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.
The carcinogens to which humans are exposed are normally in the form of complex mixtures, and much effort has gone into determining the nature of the most significant carcinogenic components in these mixtures and their mechanisms of action. Essential to achieving this aim in exposed populations is the use of biomarkers, which can characterize the chemical nature of the carcinogens involved and identify key biological effects that result from the exposure. DNA adducts are particularly appropriate as biomarkers in the case of genotoxic carcinogens as they indicate the biologically effective dose of the genotoxin in the target tissue under study. This review considers in particular the use of mass spectrometry (MS), which is having an increasing role in the determination of DNA adducts. Compared to other existing DNA damage detection methods, such as 32P-postlabeling, HPLC-fluorescence or electrochemical detection, immunoassay-based techniques and modified Comet assays, MS provides improved structural characterization of adducts. Greater selectivity in the analyses is achieved by the use of tandem MS with selected reaction monitoring or constant neutral loss of ions. Use of capillary/nano liquid chromatography and micro/nano electrospray ionization improves the analytical sensitivity and higher throughput may be obtained by the use of online-column switching. The application of microfluidics technology offers exciting new possibilities for interfacing sample preparation to the mass spectrometer. Despite these improvements in the use of MS for adduct detection, the main current requirement is to validate these methods both analytically and in molecular epidemiology studies. More knowledge of the stability of stored samples is required. Development of sensitive mass spectrometric DNA adductomic screening systems, and of long-term biomarkers (e.g., phosphotriester adducts that are not repaired efficiently) seems important areas for the future assessment of the effects of human exposure to environmental genotoxins, together with studies of dose-response relationships at low doses.
Farmer
Peter B
PB
Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, Leicester LE1 7RH, United Kingdom. pbf1@le.ac.uk
Singh
Rajinder
R
D015415:Biomarkers / Q000032:analysis*; D002274:Carcinogens, Environmental / Q000032:analysis*; D018736:DNA Adducts / Q000032:analysis*; D004785:Environmental Pollutants / Q000633:toxicity*; D005544:Forecasting; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D009153:Mutagens / Q000032:analysis*; D012306:Risk; D054928:Validation Studies as Topic
D015415:Biomarkers; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D004785:Environmental Pollutants; D009153:Mutagens