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Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.

Publication ,  Journal Article
Slotkin, TA; Skavicus, S; Seidler, FJ
Published in: Toxicology
December 2, 2015

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.

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Published In

Toxicology

DOI

EISSN

1879-3185

Publication Date

December 2, 2015

Volume

338

Start / End Page

8 / 16

Location

Ireland

Related Subject Headings

  • Toxicology
  • Risk Assessment
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Prenatal Exposure Delayed Effects
  • Pregnancy
  • Pesticides
  • Norepinephrine
  • Nicotine
  • Maternal Exposure
 

Citation

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Slotkin, T. A., Skavicus, S., & Seidler, F. J. (2015). Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos. Toxicology, 338, 8–16. https://doi.org/10.1016/j.tox.2015.09.005
Slotkin, Theodore A., Samantha Skavicus, and Frederic J. Seidler. “Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.Toxicology 338 (December 2, 2015): 8–16. https://doi.org/10.1016/j.tox.2015.09.005.
Slotkin TA, Skavicus S, Seidler FJ. Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos. Toxicology. 2015 Dec 2;338:8–16.
Slotkin, Theodore A., et al. “Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.Toxicology, vol. 338, Dec. 2015, pp. 8–16. Pubmed, doi:10.1016/j.tox.2015.09.005.
Slotkin TA, Skavicus S, Seidler FJ. Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos. Toxicology. 2015 Dec 2;338:8–16.
Journal cover image

Published In

Toxicology

DOI

EISSN

1879-3185

Publication Date

December 2, 2015

Volume

338

Start / End Page

8 / 16

Location

Ireland

Related Subject Headings

  • Toxicology
  • Risk Assessment
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Prenatal Exposure Delayed Effects
  • Pregnancy
  • Pesticides
  • Norepinephrine
  • Nicotine
  • Maternal Exposure