The modulation and inter-relationship of host factors and biomonitoring end-points will be measured in healthy individuals as a result of exposure to environmental carcinogens present in tobacco smoke and other environmental exposures. The carcinogens considered are methylating and oxidative agents. Alterations in repair processes for alkylation and oxidative DNA damage by tobacco smoking will be investigated and the frequency of polymorphisms of cytochrome P450s involved in the metabolism of nitrosamines in such a population assessed. The levels of adducts in cellular DNA formed by oxidative and alkylation damage will be measured and the excretion of such modified DNA bases in the urine of the same individuals monitored. The relationship between the levels of DNA repair, cytochrome P450s polymorphisms and the formation of DNA adducts will be examined at the individual level. The modulation of these cellular responses could have an important bearing in the carcinogenic dose response and in the identification of individuals with a high probability of developing lung cancer.
The project aims to :
1) investigate the modulation of the repair processes for alkylation and oxidative DNA damage by tobacco smoking in lymphocytes obtained from healthy individuals;
2) assess the occurrence of polymorphisms in the cytochrome P450s involved in the metabolisms of nitrosamines in such a population;
3) measure levels of adducts in cellular DNA from blood cell components formed by oxidative and alkylation damage and monitor the excretion of such modified DNA bases in the urine of the same individuals, and
4) examine the relationship between the levels of DNA repair, cytochrome P450s and DNA adducts at the individual level.
5) compare the results obtained in this present study with those obtained in a complementary case-control study coordinated by Dr. P. Boffetta (CT.......), in which the role of passive smoking and other environmental exposures in the causation of lung cancer among non-smokers will be investigated using similar experimental procedures.
Blood and urine samples will be collected from healthy male and female smokers and non-smokers between the ages of 25 and 45, all of whom will complete a self-administered questionnaire which will be used to investigate the influence of smoking status, taking vitamin supplements, hormone use, and alcohol consumption on the various biological end-points being measured.
Funding SchemeCSC - Cost-sharing contracts
2300 RA Leiden