The International Agency for Research on Cancer evaluates acetaldehyde as """"""""possibly carcinogenic to humans"""""""" while the U.S. Dept. of Health and Human Services states that acetaldehyde is """"""""reasonably anticipated to be a human carcinogen."""""""" These evaluations are based on convincing carcinogenicity studies that clearly demonstrate that acetaldehyde causes respiratory tract tumors in rats and hamsters when administered by inhalation. There is great potential for extensive human exposure to acetaldehyde. Cigarette smoke contains about 1 mg of acetaldehyde per cigarette, which is far greater than the concentrations of other carcinogens such as benzo[a]pyrene or tobacco-specific nitrosamines, widely assumed to be important as causes of cancer in smokers. Acetaldehyde is the major metabolite of ethanol and can reach significant concentrations in people who drink alcoholic beverages, especially if they are deficient in certain forms of aldehyde dehydrogenase. Acetaldehyde has been implicated as a cause of several cancer types associated with alcohol consumption. Human exposure to acetaldehyde can also occur in occupational and environmental settings. In spite of extensive human exposure to this carcinogen, little is known about its DNA adducts, which are likely central to its carcinogenic activity. We have recently characterized several DNA adducts of acetaldehyde including the Schiff base N2-ethylidenedeoxyguanosine, two diastereomeric l,N2-propanodeoxyguanosine adducts, three diastereomeric N2-dimethyldioxanyldeoxyguanosine adducts, and an interstrand G-G crosslink. These data promise to open new avenues of understanding of acetaldehyde carcinogenesis. Therefore, we propose to extend these studies in the present proposal.
Our specific aims are: 1) Develop sensitive mass spectrometric methods to detect acetaldehyde-DNA adducts. These methods will be applied for analysis of acetaldehyde-DNA adducts in vitro, in laboratory animals exposed to acetaldehyde, and in humans (Specific Aims 2, 4, and 5); 2) Investigate the formation and stereochemistry of acetaldehyde-DNA adducts in vitro, using concentrations of acetaldehyde that are likely to be achieved in vivo; 3) Synthesize oligonucleotides containing the acetaldehyde-DNA crosslink adduct and investigate its repair and mutagenicity; 4) Quantify the formation and persistence of acetaldehyde-DNA adducts in rats or mice exposed to acetaldehyde or ethanol; 5) Quantify acetaldehyde-DNA adducts in white blood cells of humans exposed to acetaldehyde. These studies will be carried out in smokers, non-smokers, casual drinkers, and people with alcohol dependence. The results of the research proposed here will provide critical data, which will be the framework for testing our hypothesis that acetaldehyde is a human carcinogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011297-02
Application #
6620533
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Mastin, Patrick
Project Start
2002-02-18
Project End
2006-11-30
Budget Start
2003-02-05
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$307,329
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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