Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium

Ayaka Mizumoto, Shinya Ohashi, Kenshiro Hirohashi, Yusuke Amanuma, Tomonari Matsuda, Manabu Muto, Ayaka Mizumoto, Shinya Ohashi, Kenshiro Hirohashi, Yusuke Amanuma, Tomonari Matsuda, Manabu Muto

Abstract

Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA-DNA cross-links. Among these, DNA adducts such as N²-ethylidene-2'-deoxyguanosine, N²-ethyl-2'-deoxyguanosine, N²-propano-2'-deoxyguanosine, and N²-etheno-2'-deoxyguanosine are central to acetaldehyde-mediated DNA damage because they are associated with the induction of DNA mutations, DNA-DNA cross-links, DSBs, and SCEs. Acetaldehyde is produced endogenously by alcohol metabolism and is catalyzed by aldehyde dehydrogenase 2 (ALDH2). Alcohol consumption increases blood and salivary acetaldehyde levels, especially in individuals with ALDH2 polymorphisms, which are highly associated with the risk of squamous cell carcinomas in the upper aerodigestive tract. Based on extensive epidemiological evidence, the International Agency for Research on Cancer defined acetaldehyde associated with the consumption of alcoholic beverages as a "group 1 carcinogen" (definite carcinogen) for the esophagus and/or head and neck. In this article, we review recent advances from studies of acetaldehyde-mediated carcinogenesis in the squamous epithelium, focusing especially on acetaldehyde-mediated DNA adducts. We also give attention to research on acetaldehyde-mediated DNA repair pathways such as the Fanconi anemia pathway and refer to our studies on the prevention of acetaldehyde-mediated DNA damage.

Keywords: DNA adduct; DNA damage; DNA repair pathway; acetaldehyde; cancer development; esophageal squamous cell carcinoma; head and neck squamous cell carcinoma.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Ethanol and acetaldehyde metabolism after alcohol ingestion. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase 1B (ADH1B), and then acetaldehyde is degraded to acetic acid by aldehyde dehydrogenase 2 (ALDH2).
Figure 2
Figure 2
Lugol chromoendoscopic images. (A): “Field cancerization” in a patient with esophageal squamous cell carcinoma (ESCC) and head and neck squamous cell carcinoma (HNSCC) synchronously. Location of (a) oropharynx, (b) uvula, (c) upper thoracic esophagus, and (d) lower thoracic esophagus. Lesions are indicated by arrowheads; (B): (a) normal esophageal mucosa, (b) esophageal mucosa with multiple dysplastic lesions known as multiple Lugol-voiding lesions. Scale bar = 0.5 cm.
Figure 3
Figure 3
Formation of acetaldehyde-mediated DNA adducts. A single molecule of acetaldehyde reacts with deoxyguanosine (dG) to generate N2-ethylidene-2′-deoxyguanosine (N2-ethylidene-dG), which can be reduced to the stable adducts, N2-ethyl-2′-deoxyguanosine (N2-Et-dG). α-S- and α-R-methyl-γ-hydroxy-1, N2-propano-2′-deoxyguanosine (CrPdG) is derived from dG and two molecules of acetaldehyde. N2-etheno-2′-deoxyguanosine (NεG) is formed from dG and α,β-unsaturated aldehydes during lipid peroxidation, which is mediated by acetaldehyde or reactive oxygen species (ROS).
Figure 4
Figure 4
Summary of acetaldehyde-mediated DNA damage. Acetaldehyde causes DNA adducts, DNA single-strand breaks, DNA double-strand breaks (DSBs), point mutations, micronuclei, frameshift mutations, base-pair mutations, deletions, DNA–DNA interstrand or intrastrand cross-links, rearrangements, and sister chromatid exchanges (SCEs). DNA adducts are considered to be partly (but deeply) involved in their formation.

References

    1. Seitz H.K., Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat. Rev. Cancer. 2007;7:599–612. doi: 10.1038/nrc2191.
    1. Brooks P.J., Zakhari S. Acetaldehyde and the genome: Beyond nuclear DNA adducts and carcinogenesis. Environ. Mol. Mutagen. 2014;55:77–91. doi: 10.1002/em.21824.
