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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：
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
项目类别：
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&apos -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

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.

项目总结