Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates.
Acetylcholine and other neurotransmitters play unique trophic roles in brain development. Accordingly, drugs and environmental toxicants that promote or interfere with neurotransmitter function evoke neurodevelopmental abnormalities by disrupting the timing or intensity of neurotrophic actions. The current review discusses three exposure scenarios involving acetylcholine systems: nicotine from maternal smoking during pregnancy, exposure to environmental tobacco smoke (ETS), and exposure to the organophosphate insecticide, chlorpyrifos (CPF). All three have long-term, adverse effects on specific processes involved in brain cell replication and differentiation, synaptic development and function, and ultimately behavioral performance. Many of these effects can be traced to the sequence of cellular events surrounding the trophic role of acetylcholine acting on its specific cellular receptors and associated signaling cascades. However, for chlorpyrifos, additional noncholinergic mechanisms appear to be critical in establishing the period of developmental vulnerability, the sites and type of neural damage, and the eventual outcome. New findings indicate that developmental neurotoxicity extends to late phases of brain maturation including adolescence. Novel in vitro and in vivo exposure models are being developed to uncover heretofore unsuspected mechanisms and targets for developmental neurotoxicants.
Slotkin
Theodore A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
D000328:Adult; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D005260:Female; D006801:Humans; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010275:Parasympathetic Nervous System / Q000502:physiology*; D010575:Pesticides / Q000633:toxicity; D011247:Pregnancy; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D002800:Cholinesterase Inhibitors; D018722:Nicotinic Agonists; D009943:Organophosphorus Compounds; D010575:Pesticides; D014028:Tobacco Smoke Pollution; D009538:Nicotine