Methylenetetrahydrofolate reductase deficiency and low dietary folate increase embryonic delay and placental abnormalities in mice.
BACKGROUND
Despite extensive research on mild methylenetetrahydrofolate reductase (MTHFR) deficiency and low dietary folate in different disorders, the association of these metabolic disturbances with a variety of congenital defects and pregnancy complications remains controversial. In this study we investigated the effects of MTHFR and dietary folate deficiency at 10.5 days post coitum (dpc) in our mouse model of mild MTHFR deficiency.


METHODS
Mthfr +/+ and +/- female mice were fed a control or folic acid-deficient diet for 6 weeks, then mated with Mthfr +/- males. At 10.5 dpc, embryos were examined and placentae were collected for histologic evaluation.


RESULTS
Maternal MTHFR and folate deficiencies resulted in increased developmental delays and smaller embryos. We also observed a low frequency of a variety of embryonic defects in the experimental groups, such as neural tube, heart looping, and turning defects; these results mimic the low incidence and multifactorial nature of these anomalies in humans. Folate-deficient mice also had increased embryonic losses and severe placental defects, including placental abruption and disturbed patterning of placental layers. Folate-deficient placentae had decreased ApoA-I expression, and there was a trend toward a negative correlation between ApoA-I expression with maternal homocysteine concentrations.


CONCLUSIONS
Our study provides biological evidence linking maternal MTHFR and dietary folate deficiencies to adverse pregnancy outcomes in mice. It underscores the importance of folate not only in reducing the incidence of early embryonic defects, but also in the prevention of developmental delays and placental abnormalities that may increase susceptibility to other defects and to reproductive complications.
Pickell
Laura
L
Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec H3Z 2Z3, Canada.
Li
Deqiang
D
Brown
Katharine
K
Mikael
Leonie G
LG
Wang
Xiao-Ling
XL
Wu
Qing
Q
Luo
Li
L
Jerome-Majewska
Loydie
L
Rozen
Rima
R
D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis; D019587:Dietary Supplements; D020964:Embryo Loss / Q000201:enzymology; D004622:Embryo, Mammalian / Q000201:enzymology; D047108:Embryonic Development; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D006330:Heart Defects, Congenital / Q000201:enzymology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009436:Neural Tube Defects / Q000201:enzymology; D010920:Placenta / Q000002:abnormalities* / Q000201:enzymology*; D011247:Pregnancy; D014803:Vitamin B Complex / Q000494:pharmacology*
D016632:Apolipoprotein A-I; D014803:Vitamin B Complex; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)