{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:40:42Z","timestamp":1791765642410,"version":"4.3.4"},"reference-count":248,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T00:00:00Z","timestamp":1699228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA121298"],"award-info":[{"award-number":["CA121298"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. The molecular mechanisms underlying these effects were examined, including altered one-carbon metabolism, the accumulation of unmetabolized folic acid, vitamin-B12-dependent mechanisms, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, differences in the effects and mechanisms mediated by folic acid compared with natural folate are highlighted. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.<\/jats:p>","DOI":"10.3390\/nu15214699","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T08:15:56Z","timestamp":1699258556000},"page":"4699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3327-0122","authenticated-orcid":false,"given":"Ali M.","family":"Fardous","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad R.","family":"Heydari","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA"},{"name":"Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3945\/ajcn.2009.28427","article-title":"Total folate and folic acid intake from foods and dietary supplements in the United States: 2003\u20132006","volume":"91","author":"Bailey","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E100","DOI":"10.1503\/cmaj.100568","article-title":"Folate status of the population in the Canadian Health Measures Survey","volume":"183","author":"Colapinto","year":"2011","journal-title":"Can. Med. Assoc. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1139\/apnm-2015-0191","article-title":"Prevalence and correlates of high red blood cell folate concentrations in the Canadian population using 3 proposed cut-offs","volume":"40","author":"Colapinto","year":"2015","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1093\/ajcn\/nqaa259","article-title":"Knowledge gaps in understanding the metabolic and clinical effects of excess folates\/folic acid: A summary, and perspectives, from an NIH workshop","volume":"112","author":"Maruvada","year":"2020","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/nyas.13499","article-title":"Safety of folic acid","volume":"1414","author":"Field","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.biochi.2016.04.010","article-title":"Excessive folic acid intake and relation to adverse health outcome","volume":"126","author":"Selhub","year":"2016","journal-title":"Biochimie"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101617","DOI":"10.1016\/j.pmedr.2021.101617","article-title":"Maternal folic acid and multivitamin supplementation: International clinical evidence with considerations for the prevention of folate-sensitive birth defects","volume":"24","author":"Wilson","year":"2021","journal-title":"Prev. Med. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1007\/s00394-015-0916-z","article-title":"Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: A randomized trial","volume":"55","author":"Obeid","year":"2016","journal-title":"Eur. J. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3945\/jn.114.201210","article-title":"Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults","volume":"145","author":"Pfeiffer","year":"2015","journal-title":"J. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1093\/ajcn\/86.3.718","article-title":"Trends in blood folate and vitamin B-12 concentrations in the United States, 1988\u20132004","volume":"86","author":"Pfeiffer","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"886","DOI":"10.3945\/jn.111.156919","article-title":"Estimation of Trends in Serum and RBC Folate in the U.S. Population from Pre- to Postfortification Using Assay-Adjusted Data from the NHANES 1988\u20132010","volume":"142","author":"Pfeiffer","year":"2012","journal-title":"J. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e84","DOI":"10.1093\/pubmed\/fdv087","article-title":"Systematic review of adverse health outcomes associated with high serum or red blood cell folate concentrations","volume":"38","author":"Colapinto","year":"2016","journal-title":"J. Public Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1093\/jn\/nxz278","article-title":"Demographic, Physiologic, and Lifestyle Characteristics Observed with Serum Total Folate Differ among Folate Forms: Cross-Sectional Data from Fasting Samples in the NHANES 2011\u20132016","volume":"150","author":"Fazili","year":"2019","journal-title":"J. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/jn\/nxz232","article-title":"Maternal and Cord Blood Folate Concentrations Are Inversely Associated with Fetal DNA Hydroxymethylation, but Not DNA Methylation, in a Cohort of Pregnant Canadian Women","volume":"150","author":"Plumptre","year":"2020","journal-title":"J. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"848","DOI":"10.3945\/ajcn.115.110783","article-title":"High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood","volume":"102","author":"Plumptre","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/mcn.12038","article-title":"Use of micronutrient supplements among pregnant women in Alberta: Results from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort","volume":"11","author":"Field","year":"2015","journal-title":"Matern. Child Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"370","DOI":"10.3390\/nu3030370","article-title":"Folic acid food fortification-its history, effect, concerns, and future directions","volume":"3","author":"Crider","year":"2011","journal-title":"Nutrients"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Shulpekova, Y., Nechaev, V., Kardasheva, S., Sedova, A., Kurbatova, A., Bueverova, E., Kopylov, A., Malsagova, K., Dlamini, J.C., and Ivashkin, V. (2021). The Concept of Folic Acid in Health and Disease. Molecules, 26.","DOI":"10.3390\/molecules26123731"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Menezo, Y., Elder, K., Clement, A., and Clement, P. (2022). Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles. Biomolecules, 12.","DOI":"10.3390\/biom12020197"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fardous, A.M., Beydoun, S., James, A.A., Ma, H., Cabelof, D.C., Unnikrishnan, A., and Heydari, A.R. (2022). The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis. Nutrients, 14.","DOI":"10.3390\/nu14010016"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Alnabbat, K.I., Fardous, A.M., Shahab, A., James, A.A., Bahry, M.R., and Heydari, A.R. (2022). High Dietary Folic Acid Intake Is Associated with Genomic Instability in Peripheral Lymphocytes of Healthy Adults. Nutrients, 14.","DOI":"10.20944\/preprints202208.0429.v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"838S","DOI":"10.1093\/jn\/127.5.838S","article-title":"Components of the AIN-93 Diets as Improvements in the AIN-76A Diet","volume":"127","author":"Reeves","year":"1997","journal-title":"J. Nutr."},{"key":"ref_23","unstructured":"Council, N.R. (1995). Nutrient Requirements of Laboratory Animals, The National Academies Press. [4th Revised ed.]."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1373\/clinchem.2006.078451","article-title":"Comparison of Serum Folate Species Analyzed by LC-MS\/MS with Total Folate Measured by Microbiologic Assay and Bio-Rad Radioassay","volume":"53","author":"Fazili","year":"2007","journal-title":"Clin. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.cmet.2020.12.002","article-title":"Tumor Reliance on Cytosolic versus Mitochondrial One-Carbon Flux Depends on Folate Availability","volume":"33","author":"Lee","year":"2021","journal-title":"Cell Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12071","DOI":"10.1073\/pnas.2003475117","article-title":"Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease","volume":"117","author":"Outtrim","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.pbj.2017.05.006","article-title":"The impact of folic acid supplementation on gestational and long term health: Critical temporal windows, benefits and risks","volume":"2","author":"Silva","year":"2017","journal-title":"Porto Biomed. J."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ledowsky, C., Mahimbo, A., Scarf, V., and Steel, A. (2022). Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review. Nutrients, 14.","DOI":"10.3390\/nu14132715"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"799","DOI":"10.2105\/AJPH.2018.304355","article-title":"Folate Nutrition Status in Mothers of the Boston Birth Cohort, Sample of a US Urban Low-Income Population","volume":"108","author":"Cheng","year":"2018","journal-title":"Am. J. Public Health"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.3945\/ajcn.116.137968","article-title":"Total folate and unmetabolized folic acid in the breast milk of a cross-section of Canadian women","volume":"105","author":"Page","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1089\/dna.2010.1082","article-title":"Significant Evidence of Association Between Polymorphisms in ZNF533, Environmental Factors, and Nonsyndromic Orofacial Clefts in the Western Han Chinese Population","volume":"30","author":"Wu","year":"2010","journal-title":"DNA Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1136\/bmj.39079.618287.0B","article-title":"Folic acid supplements and risk of facial clefts: National population based case-control study","volume":"334","author":"Wilcox","year":"2007","journal-title":"BMJ"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10654-006-9099-5","article-title":"Oral clefts and life style factors\u2014A case-cohort study based on prospective Danish data","volume":"22","author":"Bille","year":"2007","journal-title":"Eur. J. Epidemiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/j.1601-0825.2011.01810.x","article-title":"Maternal malnutrition, environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts","volume":"17","author":"Jia","year":"2011","journal-title":"Oral. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"590","DOI":"10.3390\/ijerph10020590","article-title":"High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth","volume":"10","author":"Wehby","year":"2013","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1597\/06-150.1","article-title":"Folate and Clefts of the Lip and Palate\u2014A U.K.-Based Case-Control Study: Part I: Dietary and Supplemental Folate","volume":"45","author":"Little","year":"2008","journal-title":"Cleft Palate-Craniofac. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s10654-013-9849-0","article-title":"Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: A population based case-control study","volume":"28","author":"Rozendaal","year":"2013","journal-title":"Eur. J. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1093\/ajcn\/nqaa407","article-title":"Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT)","volume":"113","author":"Murphy","year":"2021","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_39","first-page":"CD006896","article-title":"Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes","volume":"3","author":"Lassi","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1017\/S1368980012000067","article-title":"Effect of high doses of folic acid supplementation in early pregnancy on child neurodevelopment at 18 months of age: The mother-child cohort \u2018Rhea\u2019 study in Crete, Greece","volume":"15","author":"Chatzi","year":"2012","journal-title":"Public Health Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1007\/s00246-013-0749-6","article-title":"Risk Factors in the Origin of Congenital Left-Ventricular Outflow-Tract Obstruction Defects of the Heart: A Population-Based Case\u2013Control Study","volume":"35","author":"Vereczkey","year":"2014","journal-title":"Pediatr. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/bdra.23124","article-title":"Isolated atrioventricular canal defects: Birth outcomes and risk factors: A population-based hungarian case\u2013control study, 1980\u20131996","volume":"97","author":"Vereczkey","year":"2013","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1017\/S0007114510005143","article-title":"Periconceptional folic acid supplementation and anthropometric measures at birth in a cohort of pregnant women in Valencia, Spain","volume":"105","author":"Rebagliato","year":"2011","journal-title":"Br. J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1097\/scs.0b013e31815c8a87","article-title":"Periconceptional Folic Acid Use and the Prevalence of Positional Plagiocephaly","volume":"19","author":"Michels","year":"2008","journal-title":"J. Craniofac. Surg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1002\/fsn3.1235","article-title":"Association of maternal folate status in the second trimester of pregnancy with the risk of gestational diabetes mellitus","volume":"7","author":"Xie","year":"2019","journal-title":"Food Sci. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.2337\/dc15-2389","article-title":"Folic Acid Supplement Intake in Early Pregnancy Increases Risk of Gestational Diabetes Mellitus: Evidence from a Prospective Cohort Study","volume":"39","author":"Zhu","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Cheng, G., Sha, T., Gao, X., He, Q., Wu, X., Tian, Q., Yang, F., Tang, C., Wu, X., and Xie, Q. (2019). The Associations between the Duration of Folic Acid Supplementation, Gestational Diabetes Mellitus, and Adverse Birth Outcomes based on a Birth Cohort. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16224511"},{"key":"ref_48","first-page":"321","article-title":"Duration of periconceptional folic acid supplementation and risk of gestational diabetes mellitus","volume":"28","author":"Huang","year":"2019","journal-title":"Asia Pac. J. Clin. Nutr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1002\/bdr2.1579","article-title":"Periconceptional folic acid and risk for neural tube defects among higher risk pregnancies","volume":"111","author":"Petersen","year":"2019","journal-title":"Birth Defects Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"217","DOI":"10.2337\/dc20-1607","article-title":"Association of Maternal Folate and Vitamin B12 in Early Pregnancy With Gestational Diabetes Mellitus: A Prospective Cohort Study","volume":"44","author":"Chen","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1111\/1753-0407.12899","article-title":"Joint effects of folate and vitamin B12 imbalance with maternal characteristics on gestational diabetes mellitus","volume":"11","author":"Li","year":"2019","journal-title":"J. Diabetes"},{"key":"ref_52","first-page":"1910","article-title":"Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: A review of existing evidence in humans with specific focus on one-carbon metabolism","volume":"47","author":"James","year":"2018","journal-title":"Int. J. Epidemiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"R95","DOI":"10.1093\/hmg\/ddl095","article-title":"The emerging science of epigenomics","volume":"15","author":"Callinan","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra0708473","article-title":"Effect of in utero and early-life conditions on adult health and disease","volume":"359","author":"Gluckman","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1093\/aje\/kwp315","article-title":"Effect of Supplemental Folic Acid in Pregnancy on Childhood Asthma: A Prospective Birth Cohort Study","volume":"170","author":"Whitrow","year":"2009","journal-title":"Am. J. Epidemiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1017\/S0007114512003765","article-title":"Folic acid supplementation in pregnancy: Are there devils in the detail?","volume":"108","author":"Burdge","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"94","DOI":"10.3945\/ajcn.112.042572","article-title":"Folate in pregnancy and imprinted gene and repeat element methylation in the offspring","volume":"97","author":"Haggarty","year":"2012","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Hoyo, C., Murtha, A.P., Schildkraut, J.M., Forman, M.R., Calingaert, B., Demark-Wahnefried, W., Kurtzberg, J., Jirtle, R.L., and Murphy, S.K. (2011). Folic acid supplementation before and during pregnancy in the Newborn Epigenetics STudy (NEST). BMC Public Health, 11.","DOI":"10.1186\/1471-2458-11-46"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"928","DOI":"10.4161\/epi.6.7.16263","article-title":"Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy","volume":"6","author":"Hoyo","year":"2011","journal-title":"Epigenetics"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s00125-013-3086-7","article-title":"Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children","volume":"57","author":"Krishnaveni","year":"2014","journal-title":"Diabetologia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ijo.2015.189","article-title":"Maternal folate status and obesity\/insulin resistance in the offspring: A systematic review","volume":"40","author":"Xie","year":"2016","journal-title":"Int. J. Obes."