absence of acetaldehyde (0 or 360 ppmv) or formaldehyde (0 or 17 ppmv) for 3 h in a nose-only inhalation chamber, and lung tumors were counted 16 weeks later. Neither aldehyde by itself induced lung tumors. However, mice receiving both NNK and acetaldehyde or formaldehyde had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that aldehydes may increase the severity of NNK-induced lung adenomas. The aldehyde coexposure did not affect the levels of NNK-derived DNA adduct levels. Similar studies tested the ability of a 3 h nose-only carbon dioxide (0, 5, 10, or 15%) coexposure to influence lung adenoma formation by NNK. While carbon dioxide alone was not carcinogenic, it significantly increased the number of NNK-derived lung adenomas without affecting NNK-derived DNA damage. These studies indicate that the chemicals in tobacco smoke work together to form a potent lung carcinogenic mixture.

Original languageEnglish (US)
Pages (from-to)723-732
Number of pages10
JournalChemical research in toxicology
Volume34
Issue number3
DOIs
StatePublished - Mar 15 2021

Bibliographical note

Funding Information:
This work was supported by a grant from the United States Food and Drug Administration (FDA) Center for Tobacco Products (CTP) and the National Cancer Institute under award number R01 CA-184987 to L.A.P. The Masonic Cancer Center Analytical Biochemistry and Comparative Pathology Shared Resources are funded in part by the National Cancer Institute [P30 CA-077598].

Publisher Copyright:
© 2021 American Chemical Society.

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