Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain.
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 beta-amyloid peptide (Abeta), 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.
Bolin
Celeste M
CM
Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, University of Montana, Missoula, Montana, USA.
Basha
Riyaz
R
Cox
David
D
Zawia
Nasser H
NH
Maloney
Bryan
B
Lahiri
Debomoy K
DK
Cardozo-Pelaez
Fernando
F
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D051381:Rats; D020318:Rats, Long-Evans; D013482:Superoxide Dismutase / Q000378:metabolism
D007854:Lead; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; D003849:Deoxyguanosine; D005978:Glutathione