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Mass Spectrometric DNA Adduct Quantification by Multiple Reaction Monitoring and Its Future Use for the Molecular Epidemiology of Cancer

  • Bernhard H. MonienEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1140)

Abstract

The formation of DNA adducts is considered essential for tumor initiation. Quantification of DNA adducts may be achieved by various techniques of which LC-MS/MS-based multiple reaction monitoring has become the most prominent in the past decade. Adducts of single nucleosides are analyzed following enzymatic break-down of a DNA sample following adduct enrichment usually by solid-phase extraction. LC-MS/MS quantification is carried out using stable isotope-labeled internal reference substances. An upcoming challenge is the use of DNA adducts as biomarkers either for internal exposure to electrophilic genotoxins or for the approximation of cancer risk. Here we review recent studies in which DNA adducts were quantified by LC-MS/MS in DNA samples from human matrices. We outline a possible way for future research to aim at the development of an ‘adductome’ approach for the characterization of DNA adduct spectra in human tissues. The DNA adduct spectrum reflects the inner exposure of an individual’s tissue to electrophilic metabolites and, therefore, should replace the conventional and inaccurate external exposure in epidemiological studies in the future.

Abbreviations

2-AAF

2-Acetylaminofluorene

4-ABP

4-Aminobiphenyl

BaP

Benzo[a]pyrene

CYP

Cytochrome P450 monooxygenase

dA

2′-Deoxyadenosine

dC

2′-Deoxycytidine

dG

2′-Deoxyguanosine

HAA

Heterocyclic aromatic amine

LC-MS/MS

Liquid chromatography–tandem mass spectrometry

MP

1-Methylpyrene

MRM

Multiple reaction monitoring

PAH

Polycyclic aromatic hydrocarbon

PhIP

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

TLC

Thin-layer chromatography

Notes

Acknowledgements

The author gratefully acknowledges financial support from the German Research Foundation (MO 2520/1-1) and the German Institute of Human Nutrition (DIfE).

