It is well known that maternal diabetes causes various congenital malformations. Although there are many reports that
folic acid (FA) administration in pregnancy reduces the risk of
birth defects including
neural tube defects (NTDs), a precise analysis on the preventive effect of FA against diabetic
embryopathy has not been done yet. In this study, we analyzed the preventive effects of FA on congenital malformations including NTDs, cardiovascular, and skeletal malformations using a diabetic mouse model. Female mice were rendered hyperglycemic by
streptozotocin and then mated. Pregnant diabetic mice were treated daily with FA (3 mg/kg
body weight) or saline between gestational days (GD) 6 and 10. On GD 18, fetuses were examined for congenital malformations. FA did not affect plasma
glucose levels. In the DM control group, the incidence of NTDs, cardiovascular, and skeletal malformations was 28.4%, 28.5%, and 29.7%, respectively. In the FA-treated group, the corresponding proportions reduced to 6.0%, 2.5% and 12.5%, respectively. A whole-mount TUNEL revealed an increased apoptosis in the hindbrain region of embryos from DM control group on day 9.5, and the apoptosis was decreased by FA treatment. Maternal plasma
homocysteine levels on GD 9.5 were significantly lowered in DM control group compared with those in non-DM group, and FA treatment did not show a significant effect. These results indicate that FA is effective for the prevention of various diabetic
embryopathy including NTDs, cardiovascular, and skeletal malformations, and suggested that this effect is independent from
homocysteine metabolism and possibly mediated by decreasing the abnormal apoptosis during organogenesis.