Biomarkers of exposure and effect in human lymphoblastoid TK6 cells following [13C2]-acetaldehyde exposure.

The dose-response relationship for biomarkers of exposure (N(2)-ethylidene-dG adducts) and effect (cell survival and micronucleus formation) was determined across 4.5 orders of magnitude (50nM-2mM) using [(13)C2]-acetaldehyde exposures to human lymphoblastoid TK6 cells for 12h. There was a clear increase in exogenous N (2)-ethylidene-dG formation at exposure concentrations ≥ 1µM, whereas the endogenous adducts remained nearly constant across all exposure concentrations, with an average of 3.0 adducts/10(7) dG. Exogenous adducts were lower than endogenous adducts at concentrations ≤ 10µM and were greater than endogenous adducts at concentrations ≥ 250µM. When the endogenous and exogenous adducts were summed together, statistically significant increases in total adduct formation over the endogenous background occurred at 50µM. Cell survival and micronucleus formation were monitored across the exposure range and statistically significant decreases in cell survival and increases in micronucleus formation occurred at ≥ 1000µM. This research supports the hypothesis that endogenously produced reactive species, including acetaldehyde, are always present and constitute the majority of the observed biological effects following very low exposures to exogenous acetaldehyde. These data can replace default assumptions of linear extrapolation to very low doses of exogenous acetaldehyde for risk prediction.

[1]  V. Thybaud,et al.  Quantitative approaches for assessing dose–response relationships in genetic toxicology studies , 2013, Environmental and molecular mutagenesis.

[2]  T. Chiba,et al.  Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde‐derived DNA damage in the blood of Japanese alcoholics , 2012, Cancer science.

[3]  J. Gromadzińska,et al.  Detection of acetaldehyde derived N(2)-ethyl-2'-deoxyguanosine in human leukocyte DNA following alcohol consumption. , 2012, Mutation research.

[4]  K. J. Patel,et al.  Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function , 2012, Nature.

[5]  T. Chiba,et al.  Stability of acetaldehyde-derived DNA adduct in vitro. , 2012, Biochemical and biophysical research communications.

[6]  D. Hatsukami,et al.  Time course of DNA adduct formation in peripheral blood granulocytes and lymphocytes after drinking alcohol. , 2012, Mutagenesis.

[7]  S. Tannenbaum,et al.  Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer , 2012, Proceedings of the National Academy of Sciences.

[8]  T. Amagai,et al.  Analysis of N(ε) -ethyllysine in human plasma proteins by gas chromatography-negative ion chemical ionization/mass spectrometry as a biomarker for exposure to acetaldehyde and alcohol. , 2012, Alcoholism, clinical and experimental research.

[9]  Anna Trakoli.  IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 99: Some Aromatic Amines, Organic Dyes, and Related Exposures. International Agency for Research on Cancer , 2012 .

[10]  D. Hatsukami,et al.  Kinetics of DNA Adduct Formation in the Oral Cavity after Drinking Alcohol , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[11]  D. Crabb,et al.  Alcohol metabolism in human cells causes DNA damage and activates the Fanconi anemia-breast cancer susceptibility (FA-BRCA) DNA damage response network. , 2011, Alcoholism, clinical and experimental research.

[12]  K. J. Patel,et al.  Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice , 2011, Nature.

[13]  P. Di Mascio,et al.  [13C2]-Acetaldehyde promotes unequivocal formation of 1,N2-propano-2'-deoxyguanosine in human cells. , 2011, Journal of the American Chemical Society.

[14]  Jun Nakamura,et al.  Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[15]  H. Bartsch,et al.  Ethanol‐mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA‐lesions , 2011, International journal of cancer.

[16]  Dirk W Lachenmeier,et al.  Alcohol consumption and ethyl carbamate. , 2010, IARC monographs on the evaluation of carcinogenic risks to humans.

[17]  T. Oyama,et al.  Effects of acetaldehyde inhalation in mitochondrial aldehyde dehydrogenase deficient mice (Aldh2-/-). , 2010, Frontiers in bioscience.

[18]  M. Hayden,et al.  Calcific uremic arteriolopathy , 2010, Oxidative medicine and cellular longevity.