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"dvy007","DOI":"10.1093\/eep\/dvy007","article-title":"POHaD: Why we should study future fathers","volume":"4","author":"Soubry","year":"2018","journal-title":"Environ. Epigenet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"dvaa018","DOI":"10.1093\/eep\/dvaa018","article-title":"Impact of mothers\u2019 early life exposure to low or high folate on progeny outcome and DNA methylation patterns","volume":"6","author":"Ly","year":"2020","journal-title":"Environ. Epigenet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1093\/molehr\/gax029","article-title":"Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation","volume":"23","author":"Ly","year":"2017","journal-title":"Mol. Hum. Reprod."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1093\/hmg\/ddy021","article-title":"Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation","volume":"27","author":"Aarabi","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e03597","DOI":"10.1016\/j.heliyon.2020.e03597","article-title":"Excessive folic acid supplementation in pregnant mice impairs insulin secretion and induces the expression of genes associated with fatty liver in their offspring","volume":"6","author":"Kintaka","year":"2020","journal-title":"Heliyon"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/mnfr.201200186","article-title":"Effect of maternal and postweaning folic acid supplementation on global and gene-specific DNA methylation in the liver of the rat offspring","volume":"57","author":"Sie","year":"2013","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/bdra.23092","article-title":"Moderately high intake of folic acid has a negative impact on mouse embryonic development","volume":"97","author":"Mikael","year":"2013","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/bdra.20631","article-title":"Gene expression profiling in the fetal cardiac tissue after folate and low-dose trichloroethylene exposure","volume":"88","author":"Caldwell","year":"2010","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Barua, S., Chadman, K.K., Kuizon, S., Buenaventura, D., Stapley, N.W., Ruocco, F., Begum, U., Guariglia, S.R., Brown, W.T., and Junaid, M.A. (2014). Increasing maternal or post-weaning folic acid alters gene expression and moderately changes behavior in the offspring. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101674"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1093\/jn\/nxaa419","article-title":"Choline and Folic Acid in Diets Consumed during Pregnancy Interact to Program Food Intake and Metabolic Regulation of Male Wistar Rat Offspring","volume":"151","author":"Hammoud","year":"2021","journal-title":"J. Nutr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"710","DOI":"10.4161\/epi.24948","article-title":"High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring","volume":"8","author":"Cho","year":"2013","journal-title":"Epigenetics"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7216","DOI":"10.1039\/C9FO01807G","article-title":"Perigestational high folic acid: Impact on offspring\u2019s peripheral metabolic response","volume":"10","author":"Tojal","year":"2019","journal-title":"Food Funct."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1530\/JOE-14-0448","article-title":"Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal life","volume":"224","author":"Keating","year":"2015","journal-title":"J. Endocrinol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6298","DOI":"10.3390\/ijms15046298","article-title":"Maternal high folic acid supplement promotes glucose intolerance and insulin resistance in male mouse offspring fed a high-fat diet","volume":"15","author":"Huang","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1080\/19390211.2018.1426076","article-title":"High-Dose Perinatal Folic-Acid Supplementation Alters Insulin Sensitivity in Sprague-Dawley Rats and Diminishes the Expression of Adiponectin","volume":"16","author":"Morakinyo","year":"2019","journal-title":"J. Diet. Suppl."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"863","DOI":"10.2217\/epi-2016-0003","article-title":"The interplay between DNA methylation, folate and neurocognitive development","volume":"8","author":"Irwin","year":"2016","journal-title":"Epigenomics"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1007\/s43032-020-00161-2","article-title":"Maternal Folic Acid Supplementation Mediates Offspring Health via DNA Methylation","volume":"27","author":"Liu","year":"2020","journal-title":"Reprod. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"McNulty, H., Rollins, M., Cassidy, T., Caffrey, A., Marshall, B., Dornan, J., McLaughlin, M., McNulty, B.A., Ward, M., and Strain, J.J. (2019). Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: A follow-up study from a randomized controlled trial (FASSTT Offspring Trial). BMC Med., 17.","DOI":"10.1186\/s12916-019-1432-4"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Caffrey, A., McNulty, H., Rollins, M., Prasad, G., Gaur, P., Talcott, J.B., Witton, C., Cassidy, T., Marshall, B., and Dornan, J. (2021). Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: An 11-year follow-up from a randomised controlled trial. BMC Med., 19.","DOI":"10.1186\/s12916-021-01914-9"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"878","DOI":"10.3945\/ajcn.117.152769","article-title":"Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4\u20135 y of age: The prospective birth cohort Infancia y Medio Ambiente (INMA) study","volume":"106","author":"Ibarluzea","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Compa\u00f1 Gabucio, L.M., Garc\u00eda de la Hera, M., Torres Collado, L., Fern\u00e1ndez-Somoano, A., Tard\u00f3n, A., Guxens, M., Vrijheid, M., Rebagliato, M., Murcia, M., and Ibarluzea, J. (2021). The Use of Lower or Higher Than Recommended Doses of Folic Acid Supplements during Pregnancy Is Associated with Child Attentional Dysfunction at 4\u20135 Years of Age in the INMA Project. Nutrients, 13.","DOI":"10.3390\/nu13020327"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13229-020-0315-z","article-title":"Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: A study of 62 serum biomarkers","volume":"11","author":"Egorova","year":"2020","journal-title":"Mol. Autism"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e142611","DOI":"10.1001\/jamapediatrics.2014.2611","article-title":"Folic Acid Supplements During Pregnancy and Child Psychomotor Development After the First Year of Life","volume":"168","author":"Julvez","year":"2014","journal-title":"JAMA Pediatr."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Wiens, D., and Desoto, M. (2017). Is High Folic Acid Intake a Risk Factor for Autism?\u2014A Review. Brain Sci., 7.","DOI":"10.3390\/brainsci7110149"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1093\/ajcn\/nqx069","article-title":"Gene-specific DNA methylation in newborns in response to folic acid supplementation during the second and third trimesters of pregnancy: Epigenetic analysis from a randomized controlled trial","volume":"107","author":"Caffrey","year":"2018","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/ppe.12414","article-title":"Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring","volume":"32","author":"Raghavan","year":"2018","journal-title":"Paediatr. Perinat. Epidemiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1007\/s10803-021-04951-8","article-title":"Prenatal Folic Acid Supplements and Offspring\u2019s Autism Spectrum Disorder: A Meta-analysis and Meta-regression","volume":"52","author":"Liu","year":"2022","journal-title":"J. Autism Dev. Disord."