Involvement of apoptotic cell death and cell cycle perturbation in retinoic acid-induced cleft palate in mice

Toxicol Appl Pharmacol. 2007 May 15;221(1):42-56. doi: 10.1016/j.taap.2007.02.019. Epub 2007 Mar 12.


Retinoic acid (RA), a metabolite of vitamin A, plays a key role in a variety of biological processes and is essential for normal embryonic development. On the other hand, exogenous RA could cause cleft palate in offspring when it is given to pregnant animals at either the early or late phases of palatogenesis, but the pathogenetic mechanism of cleft palate caused by excess RA remains not fully elucidated. The aim of the present study was to investigate the effects of excess of RA on early palatogenesis in mouse fetuses and analyze the teratogenic mechanism, especially at the stage prior to palatal shelf elevation. We gave all-trans RA (100 mg/kg) orally to E11.5 ICR pregnant mice and observed the changes occurring in the palatal shelves of their fetuses. It was found that apoptotic cell death increased not only in the epithelium of the palatal shelves but also in the tongue primordium, which might affect tongue withdrawal movement during palatogenesis and impair the horizontal elevation of palatal shelves. In addition, RA was found to prevent the G(1)/S progression of palatal mesenchymal cells through upregulation of p21(Cip1), leading to Rb hypophospholylation. Thus, RA appears to cause G(1) arrest in palatal mesenchymal cells in a similar manner as in various cancer and embryonic cells. It is likely that apoptotic cell death and cell cycle disruption are involved in cleft palate formation induced by RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Cycle Proteins / metabolism
  • Cleft Palate / chemically induced
  • Cleft Palate / pathology*
  • Cleft Palate / ultrastructure
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / ultrastructure
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Epithelial Cells / ultrastructure
  • Female
  • Fetal Development / drug effects
  • G1 Phase / drug effects*
  • In Situ Nick-End Labeling
  • Intubation, Gastrointestinal
  • Jaw / drug effects
  • Jaw / physiopathology
  • Male
  • Maxilla / abnormalities
  • Maxilla / ultrastructure
  • Mice
  • Mice, Inbred ICR
  • Microscopy, Electron, Scanning
  • Movement / drug effects
  • Palate / abnormalities
  • Palate / ultrastructure
  • Pregnancy
  • S Phase / drug effects*
  • Tongue / abnormalities
  • Tongue / drug effects
  • Tretinoin / administration & dosage
  • Tretinoin / toxicity*


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Tretinoin