    1. Uebelacker M., Lachenmeier D.W. Quantitative determination of acetaldehyde in foods using automated digestion with simulated gastric fluid followed by headspace gas chromatography. J. Autom. Methods Manag. Chem. 2011;2011:907317. doi: 10.1155/2011/907317.
    1. Launoy G., Milan C., Day N.E., Pienkowski M.P., Gignoux M., Faivre J. Diet and squamous-cell cancer of the oesophagus: A french multicentre case-control study. Int. J. Cancer. 1998;76:7–12. doi: 10.1002/(SICI)1097-0215(19980330)76:1<7::AID-IJC2>;2-4.
    1. Salaspuro V.J., Hietala J.M., Marvola M.L., Salaspuro M.P. Eliminating carcinogenic acetaldehyde by cysteine from saliva during smoking. Cancer Epidemiol. Biomark. Prev. 2006;15:146–149. doi: 10.1158/1055-9965.EPI-05-0248.
    1. Homann N., Jousimies-Somer H., Jokelainen K., Heine R., Salaspuro M. High acetaldehyde levels in saliva after ethanol consumption: Methodological aspects and pathogenetic implications. Carcinogenesis. 1997;18:1739–1743. doi: 10.1093/carcin/18.9.1739.
    1. Salaspuro M.P. Acetaldehyde, microbes, and cancer of the digestive tract. Crit. Rev. Clin. Lab. Sci. 2003;40:183–208. doi: 10.1080/713609333.
    1. Muto M., Hitomi Y., Ohtsu A., Shimada H., Kashiwase Y., Sasaki H., Yoshida S., Esumi H. Acetaldehyde production by non-pathogenic neisseria in human oral microflora: Implications for carcinogenesis in upper aerodigestive tract. Int. J. Cancer. 2000;88:342–350. doi: 10.1002/1097-0215(20001101)88:3<342::AID-IJC4>;2-I.
    1. Linderborg K., Joly J.P., Visapaa J.P., Salaspuro M. Potential mechanism for calvados-related oesophageal cancer. Food Chem. Toxicol. 2008;46:476–479. doi: 10.1016/j.fct.2007.08.019.
    1. Linderborg K., Salaspuro M., Vakevainen S. A single sip of a strong alcoholic beverage causes exposure to carcinogenic concentrations of acetaldehyde in the oral cavity. Food Chem. Toxicol. 2011;49:2103–2106. doi: 10.1016/j.fct.2011.05.024.
    1. Brooks P.J., Enoch M.A., Goldman D., Li T.K., Yokoyama A. The alcohol flushing response: An unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med. 2009;6:e50. doi: 10.1371/journal.pmed.1000050.
    1. Ohashi S., Miyamoto S., Kikuchi O., Goto T., Amanuma Y., Muto M. Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology. 2015;149:1700–1715. doi: 10.1053/j.gastro.2015.08.054.
    1. Matsuo K., Hamajima N., Shinoda M., Hatooka S., Inoue M., Takezaki T., Tajima K. Gene-environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis. 2001;22:913–916. doi: 10.1093/carcin/22.6.913.
    1. Yang S.J. Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: A meta-analysis. World J. Gastroenterol. 2010;16:4210. doi: 10.3748/wjg.v16.i33.4210.
    1. Yokoyama A., Muramatsu T., Omori T., Yokoyama T., Matsushita S., Higuchi S., Maruyama K., Ishii H. Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in japanese alcoholics. Carcinogenesis. 2001;22:433–439. doi: 10.1093/carcin/22.3.433.
    1. Lachenmeier D.W., Salaspuro M. ALDH2-deficiency as genetic epidemiologic and biochemical model for the carcinogenicity of acetaldehyde. Regul. Toxicol. Pharmacol. 2017;86:128–136. doi: 10.1016/j.yrtph.2017.02.024.
    1. Neumark Y.D., Friedlander Y., Durst R., Leitersdorf E., Jaffe D., Ramchandani V.A., O’Connor S., Carr L.G., Li T.K. Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male jewish population. Alcohol Clin. Exp. Res. 2004;28:10–14. doi: 10.1097/01.ALC.0000108667.79219.4D.
