Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos.
Nicotine and chlorpyrifos are developmental neurotoxicants that, despite their differences in structure and mechanism of action, share many aspects for damage to the developing brain. Both are thought to generate oxidative radicals; in the current study, we evaluated their ability to produce lipid peroxidation in two in vitro models of neural cell development (PC12 and SH-SY5Y cells) and for nicotine, with treatment of adolescent rats in vivo. Nicotine and chlorpyrifos, in concentrations relevant to human exposures, elicited an increase in thiobarbituric-acid-reactive species (TBARS) in undifferentiated cells, an effect that was prevented by addition of the antioxidant, Vitamin E. Initiating differentiation with nerve growth factor, which enhances nicotinic acetylcholine receptor expression, increased the TBARS response to nicotine but not chlorpyrifos, suggesting that the two agents act by different originating mechanisms to converge on the endpoint of oxidative damage. Furthermore, nicotine protected the cells from oxidative damage evoked by chlorpyrifos and similarly blocked the antimitotic effect of chlorpyrifos. Treatment of adolescent rats with nicotine elicited increases in TBARS in multiple brain regions when given in doses that simulate plasma nicotine concentrations found in smokers or at one-tenth the dose. Our results indicate that nicotine and chlorpyrifos elicit oxidative damage to developing neural cells both in vitro and in vivo, a mechanism that explains some of the neurodevelopmental endpoints that are common to the two agents. The balance between neuroprotectant and neurotoxicant actions of nicotine may be particularly important in situations where exposure to tobacco smoke is combined with other prooxidant insults.
Qiao
Dan
D
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Seidler
Frederic J
FJ
Slotkin
Theodore A
TA
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004390:Chlorpyrifos / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis; D004347:Drug Interactions; D005731:Ganglionic Stimulants / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D009538:Nicotine / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014810:Vitamin E / Q000627:therapeutic use
D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D005731:Ganglionic Stimulants; D017392:Thiobarbituric Acid Reactive Substances; D014810:Vitamin E; D009538:Nicotine; D004247:DNA; D004390:Chlorpyrifos