According to the U.S. Dept. of Health and Human Services, acetaldehyde is """"""""reasonably anticipated to be a human carcinogen"""""""". When administered to laboratory animals by inhalation, acetaldehyde produces nasal and laryngeal carcinomas. Acetaldehyde occurs widely in the human environment, is a major constituent of cigarette smoke, and is the main metabolite of ethanol. Levels of acetaldehyde in the environment may increase with the introduction of ethanol-containing fuels. DNA adducts are critical in the carcinogenic process. In this program, we have identified DNA adducts of acetaldehyde including the major adduct N2- ethylidene-dGuo (adduct 1), the 1,A/2-propano-dGuo adducts 3 which are also formed from crotonaldehyde, and a related interstrand cross-link (adduct 4). We have developed highly sensitive mass spectrometric methods to quantify adducts 1 and 3 in human tissues. We have demonstrated that adduct 1 can be quantified in low microgram amounts of DNA, that it is an endogenous DNA adduct, and that its levels are influenced by cigarette smoking. We have also shown that adduct 3 is present in human lung DNA and has miscoding potential in human cells. In this renewal application, we propose to continue our studies on acetaldehyde DNA adducts to test our overall hypothesis that they are involved as causes of human cancer, particularly of the lung, and head and neck. Our goal is to investigate the occurrence in humans and the biological significance of acetaldehyde DNA adducts.
Our specific aims are: 1. Quantify levels of adducts 1, 3, and the related acrolein-derived adduct 5 in human lung DNA from current smokers (confirmed by urinary cotinine) and compare levels of these adducts to those derived from benzo[a]pyrene (BaP) and tobacco-specific nitrosamines in the same tissues. 2a. Determine the influence of polymorphisms in alcohol dehydrogenase (ADH1C) and aldehyde dehydrogenase (ALDH2) genes on levels of adduct 1 in leukocyte DNA of non-smokers who consume alcohol. b. Quantify levels of adduct 1 in leukocyte DNA of non-smoking, non-drinking Chinese women who regularly engage in wok cooking compared to those who do not. 3. Investigate the genotoxic properties of adduct 1 in cells, and by studies in A/J mice which compare adduct formation and tumorigenicity of compounds that do or do not generate acetaldehyde. 4. Investigate the mechanism of translesion synthesis across adduct 3 and """"""""half-excised"""""""" interstrand cross-links. We have shown that these adducts are bypassed by mammalian DNA polymerases in cells. Here we propose to identify those polymerases and characterize the translesion synthesis by in vitro and cellular approaches. These studies will provide critical data on the occurrence and biological significance of acetaldehyde DNA adducts and their possible role in human cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011297-07
Application #
7429669
Study Section
Special Emphasis Panel (ZRG1-ONC-W (02))
Program Officer
Shaughnessy, Daniel
Project Start
2002-02-18
Project End
2012-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
7
Fiscal Year
2008
Total Cost
$314,472
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Balbo, Silvia; Juanes, Rita Cervera; Khariwala, Samir et al. (2016) Increased levels of the acetaldehyde-derived DNA adduct N 2-ethyldeoxyguanosine in oral mucosa DNA from Rhesus monkeys exposed to alcohol. Mutagenesis 31:553-8
Balbo, Silvia; Brooks, Philip J (2015) Implications of acetaldehyde-derived DNA adducts for understanding alcohol-related carcinogenesis. Adv Exp Med Biol 815:71-88
Balbo, Silvia; Meng, Lei; Bliss, Robin L et al. (2012) Time course of DNA adduct formation in peripheral blood granulocytes and lymphocytes after drinking alcohol. Mutagenesis 27:485-90
Balbo, Silvia; Meng, Lei; Bliss, Robin L et al. (2012) Kinetics of DNA adduct formation in the oral cavity after drinking alcohol. Cancer Epidemiol Biomarkers Prev 21:601-8
Hecht, Stephen S (2012) Research opportunities related to establishing standards for tobacco products under the Family Smoking Prevention and Tobacco Control Act. Nicotine Tob Res 14:18-28
Lin, Ming-Yen; Chen, Mei-Chin; Wu, I-Chen et al. (2011) Areca users in combination with tobacco and alcohol use are associated with younger age of diagnosed esophageal cancer in Taiwanese men. PLoS One 6:e25347
Wu, Ming-Tsang; Lee, Tzu-Chi; Wu, I-Chen et al. (2011) Whole genome expression in peripheral-blood samples of workers professionally exposed to polycyclic aromatic hydrocarbons. Chem Res Toxicol 24:1636-43
Zhang, Siyi; Balbo, Silvia; Wang, Mingyao et al. (2011) Analysis of acrolein-derived 1,N2-propanodeoxyguanosine adducts in human leukocyte DNA from smokers and nonsmokers. Chem Res Toxicol 24:119-24
Hecht, Stephen S; Seow, Adeline; Wang, Mingyao et al. (2010) Elevated levels of volatile organic carcinogen and toxicant biomarkers in Chinese women who regularly cook at home. Cancer Epidemiol Biomarkers Prev 19:1185-92
Hecht, Stephen S; Yuan, Jian-Min; Hatsukami, Dorothy (2010) Applying tobacco carcinogen and toxicant biomarkers in product regulation and cancer prevention. Chem Res Toxicol 23:1001-8

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