    1. Zhang L., Jiang Y., Wu Q., Li Q., Chen D., Xu L., Zhang C., Zhang M., Ye L. Gene—Environment interactions on the risk of esophageal cancer among Asian populations with the G48A polymorphism in the alcohol dehydrogenase-2 gene: A meta-analysis. Tumour Biol. 2014;35:4705–4717. doi: 10.1007/s13277-014-1616-7.
    1. Zhang Y., Gu N., Miao L., Yuan H., Wang R., Jiang H. Alcohol dehydrogenase-1B Arg47His polymorphism is associated with head and neck cancer risk in Asian: A meta-analysis. Tumour Biol. 2015;36:1023–1027. doi: 10.1007/s13277-014-2727-x.
    1. Enomoto N., Takase S., Yasuhara M., Takada A. Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin. Exp. Res. 1991;15:141–144. doi: 10.1111/j.1530-0277.1991.tb00532.x.
    1. Hoshi H., Hao W., Fujita Y., Funayama A., Miyauchi Y., Hashimoto K., Miyamoto K., Iwasaki R., Sato Y., Kobayashi T., et al. Aldehyde-stress resulting from ALDH2 mutation promotes osteoporosis due to impaired osteoblastogenesis. J. Bone Miner. Res. 2012;27:2015–2023. doi: 10.1002/jbmr.1634.
    1. Yokoyama A., Mizukami T., Yokoyama T. Genetic polymorphisms of alcohol dehydrogense-1B and aldehyde dehydrogenase-2, alcohol flushing, mean corpuscular volume, and aerodigestive tract neoplasia in japanese drinkers. Adv. Exp. Med. Biol. 2015;815:265–279.
    1. Harada S., Agarwal D.P., Goedde H.W. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet (Lond. Engl.) 1981;2:982. doi: 10.1016/S0140-6736(81)91172-7.
    1. Yoshida A., Huang I.Y., Ikawa M. Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in orientals. Proc. Natl. Acad. Sci. USA. 1984;81:258–261. doi: 10.1073/pnas.81.1.258.
    1. Higuchi S., Matsushita S., Murayama M., Takagi S., Hayashida M. Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism. Am. J. Psychiatry. 1995;152:1219–1221.
    1. Goedde H.W., Agarwal D.P., Fritze G., Meier-Tackmann D., Singh S., Beckmann G., Bhatia K., Chen L.Z., Fang B., Lisker R., et al. Distribution of ADH2 and ALDH2 genotypes in different populations. Hum. Genet. 1992;88:344–346. doi: 10.1007/BF00197271.
    1. Boccia S., Hashibe M., Galli P., De Feo E., Asakage T., Hashimoto T., Hiraki A., Katoh T., Nomura T., Yokoyama A., et al. Aldehyde dehydrogenase 2 and head and neck cancer: A meta-analysis implementing a mendelian randomization approach. Cancer Epidemiol. Biomark. Prev. 2009;18:248–254. doi: 10.1158/1055-9965.EPI-08-0462.
    1. Secretan B., Straif K., Baan R., Grosse Y., El Ghissassi F., Bouvard V., Benbrahim-Tallaa L., Guha N., Freeman C., Galichet L., et al. A review of human carcinogens—Part E: Tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 2009;10:1033–1034. doi: 10.1016/S1470-2045(09)70326-2.
    1. Muto M., Nakane M., Hitomi Y., Yoshida S., Sasaki S., Ohtsu A., Yoshida S., Ebihara S., Esumi H. Association between aldehyde dehydrogenase gene polymorphisms and the phenomenon of field cancerization in patients with head and neck cancer. Carcinogenesis. 2002;23:1759–1765. doi: 10.1093/carcin/23.10.1759.
    1. Mori M., Adachi Y., Matsushima T., Matsuda H., Kuwano H., Sugimachi K. Lugol staining pattern and histology of esophageal lesions. Am. J. Gastroenterol. 1993;88:701–705.
    1. Muto M., Hironaka S., Nakane M., Boku N., Ohtsu A., Yoshida S. Association of multiple lugol-voiding lesions with synchronous and metachronous esophageal squamous cell carcinoma in patients with head and neck cancer. Gastrointest. Endosc. 2002;56:517–521. doi: 10.1016/S0016-5107(02)70436-7.
    1. Slaughter D.P., Southwick H.W., Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6:963–968. doi: 10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>;2-Q.