References

  1. 1.
    Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.Google Scholar
  2. 2.
    International Agency for Research on Cancer. (2010). Some aromatic amines, organic dyes, and related exposures (Vol. 99). Lyon: International Agency for Research on Cancer.Google Scholar
  3. 3.
    International Agency for Research on Cancer. (2010). Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures (Vol. 92). Lyon: International Agency for Research on Cancer.Google Scholar
  4. 4.
    International Agency for Research on Cancer. (2007). Smokeless tobacco and some tobacco-specific N-nitrosamines (Vol. 89). Lyon: International Agency for Research on Cancer.Google Scholar
  5. 5.
    Guengerich, F. P. (2003). Activation of dihaloalkanes by thiol-dependent mechanisms. Journal of Biochemistry and Molecular Biology, 36, 20–27.PubMedGoogle Scholar
  6. 6.
    International Agency for Research on Cancer. (2008). 1,3-butadiene, ethylene oxide and vinyl halides (vinyl fluoride, vinyl chloride and vinyl bromide) (Vol. 97). Lyon: International Agency for Research on Cancer.Google Scholar
  7. 7.
    Guengerich, F. P., Johnson, W. W., Shimada, T., Ueng, Y. F., Yamazaki, H., & Langouet, S. (1998). Activation and detoxication of aflatoxin B1. Mutation Research, 402, 121–128.PubMedGoogle Scholar
  8. 8.
    Kim, J. H., Stansbury, K. H., Walker, N. J., Trush, M. A., Strickland, P. T., & Sutter, T. R. (1998). Metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-diol by human cytochrome P450 1B1. Carcinogenesis, 19, 1847–1853.PubMedGoogle Scholar
  9. 9.
    Shou, M., Korzekwa, K. R., Crespi, C. L., Gonzalez, F. J., & Gelboin, H. V. (1994). The role of 12 cDNA-expressed human, rodent, and rabbit cytochromes P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans-7,8-dihydrodiol. Molecular Carcinogenesis, 10, 159–168.PubMedGoogle Scholar
  10. 10.
    Rendic, S., & Guengerich, F. P. (2012). Contributions of human enzymes in carcinogen metabolism. Chemical Research in Toxicology, 25, 1316–1383.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Otteneder, M., & Lutz, W. K. (1999). Correlation of DNA adduct levels with tumor incidence: Carcinogenic potency of DNA adducts. Mutation Research, 424, 237–247.PubMedGoogle Scholar
  12. 12.
    Poirier, M. C., & Beland, F. A. (1992). DNA adduct measurements and tumor incidence during chronic carcinogen exposure in animal models: Implications for DNA adduct-based human cancer risk assessment. Chemical Research in Toxicology, 5, 749–755.PubMedGoogle Scholar
  13. 13.
    Randerath, K., Reddy, M. V., & Gupta, R. C. (1981). 32P-labeling test for DNA damage. Proceedings of the National Academy of Sciences of the United States of America, 78, 6126–6129.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Farmer, P. B., & Singh, R. (2008). Use of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants: The increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens. Mutation Research, 659, 68–76.PubMedGoogle Scholar
  15. 15.
    Klaene, J. J., Sharma, V. K., Glick, J., & Vouros, P. (2012). The analysis of DNA adducts: The transition from 32P-postlabeling to mass spectrometry. Cancer Letters, 334, 10–19.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Angerer, J., Ewers, U., & Wilhelm, M. (2007). Human biomonitoring: State of the art. International Journal of Hygiene and Environmental Health, 210, 201–228.PubMedGoogle Scholar
  17. 17.
    Godschalk, R. W., Van Schooten, F. J., & Bartsch, H. (2003). A critical evaluation of DNA adducts as biological markers for human exposure to polycyclic aromatic compounds. Journal of Biochemistry and Molecular Biology, 36, 1–11.PubMedGoogle Scholar
  18. 18.
    Phillips, D. H. (2002). Smoking-related DNA and protein adducts in human tissues. Carcinogenesis, 23, 1979–2004.PubMedGoogle Scholar
  19. 19.
    Vineis, P., & Husgafvel-Pursiainen, K. (2005). Air pollution and cancer: Biomarker studies in human populations. Carcinogenesis, 26, 1846–1855.PubMedGoogle Scholar
  20. 20.
    Poirier, M. C., Stanley, J. R., Beckwith, J. B., Weinstein, I. B., & Yuspa, S. H. (1982). Indirect immunofluorescent localization of benzo[a]pyrene adducted to nucleic acids in cultured mouse keratinocyte nuclei. Carcinogenesis, 3, 345–348.PubMedGoogle Scholar
  21. 21.
    Spodheim-Maurizot, M., Saint-Ruf, G., & Leng, M. (1980). Antibodies to N-hydroxy-2-aminofluorene modified DNA as probes in the study of DNA reacted with derivatives of 2-acetylaminofluorene. Carcinogenesis, 1, 807–812.PubMedGoogle Scholar
  22. 22.
    Baasanjav-Gerber, C., Monien, B. H., Mewis, I., Schreiner, M., Barillari, J., Iori, R., et al. (2011). Identification of glucosinolate congeners able to form DNA adducts and to induce mutations upon activation by myrosinase. Molecular Nutrition & Food Research, 55, 783–792.Google Scholar
  23. 23.
    Farmer, P. B., Brown, K., Tompkins, E., Emms, V. L., Jones, D. J., Singh, R., et al. (2005). DNA adducts: Mass spectrometry methods and future prospects. Toxicology and Applied Pharmacology, 207, 293–301.Google Scholar
