title: Prenatal nicotine alters the developmental neurotoxicity of postnatal chlorpyrifos directed toward cholinergic systems: better, worse, or just "different?".
abstract: This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA. Electronic address: t.slotkin@duke.edu.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development; D004390:Chlorpyrifos / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology; D005260:Female; D006426:Hemicholinium 3 / Q000494:pharmacology; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism
chemical_list: D018678:Cholinergic Agents; D026901:Membrane Transport Proteins; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C065637:choline transporter; D006426:Hemicholinium 3; D009538:Nicotine; D002795:Choline O-Acetyltransferase; D004390:Chlorpyrifos; D000109:Acetylcholine
keywords: Acetylcholine; Brain development; Chlorpyrifos; Nicotine; Organophosphate pesticides