[19]  Fagen Zhang,et al.  Dose-response and operational thresholds/NOAELs for in vitro mutagenic effects from DNA-reactive mutagens, MMS and MNU. , 2009, Mutation research.

[20]  Lynn H Pottenger,et al.  A case for a new paradigm in genetic toxicology testing. , 2009, Mutation research.

[21]  C. McHale,et al.  The benzene metabolite, hydroquinone and etoposide both induce endoreduplication in human lymphoblastoid TK6 cells. , 2009, Mutagenesis.

[22]  D. Segerbäck,et al.  Evaluation of the DNA damaging potential of cannabis cigarette smoke by the determination of acetaldehyde derived N2-ethyl-2'-deoxyguanosine adducts. , 2009, Chemical research in toxicology.

[23]  David Goldman,et al.  The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption , 2009, PLoS medicine.

[24]  A. Matsumoto,et al.  Increased formation of gastric N(2)-ethylidene-2'-deoxyguanosine DNA adducts in aldehyde dehydrogenase-2 knockout mice treated with ethanol. , 2009, Mutation research.

[25]  Ting-kai Li,et al.  Alleles of alcohol and acetaldehyde metabolism genes modulate susceptibility to oesophageal cancer from alcohol consumption , 2009, Human Genomics.

[26]  G. Speit,et al.  Low sensitivity of the comet assay to detect acetaldehyde-induced genotoxicity. , 2008, Mutation research.

[27]  P. Brennan,et al.  N2-Ethyldeoxyguanosine as a Potential Biomarker for Assessing Effects of Alcohol Consumption on DNA , 2008, Cancer Epidemiology Biomarkers & Prevention.

[28]  Stephen D Dertinger,et al.  Interlaboratory evaluation of a flow cytometric, high content in vitro micronucleus assay. , 2008, Mutation research.

[29]  H. Arakawa,et al.  Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde. , 2007, Cancer research.

[30]  K. Kitagawa,et al.  Increased formation of hepatic N2-ethylidene-2'-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol. , 2007, Carcinogenesis.

[31]  Stephen D Dertinger,et al.  In vitro micronucleus assay scored by flow cytometry provides a comprehensive evaluation of cytogenetic damage and cytotoxicity. , 2007, Mutation research.

[32]  S. Hecht,et al.  Genotoxicity of acetaldehyde- and crotonaldehyde-induced 1,N2-propanodeoxyguanosine DNA adducts in human cells. , 2006, Mutation research.

[33]  S. Akman,et al.  Mutagenesis by exocyclic alkylamino purine adducts in Escherichia coli. , 2006, Mutation research.

[34]  S. Akman,et al.  Replication of N2-ethyldeoxyguanosine DNA adducts in the human embryonic kidney cell line 293. , 2006, Chemical research in toxicology.

[35]  H. Sugimura,et al.  Development of the adductome approach to detect DNA damage in humans. , 2006, Antioxidants & redox signaling.

[36]  F. Guengerich,et al.  Kinetic Evidence for Inefficient and Error-prone Bypass across Bulky N2-Guanine DNA Adducts by Human DNA Polymerase ι* , 2006, Journal of Biological Chemistry.

[37]  S. Hecht,et al.  Identification of an acetaldehyde adduct in human liver DNA and quantitation as N2-ethyldeoxyguanosine. , 2006, Chemical research in toxicology.

[38]  P. J. Brooks,et al.  DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. , 2005, Alcohol.

[39]  A. Siraki,et al.  Aldehyde Sources, Metabolism, Molecular Toxicity Mechanisms, and Possible Effects on Human Health , 2005, Critical reviews in toxicology.

[40]  M. Bogdanffy,et al.  Differentiating between local cytotoxicity, mitogenesis, and genotoxicity in carcinogen risk assessments: the case of vinyl acetate. , 2003, Toxicology letters.

[41]  F. Johnson,et al.  Mutagenesis by acrolein-derived propanodeoxyguanosine adducts in human cells. , 2002, Biochemistry.

[42]  S. Hecht,et al.  New DNA adducts of crotonaldehyde and acetaldehyde. , 2001, Toxicology.

