Pretreatment Effect of Folic Acid on 13-Cis-RA-Induced Cellular Damage of Developing Midfacial Processes in Cultured Rat Embryos

Abstract

Objective:Excess treatment of 13-cis-RA (Accutane®) on pregnant women induces craniofacial malformation found in infants. However, the effect of folic acid on 13-cis-RA-induced cellular damages of developing midfacial processes is still unknown. The purpose of this study was to investigate the pretreatment effect of folic acid (FA) on 13-cis-RA-induced cellular damage in developing midfacial processes in rat embryos.Materials and Methods:The rat embryos at developing midfacial processes were performed by whole embryo culture in vitro, in the presence of 13-cis-RA (20 µM) with or without pre-treatment of FA (100 µM). The midfacial morphogenesis score, PCNA and TUNEL assay staining were evaluated for morphogenesis, cell proliferation and apoptosis of the midfacial processes, respectively.Results:The 13-cis-RA-treated embryos at 24h showed atrophy of midfacial processes with significantly decreased morphogenesis score and cell proliferation, and increased apoptotic cell death. In contrast, the embryos pre-treated with FA for 18h, followed by 13-cis-RA treatment for 24h (FA-RA) showed significantly greater morphogenesis score, increased cell proliferation and lower apoptotic cell death compared to those of the 13-cis-RA-treated embryos.Conclusion:The results suggest that FA reduced the teratogenic effects of 13-cis-RA on midfacial process tissue. Future investigations regarding the anti-teratogenic mechanism of FA on the prevention of damages in midface processes induced by 13-cis-RA on pregnant woman are warranted.

Effect of folic acid on animal models, cell cultures, and human oral clefts: a literature review

“…Additionally, concomitant therapy with FA and Met completely eliminated the prevalence of ATRA-induced CP [8]. FA treatment prior to 13-cis-retinoic acid application in rat embryos significantly alleviated cellular damage in the midfacial process, thus revealing the beneficial effects produced by FA on this tissue [26].…”

“…The animal model studies analyzed demonstrated the protective effect of FA against CP [7,8,[24][25][26][27][28] (Table 2). The experimental design utilized varies among studies: in two of the studies, FA supplementation was enabled via feeding of female mice prior to mating [7,29].…”

“…In certain other studies, FA was administered through injections, either intraperitoneally [8], subcutaneously during pregnancy [24], or intravenously [30]. In a few more studies, cultured ex vivo mouse embryos were treated with FA and retinoic acid [25,26].…”

Release of Tretinoin Solubilized in Microemulsion from Carbopol and Xanthan Gel: In Vitro versus Ex Vivo Permeation Study

“…The teratogenic effect is induced by the interference of exogenous retinoic acid with its endogenous signaling, which plays a role in embryogenesis. Kriangkrait et al [ 38 ] stated that the exogenous retinoic acid increases the signaling in the mesenchyme underneath the epithelium lining, resulting in induced mesenchymal cell apoptosis.…”

The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis

“…Patients treated with a higher cumulative dose of isotretinoin had markedly high homocysteine and low folic acid levels [ 30 ]. Kriangkrai et al [ 31 ] suggested that folic acid reduced the teratogenic effects of isotretinoin-induced cellular damage in developing midfacial processes in rat embryos [ 31 ]. Folic acid is known to play an integral role in embryonic development.…”