Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism.

Marta Cosín-Tomás,Marie A Caudill,Yan Luan,Nidia Lauzon,Daniel Leclerc,Renata H Bahous,Rima Rozen,Olga V Malysheva,Karen E Christensen

doi:10.3390/nu12061716

Marta Cosín-Tomás, Marie A Caudill + Show 7 more

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https://doi.org/10.3390/nu12061716

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Journal: Nutrients	Publication Date: Jun 8, 2020
Citations: 23	License type: CC BY 4.0

Affiliation: Cornell University, McGill University Health Centre

Abstract

Fifteen to 20% of pregnant women may exceed the recommended intake of folic acid (FA) by more than four-fold. This excess could compromise neurocognitive and motor development in offspring. Here, we explored the impact of an FA-supplemented diet (5× FASD, containing five-fold higher FA than recommended) during pregnancy on brain function in murine offspring, and elucidated mechanistic changes. We placed female C57BL/6 mice for one month on control diets or 5× FASD before mating. Diets were maintained throughout pregnancy and lactation. Behavioural tests were conducted on 3-week-old pups. Pups and mothers were sacrificed at weaning. Brains and livers were collected to examine choline/methyl metabolites and immunoreactive methylenetetrahydrofolate reductase (MTHFR). 5× FASD led to hyperactivity-like behavior and memory impairment in 3-week-old pups of both sexes. Reduced MTHFR protein in the livers of FASD mothers and male pups resulted in choline/methyl metabolite disruptions in offspring liver (decreased betaine) and brain (decreased glycerophosphocholine and sphingomyelin in male pups, and decreased phosphatidylcholine in both sexes). These results indicate that moderate folate supplementation downregulates MTHFR and alters choline/methyl metabolism, contributing to neurobehavioral alterations. Our findings support the negative impact of high FA on brain development, and may lead to improved guidelines on optimal folate levels during pregnancy.

Highlights

Folate is essential for optimal brain function since it is required for methylation reactions, synthesis of nucleotides, neurotransmitters and myelin, and maintenance of homocysteine at non-toxic levels [1]
Our findings indicate that moderately increased folate intake in pregnancy downregulates methylenetetrahydrofolate reductase (MTHFR) and alters choline/methyl metabolism, contributing to neurobehavioral alterations in pups
There were no differences due to diet or sex for grip strength (Diet p = 0.934; Sex p = 0.184; Diet × Sex p = 0.415), or social interaction (Figure S1). These findings suggest that maternal 5× FASD during pregnancy and lactation leads to hyperactivity-like behavior and short-term memory impairment in offspring of both sexes

Summary

Introduction

Folate is essential for optimal brain function since it is required for methylation reactions, synthesis of nucleotides, neurotransmitters and myelin, and maintenance of homocysteine at non-toxic levels [1]. Recent concerns have been raised regarding high folate intake during pregnancy and lactation, since it has been estimated that 15–20% of pregnant women exceed recommended levels by more than four-fold due to food fortification and increased use of supplements [4,5,6]. In pregnant mice consuming folate at levels 10-fold higher than recommended (10× FASD), we observed this pseudo-MTHFR deficiency in the liver of dams and their male pups. These male pups had disturbances in methyl metabolism and memory impairment [15].

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