Carcinogenic tobacco-specific nitrosamines induction of apurinic/apyrimidinic sites in DNA of human oral cells

致癌烟草特异性亚硝胺诱导人类口腔细胞 DNA 中的无嘌呤/无嘧啶位点

基本信息

批准号：
10359388
负责人：
Jiehong Guo
金额：
$ 7.75万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-31 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359388
关键词：
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Acrolein Base Sequence Biological Markers Cancer Etiology Carcinogens Cardiovascular Diseases Cells Chemicals Cigarette Cigarette Smoker DNA DNA Adducts DNA Damage DNA Repair Data Deoxyguanosine Deoxyribonucleosides Disease Dose Electronic cigarette Excision Excision Repair Exposure to Fostering Genomic Instability Goals Habits Health Homeostasis Human Hydrolysis Hydroxylamine In Vitro International Agency for Research on Cancer Investigation Leukocytes Link Liquid Chromatography Liver Location Lung Lung diseases Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of lung Malignant neoplasm of pancreas Membrane Metabolic Activation Methods Morphologic artifacts Mucous Membrane Mutation N&apos -nitrosonornicotine Nitrosamines Oral Oral cavity Oral mucous membrane structure Oropharyngeal Prevention Process Purines Pyrimidine Rattus Site Smokeless Tobacco Smoker Structure of mucous membrane of nose Survival Rate Tissues Tobacco Tobacco use Tobacco-Associated Carcinogen Tobacco-Related Carcinoma United States adduct age effect analytical method base cancer prevention cancer risk carcinogenicity cigarette smoke cigarette smoke-induced cigarette smoking cytotoxic design electronic cigarette user epidemiologic data epidemiology study exposed human population genotoxicity human DNA in vivo malignant mouth neoplasm non-smoker oral cancer prevention prevent response silochrome smokeless tobacco user smoking cessation tandem mass spectrometry tobacco exposure tobacco products tobacco user urinary

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Acrolein Base Sequence Biological Markers Cancer Etiology Carcinogens Cardiovascular Diseases Cells Chemicals Cigarette Cigarette Smoker DNA DNA Adducts DNA Damage DNA Repair Data Deoxyguanosine Deoxyribonucleosides Disease Dose Electronic cigarette Excision Excision Repair Exposure to Fostering Genomic Instability Goals Habits Health Homeostasis Human Hydrolysis Hydroxylamine In Vitro International Agency for Research on Cancer Investigation Leukocytes Link Liquid Chromatography Liver Location Lung Lung diseases Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of lung Malignant neoplasm of pancreas Membrane Metabolic Activation Methods Morphologic artifacts Mucous Membrane Mutation N&apos -nitrosonornicotine Nitrosamines Oral Oral cavity Oral mucous membrane structure Oropharyngeal Prevention Process Purines Pyrimidine Rattus Site Smokeless Tobacco Smoker Structure of mucous membrane of nose Survival Rate Tissues Tobacco Tobacco use Tobacco-Associated Carcinogen Tobacco-Related Carcinoma United States adduct age effect analytical method base cancer prevention cancer risk carcinogenicity cigarette smoke cigarette smoke-induced cigarette smoking cytotoxic design electronic cigarette user epidemiologic data epidemiology study exposed human population genotoxicity human DNA in vivo malignant mouth neoplasm non-smoker oral cancer prevention prevent response silochrome smokeless tobacco user smoking cessation tandem mass spectrometry tobacco exposure tobacco products tobacco user urinary

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项目摘要

Project Summary Cigarette smoking is the leading cause of lung and oral cancer in the United States. Smokeless tobacco causes cancer of the mouth, esophagus and pancreas. The health effects of e-cigarettes are still under investigation but may disturb oral cavity homeostasis and cause lung and cardiovascular diseases. The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are classified as human carcinogens by the International Agency for Research on Cancer, and are recognized causes of these diseases. Metabolic activation of NNK and NNN results in formation of reactive electrophiles that modify DNA to produce a variety of products such as N7-[4-(3-pyridyl)-4-oxobut-1-yl]-deoxyguanosine (N7POBdG) that can result in apurinic/apyrimidinic (AP) sites in DNA by facile hydrolysis of the base- deoxyribonucleoside bond; other tobacco constituents may also induce AP sites. AP site accumulation may initiate the carcinogenic process. Oral cells provide the direct link between tobacco use and oral cancer in humans and elevated DNA damage has been found in oral cells of tobacco users. We propose to analyze AP sites in oral cell DNA with two specific aims: to develop a highly sensitive mass spectrometric method to quantify AP sites in human oral cell DNA, and to quantify AP sites in oral cell DNA induced by cigarette smoke, smokeless tobacco and e-cigarettes. The goals are to establish oral cell DNA AP sites as biomarkers of tobacco induced DNA damage in cigarette smokers, smokeless tobacco users, and e-cigarette users, and to ultimately identify susceptible tobacco users and design effective strategies to prevent cancer. This study may also provide preliminary data for a large epidemiologic study. We have strong preliminary data to support this proposal.

项目摘要吸烟是美国肺癌和口腔癌的主要原因。无烟烟草原因口腔，食道和胰腺癌。电子烟的健康影响仍在调查中，但可能会干扰口腔稳态，并引起肺和心血管疾病。烟草特异性硝基胺4-（甲基硝基氨基）-1-（3-吡啶基）-1-丁酮（NNK）和N'-硝酸盐（NNN）是国际癌症研究机构归类为人类致癌物，并得到认可这些疾病的原因。 NNK和NNN的代谢激活导致反应性电力的形成这会改变DNA，以产生多种产品，例如N7- [4-（3-吡啶基）-4-氧化-1-基] -DeoxyGuanosine （N7POBDG）可以通过便捷的基础水解来导致DNA中的apurinic/apyrimidinic（AP）位点脱氧核苷键；其他烟草成分也可能引起AP位点。 AP站点的积累可能启动致癌过程。口腔细胞提供烟草使用与口腔癌之间的直接联系在烟草使用者的口腔细胞中发现了人类和DNA损伤升高。我们建议分析AP 口腔细胞DNA中具有两个特定目的的位点：开发高度敏感的质谱法以量化人口腔细胞DNA中的AP位点，并量化由香烟烟雾诱导的口腔细胞DNA中的AP位点，无烟烟草和电子烟。目标是建立口服细胞DNA AP位点作为烟草的生物标志物吸烟者，无烟烟草使用者和电子烟使用者的DNA损害，并最终确定易感烟草使用者和设计有效的策略来预防癌症。这项研究也可能提供大型流行病学研究的初步数据。我们有强大的初步数据来支持该提案。