    1. Katada C., Yokoyama T., Yano T., Kaneko K., Oda I., Shimizu Y., Doyama H., Koike T., Takizawa K., Hirao M., et al. Alcohol consumption and multiple dysplastic lesions increase risk of squamous cell carcinoma in the esophagus, head, and neck. Gastroenterology. 2016;151:860–869. doi: 10.1053/j.gastro.2016.07.040.
    1. Yokoyama A., Tsutsumi E., Imazeki H., Suwa Y., Nakamura C., Yokoyama T. Polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 and the blood and salivary ethanol and acetaldehyde concentrations of japanese alcoholic men. Alcohol Clin. Exp. Res. 2010;34:1246–1256. doi: 10.1111/j.1530-0277.2010.01202.x.
    1. Aoyama I., Ohashi S., Amanuma Y., Hirohashi K., Mizumoto A., Funakoshi M., Tsurumaki M., Nakai Y., Tanaka K., Hanada M., et al. Establishment of a quick and highly accurate breath test for ALDH2 genotyping. Clin. Transl. Gastroenterol. 2017;8:e96. doi: 10.1038/ctg.2017.24.
    1. Yokoyama A., Tsutsumi E., Imazeki H., Suwa Y., Nakamura C., Mizukami T., Yokoyama T. Salivary acetaldehyde concentration according to alcoholic beverage consumed and aldehyde dehydrogenase-2 genotype. Alcohol Clin. Exp. Res. 2008;32:1607–1614. doi: 10.1111/j.1530-0277.2008.00739.x.
    1. Dong Y.J., Peng T.K., Yin S.J. Expression and activities of class Ⅳ alcohol dehydrogenase and class Ⅲ aldehyde dehydrogenase in human mouth. Alcohol. 1996;13:257–262. doi: 10.1016/0741-8329(95)02052-7.
    1. Vakevainen S., Tillonen J., Agarwal D.P., Srivastava N., Salaspuro M. High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: Strong evidence for the local carcinogenic action of acetaldehyde. Alcohol Clin. Exp. Res. 2000;24:873–877. doi: 10.1111/j.1530-0277.2000.tb02068.x.
    1. Wang M., McIntee E.J., Cheng G., Shi Y., Villalta P.W., Hecht S.S. Identification of DNA adducts of acetaldehyde. Chem. Res. Toxicol. 2000;13:1149–1157. doi: 10.1021/tx000118t.
    1. Fang J.L., Vaca C.E. Development of a 32P-postlabelling method for the analysis of adducts arising through the reaction of acetaldehyde with 2’-deoxyguanosine-3’-monophosphate and DNA. Carcinogenesis. 1995;16:2177–2185. doi: 10.1093/carcin/16.9.2177.
    1. Fang J.L., Vaca C.E. Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis. 1997;18:627–632. doi: 10.1093/carcin/18.4.627.
    1. Hecht S.S., McIntee E.J., Wang M. New DNA adducts of crotonaldehyde and acetaldehyde. Toxicology. 2001;166:31–36. doi: 10.1016/S0300-483X(01)00436-X.
    1. Matsuda T., Matsumoto A., Uchida M., Kanaly R.A., Misaki K., Shibutani S., Kawamoto T., Kitagawa K., Nakayama K.I., Tomokuni K., et al. Increased formation of hepatic N2-ethylidene-2’-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol. Carcinogenesis. 2007;28:2363–2366. doi: 10.1093/carcin/bgm057.
    1. Wang M., Yu N., Chen L., Villalta P.W., Hochalter J.B., Hecht S.S. Identification of an acetaldehyde adduct in human liver DNA and quantitation as N2-ethyldeoxyguanosine. Chem. Res. Toxicol. 2006;19:319–324. doi: 10.1021/tx0502948.
    1. Nagayoshi H., Matsumoto A., Nishi R., Kawamoto T., Ichiba M., Matsuda T. Increased formation of gastric N2-ethylidene-2’-deoxyguanosine DNA adducts in aldehyde dehydrogenase-2 knockout mice treated with ethanol. Mutat. Res. 2009;673:74–77. doi: 10.1016/j.mrgentox.2008.11.009.