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1093\/ajcn\/nqaa208","article-title":"A prospective birth cohort study on cord blood folate subtypes and risk of autism spectrum disorder","volume":"112","author":"Raghavan","year":"2020","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Yang, X., Sun, W., Wu, Q., Lin, H., Lu, Z., Shen, X., Chen, Y., Zhou, Y., Huang, L., and Wu, F. (2021). Excess Folic Acid Supplementation before and during Pregnancy and Lactation Alters Behaviors and Brain Gene Expression in Female Mouse Offspring. Nutrients, 14.","DOI":"10.3390\/nu14010066"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3389\/fnins.2019.00313","article-title":"Excess Folic Acid Supplementation Before and During Pregnancy and Lactation Activates Fos Gene Expression and Alters Behaviors in Male Mouse Offspring","volume":"13","author":"Chu","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1139\/apnm-2015-0503","article-title":"Maternal and postweaning folic acid supplementation interact to influence body weight, insulin resistance, and food intake regulatory gene expression in rat offspring in a sex-specific manner","volume":"41","author":"Huot","year":"2016","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_93","first-page":"635","article-title":"Deficient or Excess Folic Acid Supply during Pregnancy Alter Cortical Neurodevelopment in Mouse Offspring","volume":"31","author":"Panoutsopoulos","year":"2020","journal-title":"Cereb. Cortex"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Cos\u00edn-Tom\u00e1s, M., Luan, Y., Leclerc, D., Malysheva, O.V., Lauzon, N., Bahous, R.H., Christensen, K.E., Caudill, M.A., and Rozen, R. (2020). Moderate Folic Acid Supplementation in Pregnant Mice Results in Behavioral Alterations in Offspring with Sex-Specific Changes in Methyl Metabolism. Nutrients, 12.","DOI":"10.3390\/nu12061716"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1038\/s41598-017-03158-1","article-title":"High-dose maternal folic acid supplementation before conception impairs reversal learning in offspring mice","volume":"7","author":"Henzel","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1038\/srep01465","article-title":"High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring","volume":"3","author":"Girotto","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/bdra.20754","article-title":"High intake of folic acid disrupts embryonic development in mice","volume":"91","author":"Pickell","year":"2011","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.brainresbull.2021.11.008","article-title":"Excess folic acid supplementation before and during pregnancy and lactation activates \u03b2-catenin in the brain of male mouse offspring","volume":"178","author":"Wu","year":"2022","journal-title":"Brain Res. Bull."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5240127","DOI":"10.1155\/2016\/5240127","article-title":"Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways","volume":"2016","author":"Cianciulli","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Lisboa, J.V.C., Ribeiro, M.R., Luna, R.C.P., Lima, R.P.A., Nascimento, R., Monteiro, M., Lima, K.Q.F., Fechine, C., Oliveira, N.F.P., and Persuhn, D.C. (2020). Food Intervention with Folate Reduces TNF-\u03b1 and Interleukin Levels in Overweight and Obese Women with the MTHFR C677T Polymorphism: A Randomized Trial. Nutrients, 12.","DOI":"10.3390\/nu12020361"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"100104","DOI":"10.1016\/j.jnim.2019.100104","article-title":"Folate and Inflammation\u2013links between folate and features of inflammatory conditions","volume":"18","author":"Jones","year":"2019","journal-title":"J. Nutr. Intermed. Metab."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Pan, Y., Liu, Y., Guo, H., Jabir, M.S., Liu, X., Cui, W., and Li, D. (2017). Associations between Folate and Vitamin B12 Levels and Inflammatory Bowel Disease: A Meta-Analysis. Nutrients, 9.","DOI":"10.3390\/nu9040382"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.autrev.2007.03.008","article-title":"Hyperhomocysteinemia, inflammation and autoimmunity","volume":"6","author":"Lazzerini","year":"2007","journal-title":"Autoimmun. Rev."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/jn\/136.1.189","article-title":"Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women","volume":"136","author":"Troen","year":"2006","journal-title":"J. Nutr."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.3945\/ajcn.113.065623","article-title":"Prenatal folic acid and risk of asthma in children: A systematic review and meta-analysis","volume":"98","author":"Crider","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1002\/pds.3652","article-title":"Maternal high-dose folic acid during pregnancy and asthma medication in the offspring","volume":"23","author":"Hoek","year":"2014","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1097\/EDE.0000000000000380","article-title":"Maternal Folic Acid Supplementation During Pregnancy and Early Childhood Asthma","volume":"26","author":"Veeranki","year":"2015","journal-title":"Epidemiology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.fct.2014.11.006","article-title":"High dose of maternal folic acid supplementation is associated to infant asthma","volume":"75","author":"Yang","year":"2015","journal-title":"Food Chem. Toxicol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Chu, S., and Zhang, J. (2022). Periconceptional folic acid supplementation is a risk factor for childhood asthma: A case-control study. BMC Pregnancy Childbirth, 22.","DOI":"10.1186\/s12884-022-04567-5"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e135","DOI":"10.1542\/peds.2010-1690","article-title":"Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood","volume":"128","author":"Magdelijns","year":"2011","journal-title":"Pediatrics"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"72.e1","DOI":"10.1016\/j.ajog.2011.07.033","article-title":"Folic acid supplementation in early pregnancy and asthma in children aged 6 years","volume":"206","author":"Martinussen","year":"2012","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1177\/0009922817729482","article-title":"Folic Acid in Pregnancy and Childhood Asthma: A US Cohort","volume":"57","author":"Trivedi","year":"2018","journal-title":"Clin. Pediatr."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s10995-018-2610-2","article-title":"Association between Maternal 2nd Trimester Plasma Folate Levels and Infant Bronchiolitis","volume":"23","author":"Vereen","year":"2019","journal-title":"Matern. Child. Health J."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1093\/aje\/kwu019","article-title":"Association of Folic Acid Supplementation during Pregnancy and Infant Bronchiolitis","volume":"179","author":"Veeranki","year":"2014","journal-title":"Am. J. Epidemiol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1136\/adc.2008.142448","article-title":"Folic acid supplements in pregnancy and early childhood respiratory health","volume":"94","author":"London","year":"2009","journal-title":"Arch. Dis. Child."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/pai.12834","article-title":"Association of prenatal folate status with early childhood wheeze and atopic dermatitis","volume":"29","author":"Roy","year":"2018","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"615406","DOI":"10.3389\/fped.2020.615406","article-title":"Effect of Folic Acid Intake on Infant and Child Allergic Diseases: Systematic Review and Meta-Analysis","volume":"8","author":"Chen","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"731","DOI":"10.3945\/jn.111.154948","article-title":"High Circulating Folate and Vitamin B-12 Concentrations in Women During Pregnancy Are Associated with Increased Prevalence of Atopic Dermatitis in Their Offspring","volume":"142","author":"Timmermans","year":"2012","journal-title":"J. Nutr."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1398-9995.2011.02714.x","article-title":"The relationship between maternal folate status in pregnancy, cord blood folate levels, and allergic outcomes in early childhood","volume":"67","author":"Dunstan","year":"2012","journal-title":"Allergy"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"6505","DOI":"10.4049\/jimmunol.1002805","article-title":"An Endogenously Anti-Inflammatory Role for Methylation in Mucosal Inflammation Identified through Metabolite Profiling","volume":"186","author":"Kominsky","year":"2011","journal-title":"J. Immunol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1093\/hmg\/ddr044","article-title":"Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes","volume":"20","author":"Schaible","year":"2011","journal-title":"Human. Mol. Genet."