A49
Foetal leukocytic DNA damage biomarkers as signatures of in utero genotoxicity: influence of maternal diet and lifestyle?
Nigel J. Brady, Rajinder Singh, Peter B. Farmer
University of Leicester, UK
Background
Foetal exposure to genotoxins has gathered interest in recent years and has been linked to childhood cancer. Dietary exposure to genotoxic compounds is now of considerable interest since it was suggested as a possible risk factor for 35% of all cancers.1 It has been suggested that acute leukaemia, for example, may stem from DNA damage suffered by the foetus during pregnancy, which may perturb haemopoiesis and initiate leukaemogenesis. The European Commission-funded NewGeneris project (Newborns and Genotoxic Exposure Risks) is exploring such issues.2 The main emphasis of this study is to measure the degree of in utero exposure by measuring signature biomarkers of exposure and effect.
Method
The biomarker studied here is the mutagenic DNA adduct; 3-(2′-deoxy-β-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one (M1dG), which is formed endogenously from oxidative stress and may be modulated by diet. An immunoslot blot assay3 employing an M1dG-specific monoclonal antibody4 was used to determine adduct levels in maternal and foetal DNA samples from four different cohorts in Europe.
Results
Correlations between levels of maternal and foetal DNA damage have been found and inter-cohort variations in DNA adduct levels have been observed. Moreover, the similarity in levels of DNA damage in foetal samples to those levels in maternal DNA would implicate trans-placental perfusion of genotoxic agents as the driving force behind this phenomenon. Biomarker data were linked to data pertaining to diet and lifestyle in an attempt to establish a hypothesis of the molecular mechanisms of genotoxicity in utero.
Conclusion
Diet and/or lifestyle factors may modulate DNA damage in both the mother and the foetus and thus may be appreciable risk factors in the genesis of childhood cancer or the onset of cancer later in life.
Acknowledgements
The authors acknowledge the European Commission for funding under the Sixth Framework, project. Food-CT-2005-016320
References
[1] Doll, R., Peto, R., Avoidable Risks in the US, JNCI, 66, 1191-308, (1981).
[2] EU sixth framework, contract no: Food-CT-2005-016320. Website: www.newgeneris.org
[3] Singh, R., Leuratti, C., Josyula, S., Sipowicz, M. A., Diwan, B. A., Kasprzak, K. S., Schut, H. A. J., Marnett, L. J., Anderson, L. M., Shuker, D. E. G, Lobe-specific increases in malondialdehyde DNA adduct formation in the livers of mice following infection with Helicobacter Hepaticus, Carcinogenesis, 22, 1281-1287, (2001).
[4] Sevilla, C. L., Mahle, N. H., Eliezer, N., Uzieblo, A., OHara, S.M., Nokubo, M., Miller, R., Rouzer, C. A., and Marnett, L. J., Development of monoclonal antibodies to the Malondialdehyde-Deoxyguanosine Adduct, pyrimidopurinone, Chem. Res. Toxicol., 10, 172-180, (1997).
