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Etheno deoxyribonucleic acid adducts as critical exposure markers

Deoxyribonucleic acid (DNA) etheno (epsilon) bases are formed by the human carcinogen vinyl chloride (VC), by the rodent carcinogens vinyl bromide, ethyl carbamate, and vinyl carbamate and through endogenous lipid peroxidation products. In view of the ubiquity of these exocyclic adducts in tissues of different species and man, generated in part endogenously, their mutation characteristics and repair in somatic and Drosophila germ cells in vivo were investigated. The formation two promutagenic epsilon-DNA adduct was quantitated in rodents exposed to vinyl chloride and urethane and its metabolites. Accumulation and persistence of epsilon-DNA adducts in rats exposed to VC were investigated. Data indicated that background levels were affected by the animal diet. Urethane, a potent rodent lung carcinogen, with human exposure was assessed for in vivo mutagenic activity in transgenic mice. A single intra peritoneal dose yielded significant increases in mutation frequency in the lung and liver, supporting the notion that the epsilon-DNA adducts produced in target organs result in genetic changes that initiate events in urethane-induced carcinogenesis. The epsilon-adducts were quantitated in hepatic DNA from inbred rats that model for human Wilson's disease. Accumulation with age of epsilon-adducts in hepatic DNA from the rats was shown. Elevated epsilon-adduct levels were subsequently demonstrated in hepatic DNA from patients with Wilson's disease and primary haemochromatosis. Effects of dietary fatty acid intake on the formation of epsilon-DNA adducts and malonaldehyde-DNA base adducts in human white blood cells (WBC) were investigated. For the first time epsilon-adducts were detected in DNA of human WBC. High dietary linoleic acid intake dramatically increased lipid peroxidation (PO)-derived DNA adducts in vivo only in females.

As levels of the promutagenic epsilon-adduct lesions seem to be affected by dietary imbalance, alcohol and tobacco consumption, they can be used as biomarkers in molecular epidemiological studies to ascertain better the role of oxidative stress in human cancers associated with certain lifestyle patterns and dietary habits as well as the protective role of antioxidants in chemoprevention studies.

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Helmut BARTSCH, (Staff scientist)
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