Lithium-induced teratogenesis in frog embryos prevented by a polyphosphoinositide cycle intermediate or a diacylglycerol analog

Dev Biol. 1989 Apr;132(2):315-24. doi: 10.1016/0012-1606(89)90228-5.

Abstract

Microinjection of LiCl into prospective ventral blastomeres of the 32-cell Xenopus embryo gives rise to duplication of dorsoanterior structures such as the notochord, neural tube, eyes, and cement gland. We report here that this teratogenic effect of Li+ is prevented by coinjection of equimolar myo-inositol, an intermediate of the polyphosphoinositide cycle. In contrast, epi-inositol, a nonbiological positional isomer of inositol not employed in this cycle, is ineffective at rescuing Li+-injected embryos. Treatment of embryos at stage 7 with the tumor promoter, phorbol myristate acetate (an analog of the polyphosphoinositide cycle-derived second messenger, diacylglycerol), also prevents dorsoanterior duplication of Li+ embryos, while the nontransforming analog, phorbol myristate acetate-4-O-methyl ether, is without effect. Both of these rescuing agents are without obvious effects on development when administered alone (i.e., without Li+). Li+-selective microelectrode measurements demonstrate that intracellular Li+ levels are identical when Li+ is injected with or without myo-inositol. Clonal analysis shows that blastomeres injected with Li+ plus myo-inositol make a normal contribution of progeny to the later embryo. Because Li+ is a well-established inhibitor of the polyphosphoinositide cycle and can thereby have profound effects on cellular myo-inositol and diacylglycerol levels, these observations concerning inositol-mediated rescue suggest a role for altered polyphosphoinositide cycle activity in lithium-induced teratogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abnormalities, Drug-Induced
  • Animals
  • Blastomeres / drug effects*
  • Central Nervous System / drug effects
  • Central Nervous System / embryology
  • Diglycerides / pharmacology*
  • Exocrine Glands / drug effects
  • Exocrine Glands / embryology
  • Eye / drug effects
  • Eye / embryology
  • Glycerides / pharmacology*
  • Inositol / pharmacology
  • Lithium / pharmacology*
  • Lithium / toxicity
  • Microelectrodes
  • Microinjections
  • Mutation
  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Xenopus laevis

Substances

  • Diglycerides
  • Glycerides
  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Inositol
  • Lithium
  • Tetradecanoylphorbol Acetate