Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Sex-Specific Gene Expression in Brain of Young Mice and Embryos.

Yan Luan,Marie A Caudill,Rima Rozen,Daniel Leclerc,Olga V Malysheva,Marta Cosín-Tomás

doi:10.3390/nu14051051

Yan Luan, Marie A Caudill + Show 4 more

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https://doi.org/10.3390/nu14051051

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Abstract

Food fortification and increased vitamin intake have led to higher folic acid (FA) consumption by many pregnant women. We showed that FA-supplemented diet in pregnant mice (fivefold higher FA than the recommended level (5xFASD)) led to hyperactivity-like behavior and memory impairment in pups. Disturbed choline/methyl metabolism and altered placental gene expression were identified. The aim of this study was to examine the impact of 5xFASD on the brain at two developmental stages, postnatal day (P) 30 and embryonic day (E) 17.5. Female C57BL/6 mice were fed a control diet or 5xFASD for 1 month before mating. Diets were maintained throughout the pregnancy and lactation until P30 or during pregnancy until E17.5. The 5xFASD led to sex-specific transcription changes in P30 cerebral cortex and E17.5 cerebrum, with microarrays showing a total of 1003 and 623 changes, respectively. Enhanced mRNA degradation was observed in E17.5 cerebrum. Expression changes of genes involved in neurotransmission, neuronal growth and development, and angiogenesis were verified by qRT-PCR; 12 and 15 genes were verified at P30 and E17.5, respectively. Hippocampal collagen staining suggested decreased vessel density in FASD male embryos. This study provides insight into the mechanisms of neurobehavioral alterations and highlights potential deleterious consequences of moderate folate oversupplementation during pregnancy.

Highlights

Optimal folate status is essential for normal brain development and function due to the involvement of folate derivatives in key processes, including synthesis of nucleotides and neurotransmitters, methylation reactions, and regulation of plasma homocysteine concentrations [1,2]
A total of 599 genes (357 downregulated, Nutrients 2022, 14, x FOR PEER REV2IE4W2 upregulated) were differentially expressed in folic-acid-supplemented diet (FASD) male pups compared with control diet (CD) m5 oafl2e0 pups, and 419 genes (202 downregulated, 217 upregulated) were differentially expressed in FASD female pups compared with CD female pups (Figure 1)
In a recent study [11], we identified neurobehavioral abnormalities in P30 pups from dams fed FASD, and we embarked on an analysis of gene expression in the brains of P30 pups and E17.5 embryos

Summary

Introduction

Optimal folate status is essential for normal brain development and function due to the involvement of folate derivatives in key processes, including synthesis of nucleotides and neurotransmitters, methylation reactions, and regulation of plasma homocysteine concentrations [1,2]. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate-dependent methylation reactions. It synthesizes methyltetrahydrofolate for the remethylation of homocysteine to methionine, which is used to produce S-adenosylmethionine (SAM) for various methylation reactions. An alternate pathway to generate methionine is present, primarily in the liver and kidney, using the choline metabolite betaine as a methyl donor. Choline utilization for methylation is increased when folate metabolism is disturbed [3]. Reduced choline pools could affect the synthesis of the neurotransmitter acetylcholine and many important phospholipids [4]

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