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
posted on 2021-02-25, 12:03authored byLisa 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
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.