Comparison of base-excision repair capacity in proliferating and differentiated PC 12 cells following acute challenge with dieldrin.
Dieldrin, an organochlorine pesticide and known neurotoxicant, is ubiquitously distributed in the environment. Dieldrin depletes brain monoamines in some animal species and is toxic for dopaminergic neurons in vitro. Dieldrin interferes with mitochondrial electron transport and increases generation of superoxide anion. Reactive oxygen species have been shown to produce oxidative lesions to DNA bases, i.e., 8-hydroxy-2'-deoxyguanosine (8-oxodGuo). Accumulation of 8-oxodGuo has been shown to be promutagenic in proliferating cells, and can lead to degeneration in fully differentiated cells. The objective of this study was to determine the effects of dieldrin exposure on the activity of the enzyme responsible for removing 8-oxodGuo, OGG1, from undifferentiated (untreated with NGF) and differentiated (NGF-treated) PC 12 cells. Proliferating PC 12 cells exhibited a mild upregulation of glycosylase activity, reaching a maximum by 1 h and returning to baseline by 6 h. Differentiated (+) NGF cells showed a time-dependent decline in activity reaching a nadir at 3 h with a return towards baseline by 6 h. Levels of the damaged base, 8-oxodGuo, in the differentiated PC12 cells appeared to be regulated by the activity of OGG1. In contrast, levels of the damaged base in actively proliferating cells were independent of the OGG1 activity. This difference between actively dividing and differentiated cells in the regulation of base-excision repair and DNA damage accumulation explains, in part, the vulnerability of postmitotic neurons to oxidative stresses and neurotoxins.
Stedeford
T
T
Department of Neurology, College of Medicine, University of South Florida, Tampa, FL, USA.
Cardozo-Pelaez
F
F
Nemeth
N
N
Song
S
S
Harbison
R D
RD
Sanchez-Ramos
J
J
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001482:Base Composition; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D004026:Dieldrin / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D014407:Tumor Cells, Cultured
D007306:Insecticides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D020932:Nerve Growth Factor; D007770:L-Lactate Dehydrogenase; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine; D004026:Dieldrin