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Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?

Publication ,  Journal Article
Meyer, A; Seidler, FJ; Cousins, MM; Slotkin, TA
Published in: Environ Health Perspect
December 2003

The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms over and above cholinesterase inhibition. In the present study, we evaluated the effects of gestational CPF exposure on the adenylyl cyclase (AC) signaling cascade, which regulates the production of cyclic AMP, a major controller of cell replication and differentiation. In addition to basal AC activity, we assessed the AC response to direct enzymatic stimulants [forskolin, manganese (Mn(2+))]; the response to isoproterenol, which activates signaling through beta-adrenoceptors (betaARs); and the concentration of betaAR binding sites. CPF administered to pregnant rats on gestational days (GD) 9-12 elicited little or no change in any components of AC activity or betaARs. However, shifting the treatment window to GD17-20 produced regionally selective augmentation of AC activity. In the brainstem, the response to forskolin or Mn(2+) was markedly stimulated by doses at or below the threshold for observable toxicity of CPF or for inhibition of fetal brain cholinesterase, whereas comparable effects were seen in the forebrain only at higher doses. In addition, low doses of CPF reduced betaAR binding without impairing receptor-mediated stimulation of AC. These results indicate that signal transduction through the AC cascade is a target for CPF during a discrete developmental period in late gestation, an effect that is likely to contribute to the noncholinergic component of CPF's developmental neurotoxicity.

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Published In

Environ Health Perspect

DOI

ISSN

0091-6765

Publication Date

December 2003

Volume

111

Issue

16

Start / End Page

1871 / 1876

Location

United States

Related Subject Headings

  • Toxicology
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Prenatal Exposure Delayed Effects
  • Pregnancy
  • Maternal Exposure
  • Insecticides
  • Female
  • Embryonic and Fetal Development
 

Citation

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Meyer, A., Seidler, F. J., Cousins, M. M., & Slotkin, T. A. (2003). Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target? Environ Health Perspect, 111(16), 1871–1876. https://doi.org/10.1289/ehp.6468
Meyer, Armando, Frederic J. Seidler, Mandy M. Cousins, and Theodore A. Slotkin. “Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?Environ Health Perspect 111, no. 16 (December 2003): 1871–76. https://doi.org/10.1289/ehp.6468.
Meyer A, Seidler FJ, Cousins MM, Slotkin TA. Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target? Environ Health Perspect. 2003 Dec;111(16):1871–6.
Meyer, Armando, et al. “Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?Environ Health Perspect, vol. 111, no. 16, Dec. 2003, pp. 1871–76. Pubmed, doi:10.1289/ehp.6468.
Meyer A, Seidler FJ, Cousins MM, Slotkin TA. Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target? Environ Health Perspect. 2003 Dec;111(16):1871–1876.

Published In

Environ Health Perspect

DOI

ISSN

0091-6765

Publication Date

December 2003

Volume

111

Issue

16

Start / End Page

1871 / 1876

Location

United States

Related Subject Headings

  • Toxicology
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Prenatal Exposure Delayed Effects
  • Pregnancy
  • Maternal Exposure
  • Insecticides
  • Female
  • Embryonic and Fetal Development