Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe
MTHFR deficiency results in
homocystinuria and neurologic impairment. Mild
MTHFR deficiency (677C > T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary
folate impacts brain development, recent concerns have focused on high
folate intake following food fortification and increased
vitamin use. Our goal was to determine whether high dietary
folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or
folic acid-supplemented diet (
FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for
choline/methyl metabolite measurements, immunoblotting or gene expression of relevant
enzymes. Brains were examined for morphology of hippocampus and cortex. Pups of
FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR
protein levels were reduced in
FASD pup livers, with lower concentrations of
phosphocholine and glycerophosphocholine in liver and hippocampus, respectively.
FASD pup brains showed evidence of altered
acetylcholine availability and Dnmt3a
mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from
FASD dams were smaller. MTHFR
protein and
mRNA were reduced in embryonic liver, with lower concentrations of
choline,
betaine and
phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high
folate intake during pregnancy leads to pseudo-
MTHFR deficiency, disturbed
choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental
folic acid.