| Autor: |
Cosín-Tomás M; Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, McGill University, Montreal, QC H4A 3J1, Canada., Luan Y; Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, McGill University, Montreal, QC H4A 3J1, Canada., Leclerc D; Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, McGill University, Montreal, QC H4A 3J1, Canada., Malysheva OV; Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY 14853, USA., Lauzon N; Drug Discovery Platform, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Bahous RH; Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, McGill University, Montreal, QC H4A 3J1, Canada., Christensen KE; Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, McGill University, Montreal, QC H4A 3J1, Canada., Caudill MA; Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY 14853, USA., Rozen R; Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, McGill University, Montreal, QC H4A 3J1, Canada. |
| Abstrakt: |
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. |
