Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos
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- 作者：Theodore A. Slotkin ; t.slotkin@duke.edu" class="auth_mail" title="E-mail the corresponding author ; Samantha Skavicus ; Frederic J. Seidler
- 关键词：ANOVA ; analysis of variance ; βAR ; β-adrenergic receptor ; GD ; gestational day ; PN ; postnatal day
- 刊名：Toxicology
- 出版年：2015
- 出版时间：2 December 2015
- 年：2015
- 卷：338
- 期：Complete
- 页码：8-16
- 全文大小：1325 K
文摘
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 (3 mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1 mg/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 (0.2 mg/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.