Retinoic acid (RA), an active metabolite of vitamin A, plays essential signaling
roles in mammalian embryogenesis. Nevertheless, it has long been recognized
that overexposure to vitamin A or retinoic acid causes widespread teratogenesis
in rodents as well as humans. However, the mechanism of its teratogenic
effect is not yet understood. Here, we examined the effects of RA on the fetal
and placental development as an attempt to find the mechanism of its teratogenicity
through inhibition of utero-placental development. The pregnant
mice were divided into three groups: RA treated group, control treated with
dimethyl sulfoxide (DMSO) group and control non-treated group. The RA
treated group received 15 mg/kg RA by intraperitoneal injection from 8.5 to
11.5 gestation days. The pregnant mice were sacrificed by cervical dislocation
on days 9.5, 10.5, 12.5, 13.5 and 18.5 of gestation. The uteri were isolated, and
the fetuses have been exposed to morphological examination and skeletal
staining. Moreover, histological and immunohistochemical studies on placenta
have been done. Morphologically, we recorded a reduction in the number of
implanted fetuses besides hematoma in different parts of the uteri of the RA
treated animals. Furthermore, RA was found to induce decreases in fetal weight
and length, as well as malformations in the tail, forelimbs and hindlimbs, which
were confirmed by skeletal examination. Interestingly, RA treatment showed
a decrease in the expression level of epidermal growth factor receptor (EGFR)
during placenta development, especially in junctional and labyrinth zones. We
concluded that high dose of RA may have a direct teratogenic effect on the
fetus besides an indirect effect through modulating EGFR signal during the
placenta development.