Effects of the Tobacco Carcinogens N′-Nitrosonornicotine and Dibenzo[ a, l]pyrene Individually and in Combination on DNA Damage in Human Oral Leukoplakia and on Mutagenicity and Mutation Profiles in lacI Mouse Tongue

Joseph B. Guttenplan, Kun-Ming Chen, Yuan-Wan Sun, Nora A.E. Shalaby, Wieslawa Kosinska, Dhimant Desai, Krishne Gowda, Shantu Amin, Karam El-Bayoumy

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Abstract

In previous studies, we showed that the topical application of dibenzo[a,l]pyrene (DB[a,l]P), also known as dibenzo[def,p]chrysene, to the oral cavity of mice induced oral squamous cell carcinoma. We also showed that dA and dG adducts likely account for most of the mutagenic activity of DB[a,l]P in the oral tissues in vivo. Here we report for the first time that the oral treatment of lacI mice with a combination of tobacco smoke carcinogens, DB[a,l]P and N′-nitrosonornicotine (NNN), induces a higher fraction of mutations than expected from a simple sum of their induced individual mutation fractions, and a change in the mutational profile compared with that expected from the sum of the individual agents. The mutational profile of the combination of agents resembled that of the P53 gene in human head and neck cancers more than that of either of the individual agents, in that the percentage of the major class of mutations (GC > AT transitions) is similar to that seen in the P53 gene. A preliminary study was performed to understand the origin of the unexpected mutagenesis observations by measuring specific DNA adducts produced by both NNN and DB[a,l]P in human oral leukoplakia cells. No significant differences in the expected and observed major adduct levels from either agent were observed between individual or combined treatments, suggesting that additional adducts are important in mutagenesis induced by the mixture. Taken together, the above observations support the use of this animal model not only to investigate tobacco smoke-induced oral cancer but also to study chemoprevention.

Original languageEnglish (US)
Pages (from-to)1893-1899
Number of pages7
JournalChemical research in toxicology
Volume32
Issue number9
DOIs
StatePublished - Sep 16 2019

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N'-nitrosonornicotine
Oral Leukoplakia
Tobacco
Tongue
Carcinogens
DNA Damage
p53 Genes
Smoke
Mutagenesis
Mutation
DNA
DNA Adducts
Genes
Mouth Neoplasms
Chemoprevention
Head and Neck Neoplasms
Mouth
Squamous Cell Carcinoma
Animal Models
Animals

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

@article{3092bc3c14e14e4ca4465e5830fd39ab,
title = "Effects of the Tobacco Carcinogens N′-Nitrosonornicotine and Dibenzo[ a, l]pyrene Individually and in Combination on DNA Damage in Human Oral Leukoplakia and on Mutagenicity and Mutation Profiles in lacI Mouse Tongue",
abstract = "In previous studies, we showed that the topical application of dibenzo[a,l]pyrene (DB[a,l]P), also known as dibenzo[def,p]chrysene, to the oral cavity of mice induced oral squamous cell carcinoma. We also showed that dA and dG adducts likely account for most of the mutagenic activity of DB[a,l]P in the oral tissues in vivo. Here we report for the first time that the oral treatment of lacI mice with a combination of tobacco smoke carcinogens, DB[a,l]P and N′-nitrosonornicotine (NNN), induces a higher fraction of mutations than expected from a simple sum of their induced individual mutation fractions, and a change in the mutational profile compared with that expected from the sum of the individual agents. The mutational profile of the combination of agents resembled that of the P53 gene in human head and neck cancers more than that of either of the individual agents, in that the percentage of the major class of mutations (GC > AT transitions) is similar to that seen in the P53 gene. A preliminary study was performed to understand the origin of the unexpected mutagenesis observations by measuring specific DNA adducts produced by both NNN and DB[a,l]P in human oral leukoplakia cells. No significant differences in the expected and observed major adduct levels from either agent were observed between individual or combined treatments, suggesting that additional adducts are important in mutagenesis induced by the mixture. Taken together, the above observations support the use of this animal model not only to investigate tobacco smoke-induced oral cancer but also to study chemoprevention.",
author = "Guttenplan, {Joseph B.} and Kun-Ming Chen and Yuan-Wan Sun and Shalaby, {Nora A.E.} and Wieslawa Kosinska and Dhimant Desai and Krishne Gowda and Shantu Amin and Karam El-Bayoumy",
year = "2019",
month = "9",
day = "16",
doi = "10.1021/acs.chemrestox.9b00257",
language = "English (US)",
volume = "32",
pages = "1893--1899",
journal = "Chemical Research in Toxicology",
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T1 - Effects of the Tobacco Carcinogens N′-Nitrosonornicotine and Dibenzo[ a, l]pyrene Individually and in Combination on DNA Damage in Human Oral Leukoplakia and on Mutagenicity and Mutation Profiles in lacI Mouse Tongue

