{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T19:30:01Z","timestamp":1789846201078,"version":"4.0.1"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo \u2013 FAPESP","award":["2010\/10771-6"],"award-info":[{"award-number":["2010\/10771-6"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico \u2013 CNPq","award":["302157\/2008-5; 305641\/2011-5"],"award-info":[{"award-number":["302157\/2008-5; 305641\/2011-5"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior \u2013 CAPES"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Human Cell"],"published-print":{"date-parts":[[2021,11]]},"DOI":"10.1007\/s13577-021-00586-0","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T06:03:30Z","timestamp":1629353010000},"page":"1671-1681","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["One-carbon metabolism and global DNA methylation in mothers of individuals with Down syndrome"],"prefix":"10.1007","volume":"34","author":[{"given":"Cristiani Cortez","family":"Mendes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna Lancia","family":"Zampieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia Maria Rebolho Batista","family":"Arantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matias Eliseo","family":"Melendez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joice Matos","family":"Biselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 Lopes","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos Nogueira","family":"Eberlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Francesca","family":"Riccio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9lio","family":"Vannucchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valdemir Melechco","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eny Maria","family":"Goloni-Bertollo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9rika Cristina","family":"Pavarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"586_CR1","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1111\/jir.12277","volume":"60","author":"M Alexander","year":"2016","unstructured":"Alexander M, Ding Y, Foskett N, Petri H, Wandel C, Khwaja O. Population prevalence of Down\u2019s syndrome in the United Kingdom. J Intellect Disabil Res. 2016;60:874\u20138.","journal-title":"J Intellect Disabil Res"},{"key":"586_CR2","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/gim.2016.127","volume":"19","author":"G de Graaf","year":"2017","unstructured":"de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in the United States. Genet Med. 2017;19:439\u201347.","journal-title":"Genet Med"},{"key":"586_CR3","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/s100380170071","volume":"46","author":"A Jyothy","year":"2001","unstructured":"Jyothy A, Kumar KS, Mallikarjuna GN, et al. Parental age and the origin of extra chromosome 21 in Down syndrome. J Hum Genet. 2001;46:347\u201350.","journal-title":"J Hum Genet"},{"key":"586_CR4","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s00439-008-0603-8","volume":"125","author":"EG Allen","year":"2009","unstructured":"Allen EG, Freeman SB, Druschel C, et al. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum Genet. 2009;125:41\u201352.","journal-title":"Hum Genet"},{"key":"586_CR5","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1002\/bdra.23198","volume":"97","author":"CT Mai","year":"2013","unstructured":"Mai CT, Kucik JE, Isenburg J, et al. Selected birth defects data from population-based birth defects surveillance programs in the United States, 2006 to 2010: featuring trisomy conditions. Birth Defects Res Part A Clin Mol Teratol. 2013;97:709\u201325.","journal-title":"Birth Defects Res Part A Clin Mol Teratol"},{"issue":"2","key":"586_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1159\/000515121","volume":"85","author":"J Vranekovi\u0107","year":"2020","unstructured":"Vranekovi\u0107 J, Babi\u0107 Bo\u017eovi\u0107 I, Bili\u0107 \u010ca\u010de I, Brajenovi\u0107 MB. Methylenetetrahydrofolate reductase dimer configuration as a risk factor for maternal meiosis I-derived trisomy 21. Hum Hered. 