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Mir, S.A., Nagy-Szakal, D., Dowd, S.E., Szigeti, R.G., Smith, C.W., and Kellermayer, R. (2013). Prenatal Methyl-Donor Supplementation Augments Colitis in Young Adult Mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073162"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2014.09.019","article-title":"A high multivitamin diet fed to Wistar rat dams during pregnancy increases maternal weight gain later in life and alters homeostatic, hedonic and peripheral regulatory systems of energy balance","volume":"278","author":"Pannia","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.3390\/cimb44040097","article-title":"Excessive Folic Acid Mimics Folate Deficiency in Human Lymphocytes","volume":"44","author":"Alnabbat","year":"2022","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1158\/1940-6207.CAPR-11-0544","article-title":"Dietary methyl donor depletion protects against intestinal tumorigenesis in Apc(Min\/+) mice","volume":"5","author":"Kadaveru","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1158\/1940-6207.CAPR-10-0143","article-title":"Altered folate availability modifies the molecular environment of the human colorectum: Implications for colorectal carcinogenesis","volume":"4","author":"Protiva","year":"2011","journal-title":"Cancer Prev. Res."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Kelly, K.B., Kennelly, J.P., Ordonez, M., Nelson, R., Leonard, K., Stabler, S., Gomez-Munoz, A., Field, C.J., and Jacobs, R.L. (2016). Excess Folic Acid Increases Lipid Storage, Weight Gain, and Adipose Tissue Inflammation in High Fat Diet-Fed Rats. Nutrients, 8.","DOI":"10.3390\/nu8100594"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Asbaghi, O., Ashtary-Larky, D., Bagheri, R., Moosavian, S.P., Nazarian, B., Afrisham, R., Kelishadi, M.R., Wong, A., Dutheil, F., and Suzuki, K. (2021). Effects of Folic Acid Supplementation on Inflammatory Markers: A Grade-Assessed Systematic Review and Dose\u2013Response Meta-Analysis of Randomized Controlled Trials. Nutrients, 13.","DOI":"10.3390\/nu13072327"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1096\/fj.03-0382fje","article-title":"Folate deficiency and ionizing radiation cause DNA breaks in primary human lymphocytes: A comparison","volume":"18","author":"Courtemanche","year":"2004","journal-title":"FASEB J."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"E4095","DOI":"10.1073\/pnas.1619582114","article-title":"Folate rescues vitamin B(12) depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability","volume":"114","author":"Palmer","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1158\/1055-9965.EPI-07-0329","article-title":"A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: A hypothesis","volume":"16","author":"Mason","year":"2007","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/ajcn\/nqab035","article-title":"Association of folate intake and colorectal cancer risk in the postfortification era in US women","volume":"114","author":"Wang","year":"2021","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1001\/jama.297.21.2351","article-title":"Folic Acid for the Prevention of Colorectal Adenomas","volume":"297","author":"Cole","year":"2007","journal-title":"JAMA"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1093\/jnci\/djp019","article-title":"Folic acid and risk of prostate cancer: Results from a randomized clinical trial","volume":"101","author":"Figueiredo","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"682.e21","DOI":"10.1016\/j.urolonc.2020.04.003","article-title":"Rise in serum folate after androgen deprivation associated with worse prostate cancer-specific survival","volume":"38","author":"Liss","year":"2020","journal-title":"Urol. Oncol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/CEJ.0000000000000744","article-title":"Folate intake and risk of colorectal cancer: A systematic review and up-to-date meta-analysis of prospective studies","volume":"32","author":"Fu","year":"2023","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Zhang, Y.F., Shi, W.W., Gao, H.F., Zhou, L., Hou, A.J., and Zhou, Y.H. (2014). Folate intake and the risk of breast cancer: A dose-response meta-analysis of prospective studies. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100044"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1038\/bjc.2014.155","article-title":"Higher dietary folate intake reduces the breast cancer risk: A systematic review and meta-analysis","volume":"110","author":"Chen","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"e469","DOI":"10.1016\/j.clbc.2020.02.012","article-title":"Association Between One-carbon Metabolism-related Vitamins and Risk of Breast Cancer: A Systematic Review and Meta-analysis of Prospective Studies","volume":"20","author":"Zeng","year":"2020","journal-title":"Clin. Breast Cancer"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1038\/s41430-019-0394-0","article-title":"Folate intake and the risk of breast cancer: An up-to-date meta-analysis of prospective studies","volume":"73","author":"Zeng","year":"2019","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s13668-018-0237-y","article-title":"Folate and Its Impact on Cancer Risk","volume":"7","author":"Pieroth","year":"2018","journal-title":"Curr. Nutr. Rep."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1001\/jama.2009.1622","article-title":"Cancer incidence and mortality after treatment with folic acid and vitamin B12","volume":"302","author":"Ebbing","year":"2009","journal-title":"JAMA"},{"key":"ref_143","first-page":"3191","article-title":"Chemopreventive effects of dietary folate on intestinal polyps in Apc+\/\u2212 Msh2\u2212\/\u2212 Mice","volume":"60","author":"Song","year":"2000","journal-title":"Cancer Res."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1093\/carcin\/21.12.2261","article-title":"Folate deficiency reduces the development of colorectal cancer in rats","volume":"21","author":"Young","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1093\/carcin\/bgp152","article-title":"Effect of folic acid supplementation on the progression of colorectal aberrant crypt foci","volume":"30","author":"Lindzon","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1002\/ijc.29044","article-title":"Folate intake and the risk of oral cavity and pharyngeal cancer: A pooled analysis within the International Head and Neck Cancer Epidemiology Consortium","volume":"136","author":"Galeone","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1111\/jgh.12446","article-title":"Folate intake and the risk of upper gastrointestinal cancers: A systematic review and meta-analysis","volume":"29","author":"Tio","year":"2014","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1007\/s10620-020-06525-7","article-title":"Folate Intake and Risk of Pancreatic Cancer: A Systematic Review and Updated Meta-Analysis of Epidemiological Studies","volume":"66","author":"Fu","year":"2021","journal-title":"Dig. Dis. Sci."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1080\/01635581.2021.1973518","article-title":"Folate Intake and Risk of Urothelial Carcinoma: A Systematic Review and Meta-Analysis of Epidemiological Studies","volume":"74","author":"Gu","year":"2022","journal-title":"Nutr. Cancer"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3109\/09637486.2013.866641","article-title":"Folate intake and risk of bladder cancer: A meta-analysis of epidemiological studies","volume":"65","author":"He","year":"2014","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Zhang, Y.F., Zhou, L., Zhang, H.W., Hou, A.J., Gao, H.F., and Zhou, Y.H. (2014). Association between folate intake and the risk of lung cancer: A dose-response meta-analysis of prospective studies. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093465"},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Stanis\u0142awska-Sachadyn, A., Borzyszkowska, J., Krzemi\u0144ski, M., Janowicz, A., Dziadziuszko, R., Jassem, J., Rzyman, W., and Limon, J. (2019). Folate\/homocysteine metabolism and lung cancer risk among smokers. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214462"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"6547","DOI":"10.1007\/s11033-013-2686-0","article-title":"Folate intake and MTHFR polymorphism C677T is not associated with ovarian cancer risk: Evidence from the meta-analysis","volume":"40","author":"Li","year":"2013","journal-title":"Mol. Biol. Rep."