AU - Guttenplan, Joseph B.

AU - Chen, Kun-Ming

AU - Sun, Yuan-Wan

AU - Shalaby, Nora A.E.

AU - Kosinska, Wieslawa

AU - Desai, Dhimant

AU - Gowda, Krishne

AU - Amin, Shantu

AU - El-Bayoumy, Karam

PY - 2019/9/16

Y1 - 2019/9/16

N2 - In previous studies, we showed that the topical application of dibenzo[a,l]pyrene (DB[a,l]P), also known as dibenzo[def,p]chrysene, to the oral cavity of mice induced oral squamous cell carcinoma. We also showed that dA and dG adducts likely account for most of the mutagenic activity of DB[a,l]P in the oral tissues in vivo. Here we report for the first time that the oral treatment of lacI mice with a combination of tobacco smoke carcinogens, DB[a,l]P and N′-nitrosonornicotine (NNN), induces a higher fraction of mutations than expected from a simple sum of their induced individual mutation fractions, and a change in the mutational profile compared with that expected from the sum of the individual agents. The mutational profile of the combination of agents resembled that of the P53 gene in human head and neck cancers more than that of either of the individual agents, in that the percentage of the major class of mutations (GC > AT transitions) is similar to that seen in the P53 gene. A preliminary study was performed to understand the origin of the unexpected mutagenesis observations by measuring specific DNA adducts produced by both NNN and DB[a,l]P in human oral leukoplakia cells. No significant differences in the expected and observed major adduct levels from either agent were observed between individual or combined treatments, suggesting that additional adducts are important in mutagenesis induced by the mixture. Taken together, the above observations support the use of this animal model not only to investigate tobacco smoke-induced oral cancer but also to study chemoprevention.

AB - In previous studies, we showed that the topical application of dibenzo[a,l]pyrene (DB[a,l]P), also known as dibenzo[def,p]chrysene, to the oral cavity of mice induced oral squamous cell carcinoma. We also showed that dA and dG adducts likely account for most of the mutagenic activity of DB[a,l]P in the oral tissues in vivo. Here we report for the first time that the oral treatment of lacI mice with a combination of tobacco smoke carcinogens, DB[a,l]P and N′-nitrosonornicotine (NNN), induces a higher fraction of mutations than expected from a simple sum of their induced individual mutation fractions, and a change in the mutational profile compared with that expected from the sum of the individual agents. The mutational profile of the combination of agents resembled that of the P53 gene in human head and neck cancers more than that of either of the individual agents, in that the percentage of the major class of mutations (GC > AT transitions) is similar to that seen in the P53 gene. A preliminary study was performed to understand the origin of the unexpected mutagenesis observations by measuring specific DNA adducts produced by both NNN and DB[a,l]P in human oral leukoplakia cells. No significant differences in the expected and observed major adduct levels from either agent were observed between individual or combined treatments, suggesting that additional adducts are important in mutagenesis induced by the mixture. Taken together, the above observations support the use of this animal model not only to investigate tobacco smoke-induced oral cancer but also to study chemoprevention.

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U2 - 10.1021/acs.chemrestox.9b00257

DO - 10.1021/acs.chemrestox.9b00257

M3 - Article

C2 - 31433626

AN - SCOPUS:85072234352

VL - 32

SP - 1893

EP - 1899

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

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