Journal Article

Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways

Julie A. Hutt, Brian R. Vuillemenot, Edward B. Barr, Marcie J. Grimes, Fletcher F. Hahn, Charles H. Hobbs, Thomas H. March, Andrew P. Gigliotti, Steven K. Seilkop, Gregory L. Finch, Joe L. Mauderly and Steven A. Belinsky

in Carcinogenesis

Volume 26, issue 11, pages 1999-2009
Published in print November 2005 | ISSN: 0143-3334
Published online June 2005 | e-ISSN: 1460-2180 | DOI:
Life-span inhalation exposure to mainstream cigarette smoke induces lung cancer in B6C3F1 mice through genetic and epigenetic pathways

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Although cigarette smoke has been epidemiologically associated with lung cancer in humans for many years, animal models of cigarette smoke-induced lung cancer have been lacking. This study demonstrated that life time whole body exposures of female B6C3F1 mice to mainstream cigarette smoke at 250 mg total particulate matter/m3 for 6 h per day, 5 days a week induces marked increases in the incidence of focal alveolar hyperplasias, pulmonary adenomas, papillomas and adenocarcinomas. Cigarette smoke-exposed mice (n = 330) had a 10-fold increase in the incidence of hyperplastic lesions, and a 4.6-fold (adenomas and papillomas), 7.25-fold (adenocarcinomas) and 5-fold (metastatic pulmonary adenocarcinomas) increase in primary lung neoplasms compared with sham-exposed mice (n = 326). Activating point mutations in codon 12 of the K-ras gene were identified at a similar rate in tumors from sham-exposed mice (47%) and cigarette smoke-exposed mice (60%). The percentages of transversion and transition mutations were similar in both the groups. Hypermethylation of the death associated protein (DAP)-kinase and retinoic acid receptor (RAR)-β gene promoters was detected in tumors from both sham- and cigarette smoke-exposed mice, with a tendency towards increased frequency of RAR-β methylation in the tumors from the cigarette smoke-exposed mice. These results emphasize the importance of the activation of K-ras and silencing of DAP-kinase and RAR-β in lung cancer development, and confirm the relevance of this mouse model for studying lung tumorigenesis.

Keywords: CS, cigarette smoke; DAP-kinase, death associated protein kinase; RAR-β, retinoic acid receptor-β; NNK, nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NTP, National Toxicology Program; B[a]P, benzo[a]pyrene; TPM, total particulate matter; NBF, neutral buffered formalin; MSP, methylation-specific PCR

Journal Article.  8898 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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