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"85176","DOI":"10.18632\/oncotarget.13211","article-title":"Folate intake and the risk of endometrial cancer: A meta-analysis","volume":"7","author":"Du","year":"2016","journal-title":"Oncotarget"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"e000653","DOI":"10.1136\/bmjopen-2011-000653","article-title":"Cancer risk with folic acid supplements: A systematic review and meta-analysis","volume":"2","author":"Wien","year":"2012","journal-title":"BMJ Open"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1158\/1055-9965.EPI-17-1198","article-title":"Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial","volume":"28","author":"Swart","year":"2019","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"105949","DOI":"10.1155\/2012\/105949","article-title":"Folate and colorectal cancer in rodents: A model of DNA repair deficiency","volume":"2012","author":"Rosati","year":"2012","journal-title":"J. Oncol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/bjc.2017.11","article-title":"High folic acid diet enhances tumour growth in PyMT-induced breast cancer","volume":"116","author":"Hansen","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1158\/0008-5472.CAN-10-2379","article-title":"Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring","volume":"71","author":"Ly","year":"2011","journal-title":"Cancer Res."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Deghan Manshadi, S., Ishiguro, L., Sohn, K.-J., Medline, A., Renlund, R., Croxford, R., and Kim, Y.-I. (2014). Folic Acid Supplementation Promotes Mammary Tumor Progression in a Rat Model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0084635"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.urology.2013.07.012","article-title":"Opposing roles of folate in prostate cancer","volume":"82","author":"Rycyna","year":"2013","journal-title":"Urology"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Savini, C., Yang, R., Savelyeva, L., G\u00f6ckel-Krzikalla, E., Hotz-Wagenblatt, A., Westermann, F., and R\u00f6sl, F. (2019). Folate Repletion after Deficiency Induces Irreversible Genomic and Transcriptional Changes in Human Papillomavirus Type 16 (HPV16)-Immortalized Human Keratinocytes. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051100"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1093\/jn\/nxx060","article-title":"Folate Deficiency Facilitates Genomic Integration of Human Papillomavirus Type 16 DNA In Vivo in a Novel Mouse Model for Rapid Oncogenic Transformation of Human Keratinocytes","volume":"148","author":"Xiao","year":"2018","journal-title":"J. Nutr."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"16617","DOI":"10.1038\/s41598-022-21084-9","article-title":"Folic acid depletion as well as oversupplementation helps in the progression of hepatocarcinogenesis in HepG2 cells","volume":"12","author":"Sharma","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41430-022-01206-2","article-title":"Associations of dietary folate, vitamin B6 and B12 intake with cardiovascular outcomes in 115664 participants: A large UK population-based cohort","volume":"77","author":"Zhang","year":"2022","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Bo, Y., Xu, H., Zhang, H., Zhang, J., Wan, Z., Zhao, X., and Yu, Z. (2022). Intakes of Folate, Vitamin B6, and Vitamin B12 in Relation to All-Cause and Cause-Specific Mortality: A National Population-Based Cohort. Nutrients, 14.","DOI":"10.3390\/nu14112253"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"e003768","DOI":"10.1161\/JAHA.116.003768","article-title":"Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials","volume":"5","author":"Li","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1056\/NEJMoa055227","article-title":"Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction","volume":"354","author":"Ueland","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"4255","DOI":"10.1016\/j.clnu.2021.01.025","article-title":"Relationship of several serum folate forms with the risk of mortality: A prospective cohort study","volume":"40","author":"Liu","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ijcard.2016.06.024","article-title":"Serum folate concentrations and all-cause, cardiovascular disease and cancer mortality: A cohort study based on 1999\u20132010 National Health and Nutrition Examination Survey (NHANES)","volume":"219","author":"Peng","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.annepidem.2018.02.001","article-title":"The effects of folate supplementation on glucose metabolism and risk of type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials","volume":"28","author":"Zhao","year":"2018","journal-title":"Ann. Epidemiol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.ejim.2012.07.004","article-title":"Efficacy of folic acid supplementation in cardiovascular disease prevention: An updated meta-analysis of randomized controlled trials","volume":"23","author":"Yang","year":"2012","journal-title":"Eur. J. Intern. Med."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Pannia, E., Hammoud, R., Simonian, R., Arning, E., Ashcraft, P., Wasek, B., Bottiglieri, T., Pausova, Z., Kubant, R., and Anderson, G.H. (2020). [6S]-5-Methyltetrahydrofolic Acid and Folic Acid Pregnancy Diets Differentially Program Metabolic Phenotype and Hypothalamic Gene Expression of Wistar Rat Dams Post-Birth. Nutrients, 13.","DOI":"10.3390\/nu13010048"},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"(2005). Dose-dependent effects of folic acid on blood concentrations of homocysteine: A meta-analysis of the randomized trials. Am. J. Clin. Nutr., 82, 806\u2013812.","DOI":"10.1093\/ajcn\/82.4.806"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.biopha.2015.01.030","article-title":"Hypercysteinemia promotes atherosclerosis by reducing protein S-nitrosylation","volume":"70","author":"Chen","year":"2015","journal-title":"Biomed. Pharmacother."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.clineuro.2008.12.010","article-title":"Relationship of homocysteine with other risk factors and outcome of ischemic stroke","volume":"111","author":"Kalita","year":"2009","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1111\/jgs.13431","article-title":"Cognitive Status According to Homocysteine and B-Group Vitamins in Elderly Adults","volume":"63","author":"Bonetti","year":"2015","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1093\/ije\/dyu132","article-title":"Maternal homocysteine in pregnancy and offspring birthweight: Epidemiological associations and Mendelian randomization analysis","volume":"43","author":"Yajnik","year":"2014","journal-title":"Int. J. Epidemiol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1161\/01.ATV.18.3.356","article-title":"Vitamin supplementation reduces blood homocysteine levels: A controlled trial in patients with venous thrombosis and healthy volunteers","volume":"18","author":"Brouwer","year":"1998","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1046\/j.1365-2796.2000.00726.x","article-title":"The effect of different treatment regimens in reducing fasting and postmethionine-load homocysteine concentrations","volume":"248","author":"Biesma","year":"2000","journal-title":"J. Intern. Med."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3945\/ajcn.2010.29427","article-title":"A dose-finding trial of the effect of long-term folic acid intervention: Implications for food fortification policy","volume":"93","author":"Tighe","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1080\/07315724.2017.1330162","article-title":"Efficacy of Folic Acid Therapy in Patients with Hyperhomocysteinemia","volume":"36","author":"Tian","year":"2017","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/ejcn.2015.231","article-title":"What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies","volume":"70","author":"Reynolds","year":"2016","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/ajcn\/nqaa239","article-title":"High folic acid or folate combined with low vitamin B-12 status: Potential but inconsistent association with cognitive function in a nationally representative cross-sectional sample of US older adults participating in the NHANES","volume":"112","author":"Bailey","year":"2020","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.mam.2016.11.004","article-title":"Interaction between excess folate and low vitamin B12 status","volume":"53","author":"Paul","year":"2017","journal-title":"Mol. Asp. Med."