2020;85(2):61\u20135.","journal-title":"Hum Hered"},{"issue":"3","key":"586_CR7","doi-asserted-by":"publisher","first-page":"367","DOI":"10.3892\/mco.2017.1338","volume":"7","author":"Y Gu","year":"2017","unstructured":"Gu Y. Association between polymorphisms in folate metabolism genes and maternal risk for Down syndrome: a meta-analysis. Mol Clin Oncol. 2017;7(3):367\u201377.","journal-title":"Mol Clin Oncol"},{"key":"586_CR8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127423","author":"IB Bo\u017eovi\u0107","year":"2015","unstructured":"Bo\u017eovi\u0107 IB, Stankovi\u0107 A, \u017divkovi\u0107 M, Vranekovi\u0107 J, Kapovi\u0107 M, Brajenovi\u0107-Mili\u0107 B. Altered LINE-1 methylation in mothers of children with Down syndrome. PLoS ONE. 2015. https:\/\/doi.org\/10.1371\/journal.pone.0127423.","journal-title":"PLoS ONE"},{"issue":"3","key":"586_CR9","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1002\/ajmg.a.35796","volume":"161A","author":"ND Hollis","year":"2013","unstructured":"Hollis ND, Allen EG, Oliver TR, et al. Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project. Am J Med Genet A. 2013;161A(3):438\u201344.","journal-title":"Am J Med Genet A"},{"issue":"6","key":"586_CR10","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/j.nut.2004.10.017","volume":"21","author":"AE Czeizel","year":"2005","unstructured":"Czeizel AE, Puh\u00f3 E. Maternal use of nutritional supplements during the first month of pregnancy and decreased risk of Down\u2019s syndrome: case-control study. Nutrition. 2005;21(6):698\u2013704.","journal-title":"Nutrition"},{"key":"586_CR11","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1093\/ajcn\/70.4.495","volume":"70","author":"SJ James","year":"1999","unstructured":"James SJ, Pogribna M, Pogribny IP, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr. 1999;70:495\u2013501.","journal-title":"Am J Clin Nutr"},{"key":"586_CR12","doi-asserted-by":"publisher","first-page":"2539","DOI":"10.1126\/science.1064027","volume":"294","author":"P Bernard","year":"2001","unstructured":"Bernard P, Maure JF, Partridge JF, Genier S, Javerzat JP, Allshire RC. Requirement of heterochromatin for cohesion at centromeres. Science. 2001;294:2539\u201342.","journal-title":"Science"},{"key":"586_CR13","doi-asserted-by":"publisher","first-page":"155","DOI":"10.4161\/cc.5.2.2367","volume":"5","author":"IM Wilson","year":"2006","unstructured":"Wilson IM, Davies JJ, Weber M, et al. Epigenomics: mapping the methylome. Cell Cycle. 2006;5:155\u20138.","journal-title":"Cell Cycle"},{"key":"586_CR14","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1100\/tsw.2009.122","volume":"9","author":"L Migliore","year":"2009","unstructured":"Migliore L, Migheli F, Copped\u00e8 F. Susceptibility to aneuploidy in young mothers of Down syndrome children. Sci World J. 2009;9:1052\u201360.","journal-title":"Sci World J"},{"key":"586_CR15","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.mrfmmm.2005.05.012","volume":"578","author":"S Beetstra","year":"2005","unstructured":"Beetstra S, Thomas P, Salisbury C, Turner J, Fenech M. Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei. Mutat Res. 2005;578:317\u201326.","journal-title":"Mutat Res"},{"key":"586_CR16","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1053\/j.gastro.2008.10.016","volume":"136","author":"HG Linhart","year":"2009","unstructured":"Linhart HG, Troen A, Bell GW, et al. Folate deficiency induces genomic uracil misincorporation and hypomethylation but does not increase DNA point mutations. Gastroenterology. 2009;136:227-35.e3.","journal-title":"Gastroenterology"},{"key":"586_CR17","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1002\/ajmg.a.35796","volume":"161A","author":"ND Hollis","year":"2013","unstructured":"Hollis ND, Allen EG, Oliver TR, et al. Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project. Am J Med Genet A. 2013;161A:438\u201344.","journal-title":"Am J Med Genet A"},{"key":"586_CR18","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/nature05919","volume":"447","author":"AP Feinberg","year":"2007","unstructured":"Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433\u201340.","journal-title":"Nature"},{"key":"586_CR19","first-page":"77","volume":"1825","author":"LAE Hughes","year":"2012","unstructured":"Hughes LAE, Khalid-de Bakker CAJ, Smits KM, et al. The CpG island methylator phenotype in colorectal cancer: progress and problems. Biochim Biophys Acta. 2012;1825:77\u201385.","journal-title":"Biochim Biophys Acta"},{"key":"586_CR20","doi-asserted-by":"publisher","first-page":"2705860","DOI":"10.1155\/2017\/2705860","volume":"2017","author":"N Chopra-Tandon","year":"2017","unstructured":"Chopra-Tandon N, Wu H, Arcaro KF, Sturgeon SR. Relationships between global DNA methylation in circulating white blood cells and breast cancer risk factors. J Cancer Epidemiol. 2017;2017:2705860.","journal-title":"J Cancer Epidemiol"},{"key":"586_CR21","doi-asserted-by":"publisher","first-page":"242","DOI":"10.4103\/ijmy.ijmy_86_18","volume":"7","author":"K Maruthai","year":"2018","unstructured":"Maruthai K, Subramanian M. Methylation status of alu repetitive elements in children with tuberculosis disease. Int J Mycobacteriol. 2018;7:242\u20136.","journal-title":"Int J Mycobacteriol"},{"key":"586_CR22","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1111\/odi.13136","volume":"25","author":"MFJ Khan","year":"2019","unstructured":"Khan MFJ, Little J, Aleotti V, et al. LINE-1 methylation in cleft lip tissues: influence of infant MTHFR c.677C>T genotype. Oral Dis. 2019;25:1668\u201371.","journal-title":"Oral Dis"},{"key":"586_CR23","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/nrg2640","volume":"10","author":"R Cordaux","year":"2009","unstructured":"Cordaux R, Batzer MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet. 2009;10:691\u2013703.","journal-title":"Nat Rev Genet"},{"key":"586_CR24","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/s004390050508","volume":"100","author":"C Lee","year":"1997","unstructured":"Lee C, Wevrick R, Fisher RB, Ferguson-Smith MA, Lin CC. Human centromeric DNAs. Hum Genet. 1997;100:291\u2013304.","journal-title":"Hum Genet"},{"key":"586_CR25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003402","author":"N Rodi\u0107","year":"2013","unstructured":"Rodi\u0107 N, Burns KH. Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms? PLoS Genet. 2013. https:\/\/doi.org\/10.1371\/journal.pgen.1003402.","journal-title":"PLoS Genet"},{"key":"586_CR26","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.gde.2003.10.013","volume":"13","author":"PL Deininger","year":"2003","unstructured":"Deininger PL, Moran JV, Batzer MA, Kazazian HH. Mobile elements and mammalian genome evolution. Curr Opin Genet Dev. 2003;13:651\u20138.","journal-title":"Curr Opin Genet Dev"},{"key":"586_CR27","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1155\/2012\/693864","volume":"32","author":"BL Zampieri","year":"2012","unstructured":"Zampieri BL, Biselli JM, Goloni-Bertollo EM, et al. Maternal risk for Down syndrome is modulated by genes involved in folate metabolism. Dis Markers. 2012;32:73\u201381.","journal-title":"Dis Markers"},{"key":"586_CR28","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","volume":"16","author":"SA Miller","year":"1988","unstructured":"Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.","journal-title":"Nucleic Acids Res"},{"key":"586_CR29","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1054\/bjoc.2001.2007","volume":"85","author":"B Iacopetta","year":"2001","unstructured":"Iacopetta B, Grieu F, Joseph D, Elsaleh H. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer. 2001;85:827\u201330.","journal-title":"Br J Cancer"},{"key":"586_CR30","doi-asserted-by":"publisher","first-page":"7903","DOI":"10.1158\/1078-0432.CCR-04-0923","volume":"10","author":"Z Zhang","year":"2004","unstructured":"Zhang Z, Shi Q, Sturgis EM, Spitz MR, Hong WK, Wei Q. Thymidylate synthase 5\u2019- and 3\u2019-untranslated region polymorphisms associated with risk and progression of squamous cell carcinoma of the head and neck. Clin Cancer Res. 2004;10:7903\u201310.","journal-title":"Clin Cancer Res"},{"key":"586_CR31","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1093\/carcin\/bgh307","volume":"26","author":"SJ Lee","year":"2005","unstructured":"Lee SJ, Jeon HS, Jang JS, et al. DNMT3B polymorphisms and risk of primary lung cancer. Carcinogenesis. 