High intake of folic acid disrupts embryonic development in mice.
BACKGROUND
Folic acid fortification and supplementation has increased folate intake and blood folate concentrations and successfully reduced the incidence of neural tube defects. However, the developmental consequences of high folate intake are unknown. This study investigated the impact of high folate intake, alone or with methylenetetrahydrofolate reductase (MTHFR) deficiency, on embryonic and placental development in mice.


METHODS
Mthfr +/+ or +/- pregnant mice on a control diet (CD; recommended intake of folic acid for rodents) or folic acid-supplemented diet (FASD; 20-fold higher than the recommended intake) were examined for embryonic loss, delay, and defects at 10.5 and 14.5 days post coitum (dpc); 10.5-dpc placenta, and 14.5-dpc embryo hearts were studied histologically.


RESULTS
Total plasma folate was 10-fold higher in FASD compared to CD mice; plasma homocysteine levels were not affected by diet. At 10.5 dpc, the FASD was associated with embryonic delay and growth retardation, and may confer susceptibility to embryonic defects. The FASD did not adversely affect 10.5-dpc placental development. At 14.5 dpc, embryos from the FASD Mthfr +/+ group were delayed and the FASD was associated with thinner ventricular walls in embryonic hearts. There was a significant interaction between maternal MTHFR deficiency and a high folate diet for several developmental outcomes.


CONCLUSIONS
Our study suggests that high folate intake may have adverse effects on fetal mouse development and that maternal MTHFR deficiency may improve or rescue some of the adverse outcomes. These findings underscore the need for additional studies on the potential negative impact of high folate intake during pregnancy.
Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
Laura
L
Pickell
Katharine
K
Brown
Deqiang
D
Li
Xiao-Ling
XL
Wang
Liyuan
L
Deng
Qing
Q
Wu
Jacob
J
Selhub
Li
L
Luo
Loydie
L
Jerome-Majewska
Rima
R
Rozen
D000818:Animals; D000013:Congenital Abnormalities / Q000209:etiology*; D019587:Dietary Supplements / Q000009:adverse effects*; D020964:Embryo Loss / Q000209:etiology; D004622:Embryo, Mammalian / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000009:adverse effects* / Q000494:pharmacology; D006330:Heart Defects, Congenital / Q000209:etiology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy
D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)