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 ubiquitou sly distributed in the environment. Dieldrin depletes brain monoamines in s ome 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 oxi dative lesions to DNA bases, i.e., 8-hydroxy-2'-deoxyguanosine (8-oxodGuo). Accumulation of 8-oxodGuo has been shown to be promutagenic in proliferati ng cells, and can lead to degeneration in fully differentiated cells. The o bjective 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) PC12 cells. Proliferating PC 12 cells exhibited a mild upregulation of glycosyl ase activity, reaching a maximum by 1 h and returning to baseline by 6 h. D ifferentiated (+) NGF cells showed a time-dependent decline in activity rea ching a nadir at 3 h with a return towards baseline by 6 h. Levels of the d amaged base, 8-oxodGuo, in the differentiated PC12 cells appeared to be reg ulated by the activity of OGG1, In contrast, levels of the damaged base in actively proliferating cells were independent of the OGG1 activity. This di fference between actively dividing and differentiated cells in the regulati on of base-excision repair and DNA damage accumulation explains, in part, t he vulnerability of postmitotic neurons to oxidative stresses and neurotoxi ns. (C) 2001 Elsevier Science Inc.