Drug-induced limb dysplasias in fetal rabbits

Authors

  • John M. Desesso,

    1. Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298
    Current affiliation:
    1. Department of Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
    Search for more papers by this author
  • Robert L. Jordan

    1. Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298
    Search for more papers by this author

  • This study is from a dissertation (J.M.D.) submitted to the School of Basic Sciences, Medical College of Virginia, Virginia Commonwealth University in partial fulfillment of the requirements for doctor of philosophy.

  • Supported In part by a grant from the Medical College of Virginia Foundation and NIH grant HD6146.

Abstract

Pregnant New Zealand White rabbits were treated on gestation day 12 with 19.2 mg/kg methotrexate (MTX), 750 mg/kg hydroxyurea (HU), or 1,500 mg/kg acetazolamide. Rabbits were killed either 2–32 hours posttreatment for histological analysis of embryos or at day 29 for gross and skeletal examination of fetuses. MTX produced cleft palate, hydrocephalus, and fore- and hindlimb reduction defects. Histological analysis revealed pyknosis and edema in mesenchymal tissues at four to eight hours following treatment. The apical ectodermal ridges (AER) of treated embryos permanently lost their characteristic pseudostratified organization. By 32 hours the limb buds had regained their normal appearance except for the AER. HU affected all fetuses with skull and facial anomalies as well as severe reduction deformities of all limbs. Histologically HU-treated embryos had numerous, basophilic, intercellular granules (presumably cell debris) which appeared within two to four hours in the limb bud mesenchyme, neural tube, and dorsal root ganglion. The architecture of the AER was unchanged. Acetazolamide produced bilateral retarded ossification or possible aplasia of the first metacarpal and talus in nearly 80% of fetuses. Microscopic examination disclosed no apparent alterations in limb-bud morphology. Methyl green-pyronin Y staining called attention to green intracellular droplets within the endoderm of the trachea and bronchi at two hours posttreatment. It was concluded that the three drugs do not produce limb dysplasias by a common teratogenic mechanism.

Ancillary