    1. Yukawa Y., Muto M., Hori K., Nagayoshi H., Yokoyama A., Chiba T., Matsuda T. Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde-derived DNA damage in the blood of japanese alcoholics. Cancer Sci. 2012;103:1651–1655. doi: 10.1111/j.1349-7006.2012.02360.x.
    1. Yukawa Y., Ohashi S., Amanuma Y., Nakai Y., Tsurumaki M., Kikuchi O., Miyamoto S., Oyama T., Kawamoto T., Chiba T., et al. Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion. Am. J. Cancer Res. 2014;4:279–284.
    1. Balbo S., Meng L., Bliss R.L., Jensen J.A., Hatsukami D.K., Hecht S.S. Kinetics of DNA adduct formation in the oral cavity after drinking alcohol. Cancer Epidemiol. Biomarkers Prev. 2012;21:601–608. doi: 10.1158/1055-9965.EPI-11-1175.
    1. Balbo S., Juanes R.C., Khariwala S., Baker E.J., Daunais J.B., Grant K.A. Increased levels of the acetaldehyde-derived DNA adduct N2-ethyldeoxyguanosine in oral mucosa DNA from rhesus monkeys exposed to alcohol. Mutagenesis. 2016;31:553–558. doi: 10.1093/mutage/gew016.
    1. Balbo S., Hashibe M., Gundy S., Brennan P., Canova C., Simonato L., Merletti F., Richiardi L., Agudo A., Castellsague X., et al. N2-ethyldeoxyguanosine as a potential biomarker for assessing effects of alcohol consumption on DNA. Cancer Epidemiol. Biomarkers Prev. 2008;17:3026–3032. doi: 10.1158/1055-9965.EPI-08-0117.
    1. Chen L., Wang M., Villalta P.W., Luo X., Feuer R., Jensen J., Hatsukami D.K., Hecht S.S. Quantitation of an acetaldehyde adduct in human leukocyte DNA and the effect of smoking cessation. Chem. Res Toxicol. 2007;20:108–113. doi: 10.1021/tx060232x.
    1. Amanuma Y., Ohashi S., Itatani Y., Tsurumaki M., Matsuda S., Kikuchi O., Nakai Y., Miyamoto S., Oyama T., Kawamoto T., et al. Protective role of ALDH2 against acetaldehyde-derived DNA damage in oesophageal squamous epithelium. Sci. Rep. 2015;5:14142. doi: 10.1038/srep14142.
    1. Garcia C.C., Angeli J.P., Freitas F.P., Gomes O.F., de Oliveira T.F., Loureiro A.P., di Mascio P., Medeiros M.H. [13C2]-acetaldehyde promotes unequivocal formation of 1,N2-propano-2’-deoxyguanosine in human cells. J. Am. Chem. Soc. 2011;133:9140–9143. doi: 10.1021/ja2004686.
    1. Mao H., Schnetz-Boutaud N.C., Weisenseel J.P., Marnett L.J., Stone M.P. Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct. Proc. Natl. Acad. Sci. USA. 1999;96:6615–6620. doi: 10.1073/pnas.96.12.6615.
    1. Minko I.G., Kozekov I.D., Harris T.M., Rizzo C.J., Lloyd R.S., Stone M.P. Chemistry and biology of DNA containing 1,N2-deoxyguanosine adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem. Res. Toxicol. 2009;22:759–778. doi: 10.1021/tx9000489.
    1. Theruvathu J.A., Jaruga P., Nath R.G., Dizdaroglu M., Brooks P.J. Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde. Nucleic Acids Res. 2005;33:3513–3520. doi: 10.1093/nar/gki661.
    1. Matsuda T., Yabushita H., Kanaly R.A., Shibutani S., Yokoyama A. Increased DNA damage in ALDH2-deficient alcoholics. Chem. Res. Toxicol. 2006;19:1374–1378. doi: 10.1021/tx060113h.
    1. Loureiro A.P., di Mascio P., Gomes O.F., Medeiros M.H. Trans,trans-2,4-decadienal-induced 1, N2-etheno-2′-deoxyguanosine adduct formation. Chem. Res. Toxicol. 2000;13:601–609. doi: 10.1021/tx000004h.
