title: Nicotine is a developmental neurotoxicant and neuroprotectant: stage-selective inhibition of DNA synthesis coincident with shielding from effects of chlorpyrifos.
abstract: Although nicotine is now well recognized as a developmental neurotoxicant, it also may have neuroprotectant properties. In the current study, we used PC12 cells to characterize the specific developmental phases in which these effects are expressed. In undifferentiated cells, nicotine had a modest effect on DNA synthesis (10% reduction), which was nevertheless selective, as no significant reductions were seen for RNA or protein synthesis. The effects were blocked by mecamylamine, indicating mediation by nicotinic acetylcholine receptors. Initiation of differentiation with nerve growth factor, which greatly increases the receptor concentration, produced a commensurate increase in the sensitivity of DNA synthesis to nicotine, while RNA and protein synthesis again remained unaffected. The organophosphate insecticide, chlorpyrifos, also interferes with DNA synthesis in undifferentiated PC12 cells, but by mechanisms independent of nicotinic receptors. Accordingly, the effects of a combination of nicotine and chlorpyrifos should be additive. However, simultaneous exposure of undifferentiated cells to both agents produced less-than-additive effects at low concentrations of chlorpyrifos, and at high chlorpyrifos concentrations, nicotine produced outright protection: the combination of nicotine and chlorpyrifos had lesser effects than chlorpyrifos alone. The same neuroprotection was seen when cells were exposed to nicotine for 24 h, washed free of the drug for 24 h, and then exposed to chlorpyrifos. The results indicate that nicotine interferes with neural cell replication, with peak effects in early stages of differentiation. At the same time, nicotine promotes trophic actions that protect against neurotoxicants that work through other mechanisms.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Qiao
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Violin
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004390:Chlorpyrifos / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis*; D008464:Mecamylamine / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D009538:Nicotine / Q000494:pharmacology / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors; D016716:PC12 Cells; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects
chemical_list: D002800:Cholinesterase Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D019384:Nucleic Acid Synthesis Inhibitors; D011978:Receptors, Nicotinic; D012313:RNA; D008464:Mecamylamine; D009538:Nicotine; D004247:DNA; D020932:Nerve Growth Factor; D004390:Chlorpyrifos