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

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 recommen...

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Autores principales: Cosín-Tomás, Marta, Luan, Yan, Leclerc, Daniel, Malysheva, Olga V., Lauzon, Nidia, Bahous, Renata H., Christensen, Karen E., Caudill, Marie A., Rozen, Rima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352339/
https://www.ncbi.nlm.nih.gov/pubmed/32521649
http://dx.doi.org/10.3390/nu12061716
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author Cosín-Tomás, Marta
Luan, Yan
Leclerc, Daniel
Malysheva, Olga V.
Lauzon, Nidia
Bahous, Renata H.
Christensen, Karen E.
Caudill, Marie A.
Rozen, Rima
author_facet Cosín-Tomás, Marta
Luan, Yan
Leclerc, Daniel
Malysheva, Olga V.
Lauzon, Nidia
Bahous, Renata H.
Christensen, Karen E.
Caudill, Marie A.
Rozen, Rima
author_sort Cosín-Tomás, Marta
collection PubMed
description 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.
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spelling pubmed-73523392020-07-15 Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism Cosín-Tomás, Marta Luan, Yan Leclerc, Daniel Malysheva, Olga V. Lauzon, Nidia Bahous, Renata H. Christensen, Karen E. Caudill, Marie A. Rozen, Rima Nutrients Article 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. MDPI 2020-06-08 /pmc/articles/PMC7352339/ /pubmed/32521649 http://dx.doi.org/10.3390/nu12061716 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cosín-Tomás, Marta
Luan, Yan
Leclerc, Daniel
Malysheva, Olga V.
Lauzon, Nidia
Bahous, Renata H.
Christensen, Karen E.
Caudill, Marie A.
Rozen, Rima
Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism
title Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism
title_full Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism
title_fullStr Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism
title_full_unstemmed Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism
title_short Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism
title_sort moderate folic acid supplementation in pregnant mice results in behavioral alterations in offspring with sex-specific changes in methyl metabolism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352339/
https://www.ncbi.nlm.nih.gov/pubmed/32521649
http://dx.doi.org/10.3390/nu12061716
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