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

• 批准号: 10558698
• 负责人: Jiehong Guo
• 金额: $ 0.58万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-31 至 2023-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558698
• 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; Classification; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; Data; Deoxyguanosine; Deoxyribonucleosides; Derivation procedure; 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' -nitrosonornicotine; Nitrosamines; Oral; Oral cavity; Oral mucous membrane structure; Oropharyngeal; Predisposition; Prevention; Probability; Process; Purines; Pyrimidine; Rattus; Reaction; 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

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.

项目概要 在美国，吸烟是肺癌和口腔癌的主要原因。无烟烟草的原因 口腔癌、食道癌和胰腺癌。电子烟对健康的影响仍在调查中，但 可能会扰乱口腔稳态并导致肺部和心血管疾病。烟草专用 亚硝胺 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 和 N'-亚硝基降烟碱 (NNN) 是 被国际癌症研究机构列为人类致癌物，并被认可 这些疾病的原因。 NNK 和 NNN 的代谢激活导致反应性亲电子试剂的形成 修饰 DNA 以产生多种产物，例如 N7-[4-(3-吡啶基)-4-oxobut-1-yl]-脱氧鸟苷 (N7POBdG) 可以通过碱基的轻松水解在 DNA 中产生无嘌呤/无嘧啶 (AP) 位点 脱氧核糖核苷键；其他烟草成分也可能诱导 AP 位点。 AP站点积累可能 启动致癌过程。口腔细胞提供了烟草使用与口腔癌之间的直接联系 人类和烟草使用者的口腔细胞中发现 DNA 损伤增加。我们建议分析AP 口腔细胞 DNA 中的位点有两个具体目标：开发一种高灵敏度的质谱方法来定量 人类口腔细胞 DNA 中的 AP 位点，并量化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。目标是建立口腔细胞 DNA AP 位点作为烟草诱导的生物标志物 吸烟者、无烟烟草使用者和电子烟使用者的 DNA 损伤，并最终识别 易感烟草使用者并设计有效的策略来预防癌症。这项研究还可能提供 大型流行病学研究的初步数据。我们有强有力的初步数据来支持这一提议。