  24. 24.
    Monien, B. H., Müller, C., Engst, W., Frank, H., Seidel, A., & Glatt, H. R. (2008). Time course of hepatic 1-methylpyrene DNA adducts in rats determined by isotope dilution LC-MS/MS and 32P-postlabeling. Chemical Research in Toxicology, 21, 2017–2025.PubMedGoogle Scholar
  25. 25.
    Felton, J. S., Knize, M. G., Shen, N. H., Lewis, P. R., Andresen, B. D., Happe, J., et al. (1986). The isolation and identification of a new mutagen from fried ground beef: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis, 7, 1081–1086.PubMedGoogle Scholar
  26. 26.
    Glatt, H. R. (2006). Metabolic factors affecting the mutagenicity of heterocyclic amines. In K. Skog & J. Alexander (Eds.), Acrylamide and other health hazardous compounds in heat-treated foods (pp. 358–404). Cambridge: Woodhead Publishing.Google Scholar
  27. 27.
    Monien, B. H., Engst, W., Barknowitz, G., Seidel, A., & Glatt, H. R. (2012). Mutagenicity of 5-hydroxymethylfurfural in V79 cells expressing human SULT1A1: Identification and mass spectrometric quantification of DNA adducts formed. Chemical Research in Toxicology, 25, 1484–1492.PubMedGoogle Scholar
  28. 28.
    Monien, B. H., Herrmann, K., Florian, S., & Glatt, H. R. (2011). Metabolic activation of furfuryl alcohol: Formation of 2-methylfuranyl DNA adducts in Salmonella typhimurium strains expressing human sulfotransferase 1A1 and in FVB/N mice. Carcinogenesis, 32, 1533–1539.PubMedGoogle Scholar
  29. 29.
    Monien, B. H., Müller, C., Bakhiya, N., Donath, C., Frank, H., Seidel, A., et al. (2009). Probenecid, an inhibitor of transmembrane organic anion transporters, alters tissue distribution of DNA adducts in 1-hydroxymethylpyrene-treated rats. Toxicology, 262, 80–85.PubMedGoogle Scholar
  30. 30.
    Punt, A., Delatour, T., Scholz, G., Schilter, B., van Bladeren, P. J., & Rietjens, I. M. (2007). Tandem mass spectrometry analysis of N2-(trans-isoestragol-3′-yl)-2′-deoxyguanosine as a strategy to study species differences in sulfotransferase conversion of the proximate carcinogen 1′-hydroxyestragole. Chemical Research in Toxicology, 20, 991–998.PubMedGoogle Scholar
  31. 31.
    Beland, F. A., Doerge, D. R., Churchwell, M. I., Poirier, M. C., Schoket, B., & Marques, M. M. (1999). Synthesis, characterization, and quantitation of a 4-aminobiphenyl-DNA adduct standard. Chemical Research in Toxicology, 12, 68–77.PubMedGoogle Scholar
  32. 32.
    Singh, R., Gaskell, M., Le Pla, R. C., Kaur, B., Azim-Araghi, A., Roach, J., et al. (2006). Detection and quantitation of benzo[a]pyrene-derived DNA adducts in mouse liver by liquid chromatography-tandem mass spectrometry: Comparison with 32P-postlabeling. Chemical Research in Toxicology, 19, 868–878.PubMedGoogle Scholar
  33. 33.
    Goodenough, A. K., Schut, H. A., & Turesky, R. J. (2007). Novel LC-ESI/MS/MS(n) method for the characterization and quantification of 2′-deoxyguanosine adducts of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by 2-D linear quadrupole ion trap mass spectrometry. Chemical Research in Toxicology, 20, 263–276.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Phillips, D. H., & Castegnaro, M. (1999). Standardization and validation of DNA adduct postlabelling methods: Report of interlaboratory trials and production of recommended protocols. Mutagenesis, 14, 301–315.PubMedGoogle Scholar
  35. 35.
    Reddy, M. V. (2000). Methods for testing compounds for DNA adduct formation. Regulatory Toxicology and Pharmacology, 32, 256–263.PubMedGoogle Scholar
  36. 36.
    Paini, A., Scholz, G., Marin-Kuan, M., Schilter, B., O’Brien, J., van Bladeren, P. J., et al. (2011). Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays. Mutagenesis, 26, 605–618.PubMedGoogle Scholar
  37. 37.
    Ma, L., Kuhlow, A., & Glatt, H. R. (2002). Ethanol enhances the activation of 1-hydroxymethylpyrene to DNA adduct-forming species in the rat. Polycyclic Aromatic Compounds, 22, 933–946.Google Scholar
  38. 38.
    Smith, B., Cadby, P., Leblanc, J. C., & Setzer, R. W. (2010). Application of the margin of exposure (MoE) approach to substances in food that are genotoxic and carcinogenic: Example: Methyleugenol, CASRN: 93-15-2. Food and Chemical Toxicology, 48(Suppl 1), S89–S97.PubMedGoogle Scholar
  39. 39.
    Ricicki, E. M., Soglia, J. R., Teitel, C., Kane, R., Kadlubar, F., & Vouros, P. (2005). Detection and quantification of N-(deoxyguano-sin-8-yl)-4-aminobiphenyl adducts in human pancreas tissue using capillary liquid chromatography-microelectrospray mass spectrometry. Chemical Research in Toxicology, 18, 692–699.Google Scholar
  40. 40.
