title: Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.
abstract: We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. 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. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, 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 27710, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Skavicus
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004390:Chlorpyrifos / Q000633:toxicity*; D003907:Dexamethasone / Q000633:toxicity*; D005260:Female; D005865:Gestational Age; D018811:Maternal Exposure / Q000009:adverse effects*; D009538:Nicotine / Q000633:toxicity*; D009638:Norepinephrine / Q000378:metabolism; D010575:Pesticides / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment
chemical_list: D010575:Pesticides; D011943:Receptors, Adrenergic, beta; D009538:Nicotine; D003907:Dexamethasone; D004390:Chlorpyrifos; D009638:Norepinephrine
keywords: Cerebellum; Chlorpyrifos; Dexamethasone; Nicotine; Norepinephrine; Organophosphate pesticides