},{"key":"ref_186","first-page":"22","article-title":"Folic acid and vitamin B12 in pernicious anemia; studies on patients treated with these substances over a ten year period","volume":"53","author":"Will","year":"1959","journal-title":"J. Lab. Clin. Med."},{"key":"ref_187","first-page":"88","article-title":"Supplemental folic acid therapy in pernicious anemia: The effect on erythropoiesis and serum vitamin B12 concentrations in selected cases","volume":"47","author":"Lear","year":"1956","journal-title":"J. Lab. Clin. Med."},{"key":"ref_188","first-page":"667","article-title":"The effect of pteroylglutamic acid administration on the serum vitamin B12 concentration in pernicious anemia in relapse","volume":"51","author":"Bok","year":"1958","journal-title":"J. Lab. Clin. Med."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"661","DOI":"10.3233\/JAD-131265","article-title":"Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: Combined data from three cohorts","volume":"39","author":"Moore","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1111\/j.1532-5415.2012.04076.x","article-title":"Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the framingham heart study","volume":"60","author":"Morris","year":"2012","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/ajcn\/85.1.193","article-title":"Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification","volume":"85","author":"Morris","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1001\/archneur.62.4.641","article-title":"Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons","volume":"62","author":"Morris","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1080\/10408444.2020.1727842","article-title":"Fallacies of clinical studies on folic acid hazards in subjects with a low vitamin B(12) status","volume":"50","author":"Hirche","year":"2020","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/advances\/nmab106","article-title":"Perspective: The High-Folate-Low-Vitamin B-12 Interaction Is a Novel Cause of Vitamin B-12 Depletion with a Specific Etiology\u2014A Hypothesis","volume":"13","author":"Selhub","year":"2022","journal-title":"Adv. Nutr."},{"key":"ref_195","first-page":"141","article-title":"The Relationship Between Folate, Vitamin B12 and Gestational Diabetes Mellitus With Proposed Mechanisms and Foetal Implications","volume":"15","author":"Maher","year":"2021","journal-title":"J. Fam. Reprod. Health"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.braindev.2011.01.002","article-title":"Maternal micronutrients (folic acid and vitamin B12) and omega 3 fatty acids: Implications for neurodevelopmental risk in the rat offspring","volume":"34","author":"Roy","year":"2012","journal-title":"Brain Dev."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1096\/fj.201701503RR","article-title":"Maternal folic acid supplementation with vitamin B(12) deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet","volume":"32","author":"Henderson","year":"2018","journal-title":"FASEB J."},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Kulkarni, A., Dangat, K., Kale, A., Sable, P., Chavan-Gautam, P., and Joshi, S. (2011). Effects of Altered Maternal Folic Acid, Vitamin B12 and Docosahexaenoic Acid on Placental Global DNA Methylation Patterns in Wistar Rats. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017706"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.neuroscience.2011.05.010","article-title":"Altered brain neurotrophins at birth: Consequence of imbalance in maternal folic acid and vitamin B12 metabolism","volume":"190","author":"Sable","year":"2011","journal-title":"Neuroscience"},{"key":"ref_200","doi-asserted-by":"crossref","unstructured":"Sweeney, M., McPartlin, J., and Scott, J. (2007). Folic acid fortification and public health: Report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health, 7.","DOI":"10.1186\/1471-2458-7-41"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"15424","DOI":"10.1073\/pnas.0902072106","article-title":"The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake","volume":"106","author":"Bailey","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"593","DOI":"10.3945\/ajcn.113.080507","article-title":"Folic acid handling by the human gut: Implications for food fortification and supplementation","volume":"100","author":"Patanwala","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1002\/stem.2421","article-title":"Folate Receptor Alpha Upregulates Oct4, Sox2 and Klf4 and Downregulates miR-138 and miR-let-7 in Cranial Neural Crest Cells","volume":"34","author":"Mohanty","year":"2016","journal-title":"Stem Cells"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1038\/srep00980","article-title":"Nuclear localization of folate receptor alpha: A new role as a transcription factor","volume":"2","author":"Boshnjaku","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"e1263717","DOI":"10.1080\/23262133.2016.1263717","article-title":"Folate receptor alpha is more than just a folate transporter","volume":"4","author":"Mohanty","year":"2017","journal-title":"Neurogenesis"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13046-019-1123-1","article-title":"Folate receptors and transporters: Biological role and diagnostic\/therapeutic targets in cancer and other diseases","volume":"38","author":"Frigerio","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1016\/j.cellsig.2015.03.020","article-title":"Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha","volume":"27","author":"Hansen","year":"2015","journal-title":"Cell Signal."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1179\/147683009X423418","article-title":"Folate stimulates ERK1\/2 phosphorylation and cell proliferation in fetal neural stem cells","volume":"12","author":"Zhang","year":"2009","journal-title":"Nutr. Neurosci."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"11187","DOI":"10.1038\/srep11187","article-title":"Folic acid inhibits COLO-205 colon cancer cell proliferation through activating the FR\u03b1\/c-SRC\/ERK1\/2\/NF\u03baB\/TP53 pathway: In vitro and in vivo studies","volume":"5","author":"Kuo","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1093\/ajcn\/88.3.763","article-title":"Circulating folic acid in plasma: Relation to folic acid fortification","volume":"88","author":"Kalmbach","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1093\/ajcn\/65.6.1790","article-title":"Unmetabolized folic acid in serum: Acute studies in subjects consuming fortified food and supplements","volume":"65","author":"Kelly","year":"1997","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_212","doi-asserted-by":"crossref","unstructured":"Wu, S., Guo, W., Li, X., Liu, Y., Li, Y., Lei, X., Yao, J., and Yang, X. (2019). Paternal chronic folate supplementation induced the transgenerational inheritance of acquired developmental and metabolic changes in chickens. Proc. R. Soc. B Biol. Sci., 286.","DOI":"10.1098\/rspb.2019.1653"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"485179","DOI":"10.1155\/2012\/485179","article-title":"Circulating unmetabolized folic Acid: Relationship to folate status and effect of supplementation","volume":"2012","author":"Tam","year":"2012","journal-title":"Obstet. Gynecol. Int."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1124\/dmd.107.019299","article-title":"Characterization and comparative studies of zebrafish and human recombinant dihydrofolate reductases\u2014Inhibition by folic acid and polyphenols","volume":"36","author":"Kao","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1080\/07315724.2017.1333929","article-title":"Association between Serum Unmetabolized Folic Acid Concentrations and Folic Acid from Fortified Foods","volume":"36","author":"Palchetti","year":"2017","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"642306","DOI":"10.3389\/fnut.2021.642306","article-title":"Detectable Unmetabolized Folic Acid and Elevated Folate Concentrations in Folic Acid-Supplemented Canadian Children with Sickle Cell Disease","volume":"8","author":"Williams","year":"2021","journal-title":"Front. Nutr."