The Critical Period for Inducing Cranio-facial Malformations by Thalidomide in JW-NIBS Rabbits

Abstract

Thalidomide was administered orally at a dose level of 300 mg/kg to pregnant rabbits on various days during organogenesis. Various cranio-facial malformations were produced in the fetuses by treatment on days 6-11 of gestation, such as anencephaly, holoprosencephaly, dysgenetic hydrocephaly, hypoplasia of ala nasi, facial median cleft, cleft palate and microphthalmia. No external anomalies were observed from treatment on days 12-18 of gestation. Single administration of thalidomide from days 6 to 8 of gestation resulted in a greater incidence of cranio-facial malformations, especially from treatment on day 7. To study the morphogenetic process, the fetuses were observed histologically on days 10-16 of gestation. The telencephalic wall was everted at the midfrontal line in the 11 -day fetus, and the eversion became more remarkable with the fetal developmental stage.