    1. Tanaka K., Whelan K.A., Chandramouleeswaran P.M., Kagawa S., Rustgi S.L., Noguchi C., Guha M., Srinivasan S., Amanuma Y., Ohashi S., et al. ALDH2 modulates autophagy flux to regulate acetaldehyde-mediated toxicity thresholds. Am. J. Cancer Res. 2016;6:781–796.
    1. Matsuda T., Terashima I., Matsumoto Y., Yabushita H., Matsui S., Shibutani S. Effective utilization of N2-ethyl-2′-deoxyguanosine triphosphate during DNA synthesis catalyzed by mammalian replicative DNA polymerases. Biochemistry. 1999;38:929–935. doi: 10.1021/bi982134j.
    1. Terashima I., Matsuda T., Fang T.W., Suzuki N., Kobayashi J., Kohda K., Shibutani S. Miscoding potential of the N2-ethyl-2′-deoxyguanosine DNA adduct by the exonuclease-free klenow fragment of escherichia coli DNA polymerase i. Biochemistry. 2001;40:4106–4114. doi: 10.1021/bi002719p.
    1. Upton D.C., Wang X., Blans P., Perrino F.W., Fishbein J.C., Akman S.A. Replication of N2-ethyldeoxyguanosine DNA adducts in the human embryonic kidney cell line 293. Chem. Res. Toxicol. 2006;19:960–967. doi: 10.1021/tx060084a.
    1. Perrino F.W., Blans P., Harvey S., Gelhaus S.L., McGrath C., Akman S.A., Jenkins G.S., LaCourse W.R., Fishbein J.C. The N2-ethylguanine and the O6-ethyl- and O6-methylguanine lesions in DNA: Contrasting responses from the "bypass" DNA polymerase eta and the replicative DNA polymerase α. Chem. Res. Toxicol. 2003;16:1616–1623. doi: 10.1021/tx034164f.
    1. Brooks P.J., Theruvathu J.A. DNA adducts from acetaldehyde: Implications for alcohol-related carcinogenesis. Alcohol. 2005;35:187–193. doi: 10.1016/j.alcohol.2005.03.009.
    1. Matsuda T., Kawanishi M., Yagi T., Matsui S., Takebe H. Specific tandem GG to TT base substitutions induced by acetaldehyde are due to intra-strand crosslinks between adjacent guanine bases. Nucleic Acids Res. 1998;26:1769–1774. doi: 10.1093/nar/26.7.1769.
    1. Cho Y.J., Wang H., Kozekov I.D., Kurtz A.J., Jacob J., Voehler M., Smith J., Harris T.M., Lloyd R.S., Rizzo C.J., et al. Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived α-CH3-γ-OH-1,N2-propano-2’-deoxyguanosine adducts in the 5′-CpG-3′ sequence. Chem. Res. Toxicol. 2006;19:195–208. doi: 10.1021/tx050239z.
    1. Fernandes P.H., Kanuri M., Nechev L.V., Harris T.M., Lloyd R.S. Mammalian cell mutagenesis of the DNA adducts of vinyl chloride and crotonaldehyde. Environ. Mol. Mutagen. 2005;45:455–459. doi: 10.1002/em.20117.
    1. Stein S., Lao Y., Yang I.Y., Hecht S.S., Moriya M. Genotoxicity of acetaldehyde- and crotonaldehyde-induced 1, N2-propanodeoxyguanosine DNA adducts in human cells. Mutat. Res. 2006;608:1–7. doi: 10.1016/j.mrgentox.2006.01.009.
    1. Noori P., Hou S.M. Mutational spectrum induced by acetaldehyde in the HPRT gene of human t lymphocytes resembles that in the p53 gene of esophageal cancers. Carcinogenesis. 2001;22:1825–1830. doi: 10.1093/carcin/22.11.1825.
    1. Choi J.Y., Guengerich F.P. Adduct size limits efficient and error-free bypass across bulky N2-guanine DNA lesions by human DNA polymerase eta. J. Mol. Biol. 2005;352:72–90. doi: 10.1016/j.jmb.2005.06.079.
    1. Choi J.Y., Guengerich F.P. Kinetic evidence for inefficient and error-prone bypass across bulky N2-guanine DNA adducts by human DNA polymerase iota. J. Biol. Chem. 2006;281:12315–12324. doi: 10.1074/jbc.M600112200.