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"646","DOI":"10.3945\/ajcn.114.086603","article-title":"High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice","volume":"101","author":"Christensen","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_218","first-page":"888","article-title":"High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring","volume":"26","author":"Bahous","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"2050313X19850435","DOI":"10.1177\/2050313X19850435","article-title":"High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome","volume":"7","author":"Cornet","year":"2019","journal-title":"SAGE Open Med. Case Rep."},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.canlet.2014.02.024","article-title":"How folate metabolism affects colorectal cancer development and treatment; a story of heterogeneity and pleiotropy","volume":"356","author":"Jennings","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1079\/PNS2003265","article-title":"Folate, DNA methylation and colo-rectal cancer","volume":"62","author":"Pufulete","year":"2003","journal-title":"Proc. Nutr. Soc."},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1158\/1940-6207.CAPR-19-0188","article-title":"Methyl donor deficiency blocks colorectal cancer development by affecting key metabolic pathways","volume":"13","author":"Hanley","year":"2020","journal-title":"Cancer Prev. Res."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1067\/mlc.2001.117161","article-title":"Relevance of folate metabolism in the pathogenesis of colorectal cancer","volume":"138","author":"Ryan","year":"2001","journal-title":"J. Lab. Clin. Med."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"689","DOI":"10.4161\/epi.20461","article-title":"Supra-physiological folic acid concentrations induce aberrant DNA methylation in normal human cells in vitro","volume":"7","author":"Charles","year":"2012","journal-title":"Epigenetics"},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1002\/mnfr.201500819","article-title":"Folate deficiency and over-supplementation causes impaired folate metabolism: Regulation and adaptation mechanisms in Caenorhabditis elegans","volume":"60","author":"Ortbauer","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_226","doi-asserted-by":"crossref","unstructured":"Han, X., Wang, B., Jin, D., Liu, K., Wang, H., Chen, L., and Zu, Y. (2021). Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish. Biology, 11.","DOI":"10.3390\/biology11010028"},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/s41419-019-1836-2","article-title":"Folate can promote the methionine-dependent reprogramming of glioblastoma cells towards pluripotency","volume":"10","author":"Zgheib","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1093\/nutrit\/nuy025","article-title":"Maternal oversupplementation with folic acid and its impact on neurodevelopment of offspring","volume":"76","author":"Murray","year":"2018","journal-title":"Nutr. Rev."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13148-022-01282-y","article-title":"Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms","volume":"14","author":"Irwin","year":"2022","journal-title":"Clin. Epigenet."},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1093\/ije\/dyy032","article-title":"The long-term impact of folic acid in pregnancy on offspring DNA methylation: Follow-up of the Aberdeen Folic Acid Supplementation Trial (AFAST)","volume":"47","author":"Richmond","year":"2018","journal-title":"Int. J. Epidemiol."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/j.clnu.2017.07.008","article-title":"Folate and vitamin B12 status is associated with insulin resistance and metabolic syndrome in morbid obesity","volume":"37","author":"Li","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00125-007-0793-y","article-title":"Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: The Pune Maternal Nutrition Study","volume":"51","author":"Yajnik","year":"2008","journal-title":"Diabetologia"},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1515\/cclm-2012-0694","article-title":"Folic acid supplementation does not reduce intracellular homocysteine, and may disturb intracellular one-carbon metabolism","volume":"51","author":"Smith","year":"2013","journal-title":"Clin. Chem. Lab. Med. (CCLM)"},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s12031-015-0673-8","article-title":"High Gestational Folic Acid Supplementation Alters Expression of Imprinted and Candidate Autism Susceptibility Genes in a sex-Specific Manner in Mouse Offspring","volume":"58","author":"Barua","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"168","DOI":"10.3389\/fnins.2016.00168","article-title":"DNA Methylation Profiling at Single-Base Resolution Reveals Gestational Folic Acid Supplementation Influences the Epigenome of Mouse Offspring Cerebellum","volume":"10","author":"Barua","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1756-8935-7-3","article-title":"Single-base resolution of mouse offspring brain methylome reveals epigenome modifications caused by gestational folic acid","volume":"7","author":"Barua","year":"2014","journal-title":"Epigenet. Chromatin"},{"key":"ref_237","doi-asserted-by":"crossref","unstructured":"Luan, Y., Cos\u00edn-Tom\u00e1s, M., Leclerc, D., Malysheva, O.V., Caudill, M.A., and Rozen, R. (2022). Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Sex-Specific Gene Expression in Brain of Young Mice and Embryos. Nutrients, 14.","DOI":"10.3390\/nu14051051"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.3324\/haematol.2017.171074","article-title":"Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis","volume":"102","author":"Henry","year":"2017","journal-title":"Haematologica"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","article-title":"Cell Metabolism Review One-Carbon Metabolism in Health and Disease","volume":"25","author":"Ducker","year":"2017","journal-title":"Cell Metab."},{"key":"ref_240","first-page":"24","article-title":"Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: An overview","volume":"26","author":"Moran","year":"1999","journal-title":"Semin. Oncol."},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ejphar.2013.05.026","article-title":"Folic acid modulates eNOS activity via effects on posttranslational modifications and protein-protein interactions","volume":"714","author":"Taylor","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1038\/bjc.2014.567","article-title":"Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: Implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study","volume":"111","author":"Madore","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"e12787","DOI":"10.1111\/jne.12787","article-title":"Folic acid, but not folate, regulates different stages of neurogenesis in the ventral hippocampus of adult female rats","volume":"31","author":"Qiu","year":"2019","journal-title":"J. Neuroendocrinol."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.nut.2012.08.001","article-title":"Effect of maternal folic acid supplementation on hepatic proteome in newborn piglets","volume":"29","author":"Liu","year":"2013","journal-title":"Nutrition"},{"key":"ref_245","doi-asserted-by":"crossref","unstructured":"Pannia, E., Hammoud, R., Kubant, R., Sa, J.Y., Simonian, R., Wasek, B., Ashcraft, P., Bottiglieri, T., Pausova, Z., and Anderson, G.H. (2021). High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring. Nutrients, 13.","DOI":"10.3390\/nu13051477"},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1084\/jem.20171052","article-title":"Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors","volume":"215","author":"Kaittanis","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"3486","DOI":"10.1038\/s41467-021-23856-9","article-title":"Regulation of the one carbon folate cycle as a shared metabolic signature of longevity","volume":"12","author":"Annibal","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_248","doi-asserted-by":"crossref","unstructured":"Liu, Y.J., Janssens, G.E., McIntyre, R.L., Molenaars, M., Kamble, R., Gao, A.W., Jongejan, A., Weeghel, M.V., MacInnes, A.W., and Houtkooper, R.H. (2019). Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1007633"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/21\/4699\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:18:11Z","timestamp":1760131091000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/21\/4699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,6]]},"references-count":248,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["nu15214699"],"URL":"https:\/\/doi.org\/10.3390\/nu15214699","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,6]]}}}