    Zhang, S., Balbo, S., Wang, M., & Hecht, S. S. (2010). Analysis of acrolein-derived 1,N2-propanodeoxyguanosine adducts in human leukocyte DNA from smokers and nonsmokers. Chemical Research in Toxicology, 24, 119–124.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Chen, L., Wang, M., Villalta, P. W., Luo, X., Feuer, R., Jensen, J., et al. (2007). Quantitation of an acetaldehyde adduct in human leukocyte DNA and the effect of smoking cessation. Chemical Research in Toxicology, 20, 108–113.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Embrechts, J., Lemiere, F., Van Dongen, W., Esmans, E. L., Buytaert, P., Van Marck, E., et al. (2003). Detection of estrogen DNA-adducts in human breast tumor tissue and healthy tissue by combined nano LC-nano ES tandem mass spectrometry. Journal of the American Society for Mass Spectrometry, 14, 482–491.PubMedGoogle Scholar
  43. 43.
    Bessette, E. E., Spivack, S. D., Goodenough, A. K., Wang, T., Pinto, S., Kadlubar, F. F., et al. (2010). Identification of carcinogen DNA adducts in human saliva by linear quadrupole ion trap/multistage tandem mass spectrometry. Chemical Research in Toxicology, 23, 1234–1244.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Brown, K., Tompkins, E. M., Boocock, D. J., Martin, E. A., Farmer, P. B., Turteltaub, K. W., et al. (2007). Tamoxifen forms DNA adducts in human colon after administration of a single [14C]-labeled therapeutic dose. Cancer Research, 67, 6995–7002.PubMedGoogle Scholar
  45. 45.
    Gu, D., Turesky, R. J., Tao, Y., Langouet, S. A., Nauwelaers, G. C., Yuan, J. M., et al. (2012). DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 4-aminobiphenyl are infrequently detected in human mammary tissue by liquid chromatography/tandem mass spectrometry. Carcinogenesis, 33, 124–130.PubMedGoogle Scholar
  46. 46.
    Zhu, J., Chang, P., Bondy, M. L., Sahin, A. A., Singletary, S. E., Takahashi, S., et al. (2003). Detection of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine-DNA adducts in normal breast tissues and risk of breast cancer. Cancer Epidemiology, Biomarkers & Prevention, 12, 830–837.Google Scholar
  47. 47.
    Gorlewska-Roberts, K., Green, B., Fares, M., Ambrosone, C. B., & Kadlubar, F. F. (2002). Carcinogen-DNA adducts in human breast epithelial cells. Environmental and Molecular Mutagenesis, 39, 184–192.PubMedGoogle Scholar
  48. 48.
    Perera, F., Mayer, J., Jaretzki, A., Hearne, S., Brenner, D., Young, T. L., et al. (1989). Comparison of DNA adducts and sister chromatid exchange in lung cancer cases and controls. Cancer Research, 49, 4446–4451.PubMedGoogle Scholar
  49. 49.
    Tang, D., Phillips, D. H., Stampfer, M., Mooney, L. A., Hsu, Y., Cho, S., et al. (2001). Association between carcinogen-DNA adducts in white blood cells and lung cancer risk in the physicians health study. Cancer Research, 61, 6708–6712.PubMedGoogle Scholar
  50. 50.
    Newcomb, P. A., Solomon, C., & White, E. (1999). Tamoxifen and risk of large bowel cancer in women with breast cancer. Breast Cancer Research and Treatment, 53, 271–277.PubMedGoogle Scholar
  51. 51.
    Qian, G. S., Ross, R. K., Yu, M. C., Yuan, J. M., Gao, Y. T., Henderson, B. E., et al. (1994). A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiology, Biomarkers & Prevention, 3, 3–10.Google Scholar
  52. 52.
    Nair, J., Carmichael, P. L., Fernando, R. C., Phillips, D. H., Strain, A. J., & Bartsch, H. (1998). Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilson’s disease and primary hemochromatosis. Cancer Epidemiology, Biomarkers & Prevention, 7, 435–440.Google Scholar
  53. 53.
    Bartsch, H., Arab, K., & Nair, J. (2011). Biomarkers for hazard identification in humans. Environmental Health, 10(Suppl 1), S11.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Poirier, M. C. (2004). Chemical-induced DNA damage and human cancer risk. Nature Reviews. Cancer, 4, 630–637.PubMedGoogle Scholar
  55. 55.
    Singh, R., Teichert, F., Seidel, A., Roach, J., Cordell, R., Cheng, M. K., et al. (2010). Development of a targeted adductomic method for the determination of polycyclic aromatic hydrocarbon DNA adducts using online column-switching liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry, 24, 2329–2340.PubMedGoogle Scholar
  56. 56.
    Chou, P. H., Kageyama, S., Matsuda, S., Kanemoto, K., Sasada, Y., Oka, M., et al. (2010). Detection of lipid peroxidation-induced DNA adducts caused by 4-oxo-2(E)-nonenal and 4-oxo-2(E)-hexenal in human autopsy tissues. Chemical Research in Toxicology, 23, 1442–1448.PubMedGoogle Scholar
  57. 57.
    Matsuda, T., Tao, H., Goto, M., Yamada, H., Suzuki, M., Wu, Y., et al. (2013). Lipid peroxidation-induced DNA adducts in human gastric mucosa. Carcinogenesis, 34, 121–127.PubMedGoogle Scholar
  58. 58.
    Benford, D., Bolger, P. M., Carthew, P., Coulet, M., DiNovi, M., Leblanc, J. C., et al. (2010). Application of the Margin of Exposure (MOE) approach to substances in food that are genotoxic and carcinogenic. Food and Chemical Toxicology, (48 Suppl 1), S2–S24.PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.German Institute of Human Nutrition (DIfE) Potsdam RehbrückeNuthetalGermany
  2. 2.Department of Food SafetyFederal Institute for Risk Assessment, Unit 54BerlinGermany

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