    1. Choi J.Y., Angel K.C., Guengerich F.P. Translesion synthesis across bulky N2-alkyl guanine DNA adducts by human DNA polymerase κ. J. Biol Chem. 2006;281:21062–21072. doi: 10.1074/jbc.M602246200.
    1. Akasaka S., Guengerich F.P. Mutagenicity of site-specifically located 1,N2-ethenoguanine in chinese hamster ovary cell chromosomal DNA. Chem. Res. Toxicol. 1999;12:501–507. doi: 10.1021/tx980259j.
    1. Kotova N., Vare D., Schultz N., Gradecka Meesters D., Stepnik M., Grawe J., Helleday T., Jenssen D. Genotoxicity of alcohol is linked to DNA replication-associated damage and homologous recombination repair. Carcinogenesis. 2013;34:325–330. doi: 10.1093/carcin/bgs340.
    1. Jansson T. The frequency of sister chromatid exchanges in human lymphocytes treated with ethanol and acetaldehyde. Hereditas. 1982;97:301–303. doi: 10.1111/j.1601-5223.1982.tb00774.x.
    1. Wilson D.M., 3rd, Thompson L.H. Molecular mechanisms of sister-chromatid exchange. Mutat. Res. 2007;616:11–23. doi: 10.1016/j.mrfmmm.2006.11.017.
    1. Singh N.P., Khan A. Acetaldehyde: Genotoxicity and cytotoxicity in human lymphocytes. Mutat. Res. 1995;337:9–17. doi: 10.1016/0921-8777(95)00006-6.
    1. Obe G., Jonas R., Schmidt S. Metabolism of ethanol in vitro produces a compound which induces sister-chromatid exchanges in human peripheral lymphocytes in vitro: Acetaldehyde not ethanol is mutagenic. Mutat. Res. 1986;174:47–51. doi: 10.1016/0165-7992(86)90075-8.
    1. Dellarco V.L. A mutagenicity assessment of acetaldehyde. Mutat. Res. 1988;195:1–20. doi: 10.1016/0165-1110(88)90013-9.
    1. Helander A., Lindahl-Kiessling K. Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutat. Res. 1991;264:103–107. doi: 10.1016/0165-7992(91)90124-M.
    1. Lambert B., Chen Y., He S.M., Sten M. DNA cross-links in human leucocytes treated with vinyl acetate and acetaldehyde in vitro. Mutat. Res. 1985;146:301–303. doi: 10.1016/0167-8817(85)90072-0.
    1. Kayani M.A., Parry J.M. The in vitro genotoxicity of ethanol and acetaldehyde. Toxicol. In Vitro. 2010;24:56–60. doi: 10.1016/j.tiv.2009.09.003.
    1. Paget V., Lechevrel M., Sichel F. Acetaldehyde-induced mutational pattern in the tumour suppressor gene tp53 analysed by use of a functional assay, the fasay (functional analysis of separated alleles in yeast) Mutat. Res. 2008;652:12–19. doi: 10.1016/j.mrgentox.2007.11.010.
    1. Lin D.C., Hao J.J., Nagata Y., Xu L., Shang L., Meng X., Sato Y., Okuno Y., Varela A.M., Ding L.W., et al. Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat. Genet. 2014;46:467–473. doi: 10.1038/ng.2935.
    1. Sawada G., Niida A., Uchi R., Hirata H., Shimamura T., Suzuki Y., Shiraishi Y., Chiba K., Imoto S., Takahashi Y., et al. Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology. 2016;150:1171–1182. doi: 10.1053/j.gastro.2016.01.035.
    1. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576–582.
    1. Woutersen R.A., Appelman L.M., van Garderen-Hoetmer A., Feron V.J. Inhalation toxicity of acetaldehyde in rats. Ⅲ. Carcinogenicity study. Toxicology. 1986;41:213–231. doi: 10.1016/0300-483X(86)90201-5.
    1. Feron V.J., Kruysse A., Woutersen R.A. Respiratory tract tumours in hamsters exposed to acetaldehyde vapour alone or simultaneously to benzo(a)pyrene or diethylnitrosamine. Eur. J. Cancer Clin. Oncol. 1982;18:13–31. doi: 10.1016/0277-5379(82)90020-7.
