Retinoic Acid Retards Fetal And Hindlinb Skeletal Development In A Retinoic Acid-induced Clubfoot Model

BackgrounBackground and objectiveRetinoic acid (RA) has been shown to induce congenital clubfoot in animal models, but it isunknown if the effect of RA on the formation of clubfoot in vivo results from generalized growthretardation or from the specific effects of hindlimb skeletal development.Materials and methodsExperiment were randomly divided into control and experimental groups. Experimentalclubfoot deformity in rat fetuses was performed by maternal administration of RA (120 mg/kg,130 mg/kg or 140 mg/kg body weight) as an intragastric dose on embryonic day 10 (E10) and acontrol group (C) was administered an equivalent dose of solvent. Fetal hindlimb skeletalossification was assessed by double staining. The degree of RA-induced delay was determinedby comparison of RA fetuses on E21 with C fetuses on E17–E21. The skeletal differentiationscoring system was slightly modified and used to quantify the degree of deformity from E17 toE21.ResultsPrenatal RA exposure decreased in relation to fetal body weight, length and skeletalossification of hindlimb compared with the C fetuses. These effects were dependent on thedosage level of RA. The normal development curves indicated that the RA-induced fetusesshowed delayed increase in body weight and skeletal ossification development. However, therewas no uniform effect on the skeletons of hindlimbs, not least retardation in ossification andinduction malformation on the talus and calcaneus.Conclusion Our results demonstrate that prenatal RA exposure has retardation effects on the developinghindlimb skeleton that are independent of those on overall fetal growth. The normal skeletalossification shows that the talus and calcaneus are poorly ossified and it delayed by almost oneday in the RA120 mg/kg group. Therefore, during the susceptible stages, different regions of thelimb bud respond differently to teratogenic effects of RA.