Differential teratogenesis of all-trans-retinoic acid administered on gestational day 9.5 to SWV and C57BL/6N mice: emphasis on limb dysmorphology.
BACKGROUND
Mouse strain differences in teratologic response are well documented. However, because retinoids cause similar malformation syndromes across many species, the strain differences may be predicted to be minimal. The goals of this study were to characterize and explain the differences between the C57BL/6N and SWV mouse strains in terms of all-trans-retinoic acid (RA)-induced teratologic effects at the time of gestation that cause postaxial forelimb ectrodactyly.


METHODS
Visceral and skeletal malformations were determined by Wilson's sectioning and double-staining techniques, respectively; developmental staging was performed according to the somite count; and retinoid concentrations were assessed by HPLC.


RESULTS
C57BL/6N mice were more susceptible than SWV mice to induction of embryolethality, cardiovascular defects, and forelimb ectrodactyly, whereas the opposite was true for the induction of ear, thymus, and tail agenesis, and cleft palate, gastroschisis, and anal atresia. As determined by somite counts, 1 strain intercross was developmentally advanced compared to the parental strains and the reciprocal cross. Retinoid susceptibility was equivalent between the reciprocal crosses for some malformations and determined by the maternal genotype for others. Toxicokinetic experiments showed that whole-embryo peak retinoid concentrations did not differ between the strains, but the area under the curve (AUC) for all-trans-RA was 1.3 times higher in C57BL/6N than in SWV embryos.


CONCLUSIONS
The malformation spectrum induced by RA was strain-specific, and the strain sensitivity for forelimb ectrodactyly was consistent with all previously tested teratogenic agents (i.e., C57BL/6N was more sensitive than SWV). The strain differences in teratologic effects were not explained by developmental timing differences or toxicokinetic differences at the whole-embryo level.
Collins
M D
MD
Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. mdc@ucla.edu
Eckhoff
C
C
Weiss
R
R
Resnick
E
E
Nau
H
H
Scott
W J
WJ
D000014:Abnormalities, Drug-Induced; D000818:Animals; D004334:Drug Administration Schedule; D005260:Female; D017880:Limb Deformities, Congenital / Q000139:chemically induced* / Q000175:diagnosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014212:Tretinoin / Q000009:adverse effects* / Q000493:pharmacokinetics
D014212:Tretinoin