Timing of implantation and closure of the palatal shelf in New Zealand white and Japanese white rabbits.
Two specific developmental events, namely implantation and palatal shelf closure, are of specific interest because they define, respectively, the beginning and the end of the treatment period in embryo-fetal developmental toxicity studies for pharmaceutical products. Thus, a detailed evaluation of the timing of implantation and closure of the hard palate is necessary to assure use of the proper exposure window in developmental toxicity studies in rabbits, the nonrodent species most commonly evaluated in regulatory developmental toxicology studies. The purpose of this study was to determine the timeline for implantation and closure of the hard palate in the New Zealand White rabbit, and to determine if this timeline differed in the Japanese White rabbit. To describe the timing of implantation, the uteri from does of the New Zealand White rabbit and the Japanese White rabbit were examined on gestation days (GDs) 5 through 8 for macroscopic evidence of implantation. To assess palatal shelf closure, fetuses were removed on GDs 17, 18, and 19 and fixed in Bouin's solution. The fetuses were then categorized into five stages of palatal shelf closure: open (Stage I); approach of the palatal shelves (Stage II); partial closure of the hard palate (Stage III); full closure of the hard palate (Stage IV); and full closure of the soft palate (Stage V). In both the New Zealand White and Japanese White rabbit strains, implantation was initiated on GD 6.5 and was completed on GD 7. Partial closure of the palate began on GD 17.5, and by GD 19, closure of the hard palate was completed in all fetuses, and closure of the soft palate was completed in 75-96% of the fetuses. The timing of implantation and palatal shelf closure were comparable between the New Zealand White rabbit and the Japanese White rabbit. Therefore, treatment beginning on GD 7 and continuing until GD 19 encompasses the period of major organogenesis and is considered appropriate for use in developmental toxicity studies using either of these two strains of rabbits.
Sivaraman
Lakshmi
L
Pfizer Global Research & Development, Groton, Connecticut 06340, USA. lakshmi.sivaraman@pfizer.com
Horimoto
Masao
M
Tassinari
Melissa
M
Hurtt
Mark
M
Cappon
Gregg
G
D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions; D010064:Embryo Implantation / Q000502:physiology*; D005260:Female; D010159:Palate / Q000196:embryology* / Q000502:physiology; D011247:Pregnancy; D011817:Rabbits; D013045:Species Specificity; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*