Age-dependent increase of indigenous DNA adducts in rat brain is associated with a lipid peroxidation product

Indigenous DNA adducts (I-compounds) are considered to be a biomarker of aging tissues. Thus far, few studies have been conducted to investigate the accumulation patterns of I-compounds in the brain during aging. Particularly, identities of age-dependent I-compounds have largely remained unknown. In the current study, we have determined the amounts of I-compounds in the brains of male Fischer 344 rats at ages 1, 6, 12, 18, and 24 months using a 32P-postlabeling technique. The results indicate that I-compounds increase in the rat brain age dependently from 6 to 24 months of age. Total I-adduct levels (central and upper cutouts) increase 3.5-fold from 6 to 24 months. Contrary to the results of other investigators, brains of 1-month-old rats contain the highest level of I-compounds, which may be due to the hypermetabolic status during the infant period. In an effort to characterize I-compounds, different deoxynucleosides were coincubated with malondialdehyde (MDA). The results show that only deoxyguanosine (dGMP)-MDA adducts overlap with I-compounds of the rat brain DNA adducts map. A total of five dGMP-MDA adducts have been identified as responsible for I-compounds in brain tissues. It is known that brain tissue contains high levels of lipids that are susceptible to oxygen free radicals and that MDA is the most abundant and genotoxic product of lipid peroxidation. The present study provides supporting evidence that lipid peroxidation and its product (MDA) may play an important role in endogenous brain DNA modification, which may partly contribute to cerebral aging and age-related degenerative disorders of the brain. The accumulation of I-compounds with aging may serve as an index of indirect oxidative damage to DNA as evidenced by the presence of MDA-DNA adducts.