[43]  S. Shibutani,et al.  Miscoding potential of the N2-ethyl-2'-deoxyguanosine DNA adduct by the exonuclease-free Klenow fragment of Escherichia coli DNA polymerase I. , 2001, Biochemistry.

[44]  S. Hecht,et al.  Identification of DNA adducts of acetaldehyde. , 2000, Chemical research in toxicology.

[45]  M. Sako,et al.  A Convenient Method for the Preparation of N(2)-Ethylguanine Nucleosides and Nucleotides. , 1999, The Journal of organic chemistry.

[46]  S. L. Hazen,et al.  Human neutrophils employ myeloperoxidase to convert alpha-amino acids to a battery of reactive aldehydes: a pathway for aldehyde generation at sites of inflammation. , 1998, Biochemistry.

[47]  R. Grafström,et al.  Formation of DNA adducts in human buccal epithelial cells exposed to acetaldehyde and methylglyoxal in vitro. , 1998, Chemico-biological interactions.

[48]  C. Vaca,et al.  Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. , 1997, Carcinogenesis.

[49]  T. Takeshita,et al.  Elevated levels of hemoglobin-associated acetaldehyde related to alcohol drinking in the atypical genotype of low Km aldehyde dehydrogenase. , 1997, Cancer research.

[50]  L. Migliore,et al.  Detection of the centromere in micronuclei by fluorescence in situ hybridization: its application to the human lymphocyte micronucleus assay after treatment with four suspected aneugens. , 1996, Mutagenesis.

[51]  O. Yokosuka,et al.  High incidence of ADH2*1/ALDH2*1 genes among Japanese alcohol dependents and patients with alcoholic liver disease , 1996, Hepatology.

[52]  C. Vaca,et al.  Development of a 32P-postlabelling method for the analysis of adducts arising through the reaction of acetaldehyde with 2'-deoxyguanosine-3'-monophosphate and DNA. , 1995, Carcinogenesis.

[53]  J. Kuykendall,et al.  Formation and stability of acetaldehyde-induced crosslinks between poly-lysine and poly-deoxyguanosine. , 1994, Mutation research.

[54]  C. Harris,et al.  Pathobiological effects of acetaldehyde in cultured human epithelial cells and fibroblasts. , 1994, Carcinogenesis.

[55]  J. Kuykendall,et al.  Reaction kinetics of DNA-histone crosslinking by vinyl acetate and acetaldehyde. , 1992, Carcinogenesis.

[56]  J. Kuykendall,et al.  Efficiency of DNA-histone crosslinking induced by saturated and unsaturated aldehydes in vitro. , 1992, Mutation research.

[57]  V. Feron,et al.  Inhalation toxicity of acetaldehyde in rats. IV. Progression and regression of nasal lesions after discontinuation of exposure. , 1987, Toxicology.

[58]  V J Feron,et al.  Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. , 1986, Toxicology.

[59]  V. Feron,et al.  Inhalation toxicity of acetaldehyde in rats. II. Carcinogenicity study: interim results after 15 months. , 1984, Toxicology.

[60]  R. Bird,et al.  Effect of malonaldehyde and acetaldehyde on cultured mammalian cells. Production of micronuclei and chromosomal aberrations. , 1982, Mutation research.

[61]  Vernon E Walker,et al.  Biomarkers in toxicology and risk assessment: informing critical dose-response relationships. , 2008, Chemical research in toxicology.

[62]  D. Hatsukami,et al.  Quantitation of an acetaldehyde adduct in human leukocyte DNA and the effect of smoking cessation. , 2007, Chemical research in toxicology.

[63]  P. Di Micco,et al.  Journal of Translational Medicine BioMed Central Methodology , 2005 .

[64]  S. Hecht,et al.  New aspects of DNA adduct formation by the carcinogens crotonaldehyde and acetaldehyde. , 2001, Advances in experimental medicine and biology.

[65]  J. Mccormick,et al.  Acetaldehyde‐induced mutation at the hprt Locus in Human Lymphocytes In Vitro , 1990, Environmental and molecular mutagenesis.

[66]  A Yoshida,et al.  Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[67]  J. Higginson.  International Agency for Research on Cancer. , 1968, WHO chronicle.