DNA adducts, which may be formed by exogenous and endogenous mechanisms, play key mechanistic roles in carcinogenesis and the progression of the neoplastic process. Endogenous chemicals leading to adduct formation may arise as a consequence of normal metabolism, action of reactive oxygen species, and exposure to carcinogens (initiators and promoters). Thus, endogenous DNA adducts: are mechanistically linked to lifestyle factors. It is proposed to develop nutritional and pharmacological techniques to modulate the formation of endogenous DNA adducts in vivo, based on existing knowledge of the mechanisms of action of the modulators. A major focus of the project will be studies of nutritional modulation of bulky oxidative DNA lesions (termed type II I-compounds), which arise in tissue DNA of rats at or shortly after normal birth. The micronutrient content of the maternal diet during pregnancy and the early post-delivery period will be systematically varied in order to recognize possible nutritional factors preventing or exacerbating postnatal oxidative DNA lesions. Additional experiments will determine whether these DNA adducts are mechanistically linked to perinatal atmospheric oxygen content and whether their formation is intensified by glutathione (antioxidant) depletion. Using pro-oxidant carcinogens, the target organ-dependent formation and persistence of oxidative DNA lesions will be investigated in adult rats in order to further elucidate the possible mechanistic relationship between these DNA alterations and carcinogenesis. A positive correlation would strongly support the idea that postnatal oxidative DNA damage is causally linked to neoplasia later in life. These experiments will also show whether bulky oxidative DNA lesions represent a more valid biomarker of oxidative stress-associated DNA damage than 8-oxodeoxyguanosine. Type II I-compounds represent a class of bulky endogenous tissue DNA modifications which are distinct from type Il-compounds. Some of the latter are associated inversely with carcinogenesis, and therefore such endogenous DNA modifications are postulated to play a functional role in normal cells. It is proposed to characterize the chemical structures of those type I and type III-compounds, which are available in sufficient quantities from in vitro and in vivo sources, by liquid chromatography/electrospray tandem mass spectrometry. Further studies will explore possible relationships between cholesterol biosynthesis and type I I-compounds and effects of pharmacological modulators on endogenous DNA adducts. This project will enhance our knowledge of mechanisms of chemical carcinogenesis and, it is hoped, will eventually lead to cancer preventive strategies in humans.
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