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Glucocorticoids enhance intracellular signaling via adenylate cyclase at three distinct loci in the fetus: a mechanism for heterologous teratogenic sensitization?

Publication ,  Journal Article
Slotkin, TA; Lau, C; McCook, EC; Lappi, SE; Seidler, FJ
Published in: Toxicol Appl Pharmacol
July 1994

Although high doses of glucocorticoids are teratogenic, endogenous hormones are necessary for development. Because of the central role of cAMP to control cell differentiation, we examined the dose dependence, tissue selectivity, and critical periods involved in glucocorticoid regulation of fetal intracellular signaling mediated by adenylate cyclase. Pregnant rats were given dexamethasone at doses spanning the threshold for therapeutic effects (0.05, 0.2, and 0.8 mg/kg) on either Gestational Days 11, 12, and 13 or Days 17, 18, and 19. Development of adenylate cyclase was evaluated in cell membrane preparations using basal activity in the absence or presence of GTP, maximal G-protein activation by fluoride, and maximal catalytic subunit stimulation by forskolin-Mn2+. Even at the lowest dose, dexamethasone on gestational days 11 through 13 enhanced fetal adenylate cyclase activity by accelerating development of both the G-protein component and the catalytic subunit. As a result, supersensitivity of the response to beta-adrenergic receptor stimulation by isoproterenol was also produced, even though development of beta-adrenergic receptors was unaffected. Treatment with dexamethasone later in gestation similarly fostered development of both G-protein and catalytic subunit components, with selectivity for liver and heart as opposed to brain. Again, heterologous sensitization to isoproterenol stimulation was demonstrable; in addition, late gestational treatment elevated yet a third signal transduction locus, the beta-adrenergic receptor binding site. These effects are likely contributors to glucocorticoid teratogenesis (high doses) or to more subtle disruption of cell development (low doses); because adenylate cyclase is at the convergence of multiple neuronal, hormonal, and environmental inputs, glucocorticoids may sensitize the cell to heterologous stimuli, lowering the threshold for teratogenesis by other agents.

Duke Scholars

Published In

Toxicol Appl Pharmacol

DOI

ISSN

0041-008X

Publication Date

July 1994

Volume

127

Issue

1

Start / End Page

64 / 75

Location

United States

Related Subject Headings

  • Toxicology
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pregnancy
  • Liver
  • Guanosine Triphosphate
  • Gestational Age
  • GTP-Binding Proteins
 

Citation

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Slotkin, T. A., Lau, C., McCook, E. C., Lappi, S. E., & Seidler, F. J. (1994). Glucocorticoids enhance intracellular signaling via adenylate cyclase at three distinct loci in the fetus: a mechanism for heterologous teratogenic sensitization? Toxicol Appl Pharmacol, 127(1), 64–75. https://doi.org/10.1006/taap.1994.1140
Slotkin, T. A., C. Lau, E. C. McCook, S. E. Lappi, and F. J. Seidler. “Glucocorticoids enhance intracellular signaling via adenylate cyclase at three distinct loci in the fetus: a mechanism for heterologous teratogenic sensitization?Toxicol Appl Pharmacol 127, no. 1 (July 1994): 64–75. https://doi.org/10.1006/taap.1994.1140.
Slotkin, T. A., et al. “Glucocorticoids enhance intracellular signaling via adenylate cyclase at three distinct loci in the fetus: a mechanism for heterologous teratogenic sensitization?Toxicol Appl Pharmacol, vol. 127, no. 1, July 1994, pp. 64–75. Pubmed, doi:10.1006/taap.1994.1140.
Journal cover image

Published In

Toxicol Appl Pharmacol

DOI

ISSN

0041-008X

Publication Date

July 1994

Volume

127

Issue

1

Start / End Page

64 / 75

Location

United States

Related Subject Headings

  • Toxicology
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pregnancy
  • Liver
  • Guanosine Triphosphate
  • Gestational Age
  • GTP-Binding Proteins