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

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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.