Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead (Pb) has been shown to elevate the Alzheimer's disease (AD) related β-amyloid peptide (Aβ), which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2′-deoxyguanosine (oxo⁸dG) levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase (Ogg1) in rats developmentally exposed to Pb. Oxo⁸dG was transiently modulated early in life (Postnatal day 5), but was later elevated 20 months after exposure to Pb had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo⁸dG accumulation was observed. The effect of Pb on oxo⁸dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase (SOD1), manganese-SOD (SOD2), and reduced-form glutathion (GSH). These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances.

Key words: Alzheimer • epigenetic • free radicals • methylation • Ogg1 • oxidative stress