Critical period of phenytoin teratogenic action in the sea urchin Arbacia punctulata embryo

S. Estus, J. L. Blumer

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

We characterized the susceptibility of sea urchin embryogenesis to phenytoin developmental toxicity. Concentration-dependent effects were assessed by exposing embryos from fertilization through the late gastrula/prism stage and scoring abnormal development via light microscopy. Malformations were observed as early as the first cleavage, when asymmetric, incomplete and arrested cleavage were noted, and also at the prism stage. These effects were concentration-dependent with an EC50 value of approximately 40 μM at both the cleavage and prism stages. Several phenytoin analogs of varying toxicity were identified. Comparison of zygote uptake of phenytoin and one nonteratogenic analog found that toxicity was not limited by uptake as the analog achieved intracellular concentrations which would have been sufficient to induce abnormal development if it had an intracellular potency equal to that of phenytoin. Periods in sea urchin embryogenesis susceptible to phenytoin actions were identified by exposing embryos to phenytoin (120 μM) for discrete intervals after fertilization and scoring development at the prism stage. A critical period of unique susceptibility coincided with the cleavage and morula stages (0- ~ 64 cells/embryo, 0-5 hr after fertilization). Drug exposure after this period did not alter development. Studies examining phases of the cell cycle for susceptibility to phenytoin effects on cleavage found that drug exposure confined to M phase was necessary and sufficient to manifest developmental toxicity. Drug uptake was similar during the sensitive and insensitive developmental stages and cell cycle phases and thus was not responsible for the variations in susceptibility observed. We conclude that the direct effects of phenytoin on sea urchin embryogenesis are confined to the cleavage and morula stages. Furthermore, the molecular targets for the cleavage effects appear most sensitive during the M phase of the cell cycle.

Original languageEnglish
Pages (from-to)782-789
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume251
Issue number2
StatePublished - 1989

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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