Final Report Summary - DIEPHY (Dietary exposures to polycyclic aromatic hydrocarbons and DNA damage)
The general objectives of the DIEPHY project were to:
- provide an adequate basis for interpretation of human cancer data from experiments in vitro and rodent studies using novel approaches with respect to the induction and repair of DNA-lesions from Polyaromatic hydrocarbons (PAHs), as well as study the relation between DNA adducts and oxidative stress;
- trace the origin of high levels of 'background' DNA adducts of the PAH type found in certain non-smoking individuals from the general population, while taking into consideration possible modulation by genetic factors, exposure to toxic agents that affect DNA repair, and diet;
- assess the protective effects of selected dietary constituents against gentotoxic damage in vitro, as well as in mammals including humans
The specific objectives of the project fall under the two following categories:
- Experimental investigations: The mere presence of low level DNA damage in humans cannot be equated with risk for cancer. A basic understanding concerning the generation and repair mechanisms was required and this entailed that studies be conducted in cultivated mammalian cells, as well as in experimental animals.
- Human studies: The use of molecular biomarkers in conjunction with genotyping might have provided important tools in identifying potentially carcinogenic and protective substances present in the diet. This type of information could provide an important input to health advisories for the general population.
The results achieved are stated below:
- Experimental investigations: The project integrated a complementary set of research areas from molecular biology and cytogenetics, applied to in vitro systems as well as in the rodent, with the aim to bridge the gap between model systems and humans, one of the vital challenges for contemporary applied toxicology. The overall objective was to provide new information on the formation and repair of DNA-lesions from PAHs, induction of apoptosis, and chromosome damage, as well as identify natural compounds / food additives that offer promise as protective agents. In this manner data were generated that could facilitate the design and interpretation of the conducted human studies.
- Human studies: The development of extremely sensitive methods for detection of low levels of pro-mutagenic DNA adducts and oxidative damages offered a possibility of extending the resolution of conventional epidemiology. There had been several studies linking PAH exposure and genetic polymorphism of metabolising and detoxifying enzymes in a general fashion. However, an in-depth analysis of the underlying non-occupational reasons for unusually high adduct levels occasionally found in non-smoking individuals was undertaken and this issue was investigated in this project. It was well-known that hereditary defects in DNA repair are associated with an increased risk for cancer, exemplified by diseases such as xeroderma pigmentosum, hereditary nonpolyposis colon cancer, familial breast cancer and ataxia telangiectasia. For this reason, polymorphism of major genes involved in DNA repair was also investigated in the selected populations.
- provide an adequate basis for interpretation of human cancer data from experiments in vitro and rodent studies using novel approaches with respect to the induction and repair of DNA-lesions from Polyaromatic hydrocarbons (PAHs), as well as study the relation between DNA adducts and oxidative stress;
- trace the origin of high levels of 'background' DNA adducts of the PAH type found in certain non-smoking individuals from the general population, while taking into consideration possible modulation by genetic factors, exposure to toxic agents that affect DNA repair, and diet;
- assess the protective effects of selected dietary constituents against gentotoxic damage in vitro, as well as in mammals including humans
The specific objectives of the project fall under the two following categories:
- Experimental investigations: The mere presence of low level DNA damage in humans cannot be equated with risk for cancer. A basic understanding concerning the generation and repair mechanisms was required and this entailed that studies be conducted in cultivated mammalian cells, as well as in experimental animals.
- Human studies: The use of molecular biomarkers in conjunction with genotyping might have provided important tools in identifying potentially carcinogenic and protective substances present in the diet. This type of information could provide an important input to health advisories for the general population.
The results achieved are stated below:
- Experimental investigations: The project integrated a complementary set of research areas from molecular biology and cytogenetics, applied to in vitro systems as well as in the rodent, with the aim to bridge the gap between model systems and humans, one of the vital challenges for contemporary applied toxicology. The overall objective was to provide new information on the formation and repair of DNA-lesions from PAHs, induction of apoptosis, and chromosome damage, as well as identify natural compounds / food additives that offer promise as protective agents. In this manner data were generated that could facilitate the design and interpretation of the conducted human studies.
- Human studies: The development of extremely sensitive methods for detection of low levels of pro-mutagenic DNA adducts and oxidative damages offered a possibility of extending the resolution of conventional epidemiology. There had been several studies linking PAH exposure and genetic polymorphism of metabolising and detoxifying enzymes in a general fashion. However, an in-depth analysis of the underlying non-occupational reasons for unusually high adduct levels occasionally found in non-smoking individuals was undertaken and this issue was investigated in this project. It was well-known that hereditary defects in DNA repair are associated with an increased risk for cancer, exemplified by diseases such as xeroderma pigmentosum, hereditary nonpolyposis colon cancer, familial breast cancer and ataxia telangiectasia. For this reason, polymorphism of major genes involved in DNA repair was also investigated in the selected populations.