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Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity.

Publication ,  Journal Article
Auman, JT; Seidler, FJ; Slotkin, TA
Published in: Brain Res Dev Brain Res
May 11, 2000

Chlorpyrifos has been hypothesized to interact with receptors and transduction proteins involved in the production of cyclic AMP, contributing to adverse effects on cell replication and differentiation. We studied the effects of neonatal chlorpyrifos exposure on hepatic adenylyl cyclase (AC) activity, as the liver accumulates the highest concentrations of chlorpyrifos and is the site for generation of its active metabolite, chlorpyrifos oxon. Newborn rats were given 1 mg/kg of chlorpyrifos s.c. on PN1-4. On PN5, 24 h after the last dose, AC catalytic activity was induced as assessed by the response to the direct AC stimulant, Mn(2+). In contrast, AC activation dependent upon interaction of the enzyme with G-proteins (forskolin) did not show any enhancement, suggesting impairment of G-protein function. This conclusion was confirmed by impaired responsiveness to fluoride, which directly activates G-proteins. In addition, the response of AC to hormonal signals was altered in a receptor-selective manner, with an enhanced response to glucagon but not to the beta-adrenoceptor agonist, isoproterenol. The effects of chlorpyrifos on AC signaling displayed a critical developmental period of vulnerability, as treatment of older rats (PN11-14) failed to cause substantial induction of AC or interference with G-protein signaling, although it did still enhance the glucagon response. In all cases, the effects of chlorpyrifos disappeared within a few days of discontinuing treatment. These results stand in contrast to the delayed deterioration of AC signaling seen in the brain after the same chlorpyrifos treatment. The temporal and organ selectivity of chlorpyrifos' effects on the AC cascade suggest that disruption of membrane signaling occurs consequent to selective effects on cell development, rather than representing a direct interaction between chlorpyrifos and signaling proteins.

Duke Scholars

Published In

Brain Res Dev Brain Res

DOI

ISSN

0165-3806

Publication Date

May 11, 2000

Volume

121

Issue

1

Start / End Page

19 / 27

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Receptors, Glucagon
  • Receptors, Adrenergic, beta
  • Rats
  • Pregnancy
  • Neurotoxins
  • Neurology & Neurosurgery
  • Liver
  • Isoproterenol
  • Glucagon
 

Citation

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ICMJE
MLA
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Auman, J. T., Seidler, F. J., & Slotkin, T. A. (2000). Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity. Brain Res Dev Brain Res, 121(1), 19–27. https://doi.org/10.1016/s0165-3806(00)00021-3
Auman, J. T., F. J. Seidler, and T. A. Slotkin. “Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity.Brain Res Dev Brain Res 121, no. 1 (May 11, 2000): 19–27. https://doi.org/10.1016/s0165-3806(00)00021-3.
Auman, J. T., et al. “Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity.Brain Res Dev Brain Res, vol. 121, no. 1, May 2000, pp. 19–27. Pubmed, doi:10.1016/s0165-3806(00)00021-3.
Journal cover image

Published In

Brain Res Dev Brain Res

DOI

ISSN

0165-3806

Publication Date

May 11, 2000

Volume

121

Issue

1

Start / End Page

19 / 27

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Receptors, Glucagon
  • Receptors, Adrenergic, beta
  • Rats
  • Pregnancy
  • Neurotoxins
  • Neurology & Neurosurgery
  • Liver
  • Isoproterenol
  • Glucagon