    1. Noguchi C., Grothusen G., Anandarajan V., Martinez-Lage Garcia M., Terlecky D., Corzo K., Tanaka K., Nakagawa H., Noguchi E. Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast. Cell Cycle. 2017;16:45–58. doi: 10.1080/15384101.2016.1237326.
    1. Koivisto P., Robins P., Lindahl T., Sedgwick B. Demethylation of 3-methylthymine in DNA by bacterial and human DNA dioxygenases. J. Biol. Chem. 2004;279:40470–40474. doi: 10.1074/jbc.M407960200.
    1. Choudhury S., Pan J., Amin S., Chung F.L., Roy R. Repair kinetics of trans-4-hydroxynonenal-induced cyclic 1,N2-propanodeoxyguanine DNA adducts by human cell nuclear extracts. Biochemistry. 2004;43:7514–7521. doi: 10.1021/bi049877r.
    1. Dong H., Nebert D.W., Bruford E.A., Thompson D.C., Joenje H., Vasiliou V. Update of the human and mouse fanconi anemia genes. Hum. Genomics. 2015;9:32. doi: 10.1186/s40246-015-0054-y.
    1. Clauson C., Scharer O.D., Niedernhofer L. Advances in understanding the complex mechanisms of DNA interstrand cross-link repair. Cold Spring Harb. Perspect. Biol. 2013;5:a012732. doi: 10.1101/cshperspect.a012732.
    1. Kottemann M.C., Smogorzewska A. Fanconi anaemia and the repair of watson and crick DNA crosslinks. Nature. 2013;493:356–363. doi: 10.1038/nature11863.
    1. Moldovan G.L., D’Andrea A.D. How the fanconi anemia pathway guards the genome. Annu. Rev. Genet. 2009;43:223–249. doi: 10.1146/annurev-genet-102108-134222.
    1. Walden H., Deans A.J. The fanconi anemia DNA repair pathway: Structural and functional insights into a complex disorder. Annu. Rev. Biophys. 2014;43:257–278. doi: 10.1146/annurev-biophys-051013-022737.
    1. Thompson L.H., Hinz J.M. Cellular and molecular consequences of defective fanconi anemia proteins in replication-coupled DNA repair: Mechanistic insights. Mutat. Res. 2009;668:54–72. doi: 10.1016/j.mrfmmm.2009.02.003.
    1. Abraham J., Balbo S., Crabb D., Brooks P.J. Alcohol metabolism in human cells causes DNA damage and activates the fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network. Alcohol Clin. Exp. Res. 2011;35:2113–2120. doi: 10.1111/j.1530-0277.2011.01563.x.
    1. Marietta C., Thompson L.H., Lamerdin J.E., Brooks P.J. Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: Implications for alcohol-related carcinogenesis. Mutat. Res. 2009;664:77–83. doi: 10.1016/j.mrfmmm.2009.03.011.
    1. Obe G., Natarajan A.T., Meyers M., Hertog A.D. Induction of chromosomal aberrations in peripheral lymphocytes of human blood in vitro, and of sces in bone-marrow cells of mice in vivo by ethanol and its metabolite acetaldehyde. Mutat. Res. 1979;68:291–294. doi: 10.1016/0165-1218(79)90160-5.
    1. Mechilli M., Schinoppi A., Kobos K., Natarajan A.T., Palitti F. DNA repair deficiency and acetaldehyde-induced chromosomal alterations in CHO cells. Mutagenesis. 2008;23:51–56. doi: 10.1093/mutage/gem042.
    1. Lorenti Garcia C., Mechilli M., Proietti De Santis L., Schinoppi A., Kobos K., Palitti F. Relationship between DNA lesions, DNA repair and chromosomal damage induced by acetaldehyde. Mutat. Res. 2009;662:3–9. doi: 10.1016/j.mrfmmm.2008.11.008.
    1. Langevin F., Crossan G.P., Rosado I.V., Arends M.J., Patel K.J. FANCD2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature. 2011;475:53–58. doi: 10.1038/nature10192.
    1. Stewart M.J., Malek K., Crabb D.W. Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues. J. Investig. Med. 1996;44:42–46.

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