{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:28:27Z","timestamp":1790774907485,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,2,23]],"date-time":"2019-02-23T00:00:00Z","timestamp":1550880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vitamins B9 (folate) and B12 act as methyl donors in the one-carbon metabolism which influences epigenetic mechanisms. We previously showed that an embryofetal deficiency of vitamins B9 and B12 in the rat increased brain expression of let-7a and miR-34a microRNAs involved in the developmental control of gene expression. This was reversed by the maternal supply with folic acid (3 mg\/kg\/day) during the last third of gestation, resulting in a significant reduction of associated birth defects. Since the postnatal brain is subject to intensive developmental processes, we tested whether further folate supplementation during lactation could bring additional benefits. Vitamin deficiency resulted in weaned pups (21 days) in growth retardation, delayed ossification, brain atrophy and cognitive deficits, along with unchanged brain level of let-7a and decreased expression of miR-34a and miR-23a. Whereas maternal folic acid supplementation helped restore the levels of affected microRNAs, it led to a reduction of structural and functional defects taking place during the perinatal\/postnatal periods, such as learning\/memory capacities. Our data suggest that a gestational B-vitamin deficiency could affect the temporal control of the microRNA regulation required for normal development. Moreover, they also point out that the continuation of folate supplementation after birth may help to ameliorate neurological symptoms commonly associated with developmental deficiencies in folate and B12.<\/jats:p>","DOI":"10.3390\/ijms20040973","type":"journal-article","created":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T03:06:52Z","timestamp":1551064012000},"page":"973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Developmental Impairments in a Rat Model of Methyl Donor Deficiency: Effects of a Late Maternal Supplementation with Folic Acid"],"prefix":"10.3390","volume":"20","author":[{"given":"Andr\u00e9a","family":"Geoffroy","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7794-5975","authenticated-orcid":false,"given":"Lynda","family":"Saber-Cherif","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-5026","authenticated-orcid":false,"given":"Gr\u00e9gory","family":"Pouri\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9borah","family":"Helle","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8591-0721","authenticated-orcid":false,"given":"R\u00e9my","family":"Umoret","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5067-042X","authenticated-orcid":false,"given":"Jean-Louis","family":"Gu\u00e9ant","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Bossenmeyer-Pouri\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Daval","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm U1256, NGERE, Facult\u00e9 de M\u00e9decine, 9 avenue de la For\u00eat de Haye, F-54500 Vandoeuvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1093\/jn\/134.1.162","article-title":"Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain","volume":"134","author":"Craciunescu","year":"2004","journal-title":"J. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aranda, P., Agirre, X., Ballestar, E., Andreu, E.J., Rom\u00e1n-G\u00f3mez, J., Prieto, I., Mart\u00edn-Subero, J.I., Cigudosa, J.C., Siebert, R., and Esteller, M. (2009). Epigenetic signatures associated with different levels of differentiation potential in human stem cells. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007809"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nsmb.2489","article-title":"Epigenetic programming and reprogramming during development","volume":"20","author":"Cantone","year":"2013","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.tem.2013.01.010","article-title":"Folate and fetal programming: A play in epigenomics?","volume":"24","author":"Namour","year":"2013","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.biochi.2013.01.020","article-title":"Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase","volume":"95","author":"Alberto","year":"2013","journal-title":"Biochimie"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1139\/o79-007","article-title":"Relationship between tissue levels of S-adenosylmethionine, S-adenylhomocysteine, and transmethylation reactions","volume":"57","author":"Hoffman","year":"1979","journal-title":"Can. J. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0166-2236(03)00032-8","article-title":"Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders","volume":"26","author":"Mattson","year":"2003","journal-title":"Trends Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e553","DOI":"10.1038\/cddis.2013.69","article-title":"Decreased vitamin B12 availability induces ER stress through impaired SIRT1-deacetylation of HSF1","volume":"4","author":"Ghemrawi","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3980","DOI":"10.1096\/fj.12-205757","article-title":"Homocysteinylation of neuronal proteins contributes to folate deficiency-associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells","volume":"26","author":"Akchiche","year":"2012","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.bbrc.2017.09.054","article-title":"Both nitric oxide and nitrite prevent homocysteine-induced endoplasmic reticulum stress and subsequent apoptosis via cGMP-dependent pathway in neuronal cells","volume":"493","author":"Jeong","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","first-page":"703","article-title":"Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects","volume":"86","author":"Kirke","year":"1993","journal-title":"Q. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1177\/15648265080292S114","article-title":"Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development","volume":"29","author":"Molloy","year":"2008","journal-title":"Food Nutr. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S126","DOI":"10.1177\/15648265080292S117","article-title":"Effects of vitamin B12 and folate deficiency on brain development in children","volume":"29","author":"Black","year":"2008","journal-title":"Food Nutr. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1111\/j.1753-4887.2004.tb00065.x","article-title":"Folate and vitamin B12 recommended intakes and status in the United States","volume":"62","author":"Bailey","year":"2004","journal-title":"Nutr. Rev."},{"key":"ref_15","first-page":"CD007950","article-title":"Effects and safety of periconceptional folate supplementation for preventing birth defects","volume":"10","author":"Dowswell","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1159\/000332125","article-title":"Periconceptional folic acid-containing multivitamin supplementation for the prevention of neural tube defects and cardiovascular malformations","volume":"59","author":"Czeizel","year":"2011","journal-title":"Ann. Nutr. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1159\/000330776","article-title":"Prevention of neural-tube defects with periconceptional folic acid, methylfolate, or multivitamins?","volume":"58","author":"Czeizel","year":"2011","journal-title":"Ann. Nutr. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/1475-2891-11-75","article-title":"Effect of folate intake on health outcomes in pregnancy: A systematic review and meta-analysis on birth weight, placental weight and length of gestation","volume":"11","author":"Fekete","year":"2012","journal-title":"Nutr. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.siny.2007.07.002","article-title":"Prediction and perinatal outcomes of fetal growth restriction","volume":"12","author":"Breeze","year":"2007","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1467-8624.2009.01384.x","article-title":"Prenatal antecedents of newborn neurological maturation","volume":"81","author":"DiPietro","year":"2010","journal-title":"Child Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11366","DOI":"10.1073\/pnas.1203350109","article-title":"Prenatal growth in humans and postnatal brain maturation into late adolescence","volume":"109","author":"Raznahan","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e755","DOI":"10.1038\/cddis.2013.278","article-title":"Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124","volume":"4","author":"Kerek","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1007\/s12035-016-0035-8","article-title":"Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways","volume":"54","author":"Geoffroy","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.biochi.2016.02.012","article-title":"The metabolic basis for developmental disorders due to defective folate transport","volume":"126","author":"Desai","year":"2016","journal-title":"Biochimie"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R173","DOI":"10.1186\/gb-2007-8-8-r173","article-title":"MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system","volume":"8","author":"Kapsimali","year":"2007","journal-title":"Genome Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.neuron.2009.10.020","article-title":"MicroRNAs potentiate neural development","volume":"64","author":"Fineberg","year":"2009","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1242\/jcs.069104","article-title":"MicroRNAs and their roles in mammalian stem cells","volume":"124","author":"Yi","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.yexcr.2013.09.022","article-title":"miRNAs in brain development","volume":"321","author":"Petri","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.molmed.2008.07.001","article-title":"let-7 microRNAs in development, stem cells and cancer","volume":"14","author":"Slack","year":"2008","journal-title":"Trends Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.4161\/cc.7.24.7397","article-title":"The let-7 microRNA target gene, Mlin41\/Trim71 is required for mouse embryonic survival and neural tube closure","volume":"7","author":"Liang","year":"2008","journal-title":"Cell Cycle"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/jbt.20412","article-title":"Effect of microRNA-34a in cell cycle, differentiation, and apoptosis: A review","volume":"26","author":"Chen","year":"2012","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1111\/j.1471-4159.2008.05715.x","article-title":"Notch: From neural development to neurological disorders","volume":"107","author":"Lathia","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1111\/j.1460-9568.2005.03978.x","article-title":"Regulation of miRNA expression during neural cell specification","volume":"21","author":"Smirnova","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ijdevneu.2010.10.001","article-title":"Developmentally regulated expression of Sox9 and microRNAs 124, 128 and 23 in neuroepithelial stem cells in the developing spinal cord","volume":"29","author":"Farrell","year":"2011","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/nature01730","article-title":"Hes1 is a target of microRNA-23 during retinoic-acid-induced neuronal differentiation of NT2 cells","volume":"423","author":"Kawasaki","year":"2003","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1132","DOI":"10.1038\/cddis.2014.92","article-title":"MicroRNA-23a\/b and microRNA-27a\/b suppress Apaf-1 protein and alleviate hypoxia-induced neuronal apoptosis","volume":"5","author":"Chen","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1016\/j.prp.2018.09.004","article-title":"miR-23 regulates cell proliferation and apoptosis of vascular smooth muscle cells in coronary heart disease","volume":"214","author":"Liu","year":"2018","journal-title":"Pathol. Res. Pract."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1242\/dmm.001065","article-title":"miR-23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination","volume":"2","author":"Lin","year":"2009","journal-title":"Dis. Models Mech."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17468","DOI":"10.1073\/pnas.1317182110","article-title":"MicroRNA-23a promotes myelination in the central nervous system","volume":"110","author":"Lin","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"19879","DOI":"10.1073\/pnas.1007698107","article-title":"A network connecting Runx2, SATB2, and the miR-23a~27a~24-2 cluster regulates the osteoblast differentiation program","volume":"107","author":"Hassan","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/nutrit\/nuv107","article-title":"Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults","volume":"74","author":"Sechi","year":"2016","journal-title":"Nutr. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1083\/jcb.201306136","article-title":"Cell biology in neuroscience: Death of developing neurons: New insights and implications for connectivity","volume":"203","author":"Dekkers","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.braindev.2015.10.008","article-title":"Activity-dependent synaptic plasticity modulates the critical phase of brain development","volume":"38","author":"Chaudhury","year":"2016","journal-title":"Brain Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.nbd.2015.07.007","article-title":"Cellular and molecular introduction to brain development","volume":"92","author":"Jiang","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3109\/00365513.2012.657230","article-title":"Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation?","volume":"72","author":"Breimer","year":"2012","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1210\/er.2009-0039","article-title":"Child health, developmental plasticity, and epigenetic programming","volume":"32","author":"Hochberg","year":"2011","journal-title":"Endocr. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2353\/ajpath.2007.060339","article-title":"Gestational vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats","volume":"170","author":"Blaise","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1073\/pnas.0809217106","article-title":"Vitamin B deficiency causes neural cell loss and cognitive impairment in the developing rat","volume":"106","author":"Daval","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1515\/CCLM.2006.178","article-title":"A robust liquid chromatography tandem mass spectrometry method for total plasma homocysteine determination in clinical practice","volume":"44","author":"Ducros","year":"2006","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1515\/cclm.2002.193","article-title":"Hyperhomocysteinemia is related to a decreased blood level of vitamin B12 in the second and third trimester of normal pregnancy","volume":"40","author":"Chery","year":"2002","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1242\/dev.120.5.1109","article-title":"The role of Pax-1 in axial skeleton development","volume":"120","author":"Wallin","year":"1994","journal-title":"Development"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/nmeth843","article-title":"In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes","volume":"3","author":"Kloosterman","year":"2006","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/4\/973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:34:19Z","timestamp":1760186059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/4\/973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,23]]},"references-count":52,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["ijms20040973"],"URL":"https:\/\/doi.org\/10.3390\/ijms20040973","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,23]]}}}