2005;26:403\u20139.","journal-title":"Carcinogenesis"},{"key":"586_CR32","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1158\/1055-9965.EPI-07-2608","volume":"17","author":"AY Jung","year":"2008","unstructured":"Jung AY, Poole EM, Bigler J, Whitton J, Potter JD, Ulrich CM. DNA methyltransferase and alcohol dehydrogenase: gene-nutrient interactions in relation to risk of colorectal polyps. Cancer Epidemiol Biomarkers Prev. 2008;17:330\u20138.","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"586_CR33","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1590\/S1516-31802010000400008","volume":"128","author":"CC Mendes","year":"2010","unstructured":"Mendes CC, Biselli JM, Zampieri BL, et al. 19-base pair deletion polymorphism of the dihydrofolate reductase (DHFR) gene: maternal risk of Down syndrome and folate metabolism. Sao Paulo Med J. 2010;128:215\u20138.","journal-title":"Sao Paulo Med J"},{"key":"586_CR34","doi-asserted-by":"publisher","first-page":"2561","DOI":"10.1007\/s11033-011-1008-7","volume":"39","author":"GH Marucci","year":"2012","unstructured":"Marucci GH, Zampieri BL, Biselli JM, et al. Polymorphism C1420T of serine hydroxymethyltransferase gene on maternal risk for Down syndrome. Mol Biol Rep. 2012;39:2561\u20136.","journal-title":"Mol Biol Rep"},{"key":"586_CR35","doi-asserted-by":"publisher","first-page":"R77","DOI":"10.1186\/bcr2721","volume":"12","author":"NG Bediaga","year":"2010","unstructured":"Bediaga NG, Acha-Sagredo A, Guerra I, et al. DNA methylation epigenotypes in breast cancer molecular subtypes. Breast Cancer Res. 2010;12:R77.","journal-title":"Breast Cancer Res"},{"key":"586_CR36","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1016\/j.bbi.2011.01.017","volume":"25","author":"V Bollati","year":"2011","unstructured":"Bollati V, Galimberti D, Pergoli L, et al. A DNA methylation in repetitive elements and Alzheimer disease. Brain Behav Immun. 2011;25:1078\u201383.","journal-title":"Brain Behav Immun"},{"key":"586_CR37","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1039\/b104038n","volume":"126","author":"R Haddad","year":"2001","unstructured":"Haddad R, Mendes MA, H\u00f6ehr NF, Eberlin MN. Amino acid quantitation in aqueous matrices via trap and release membrane introduction mass spectrometry: homocysteine in human plasma. Analyst. 2001;126:1212\u20135.","journal-title":"Analyst"},{"key":"586_CR38","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.ejphar.2006.06.003","volume":"543","author":"CR de Andrade","year":"2006","unstructured":"de Andrade CR, Fukada SY, Olivon VC, et al. Alpha1D-adrenoceptor-induced relaxation on rat carotid artery is impaired during the endothelial dysfunction evoked in the early stages of hyperhomocysteinemia. Eur J Pharmacol. 2006;543:83\u201391.","journal-title":"Eur J Pharmacol"},{"key":"586_CR39","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.ab.2008.06.023","volume":"381","author":"VM Carvalho","year":"2008","unstructured":"Carvalho VM, Kok F. Determination of serum methylmalonic acid by alkylative extraction and liquid chromatography coupled to tandem mass spectrometry. Anal Biochem. 2008;381:67\u201373.","journal-title":"Anal Biochem"},{"key":"586_CR40","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1038\/pr.2016.31","volume":"79","author":"K Huen","year":"2016","unstructured":"Huen K, Harley K, Kogut K, Rauch S, Eskenazi B, Holland N. DNA methylation of LINE-1 and Alu repetitive elements in relation to sex hormones and pubertal timing in Mexican-American children. Pediatr Res. 2016;79:855\u201362.","journal-title":"Pediatr Res"},{"issue":"2","key":"586_CR41","doi-asserted-by":"publisher","first-page":"188","DOI":"10.4161\/epi.6.2.13528","volume":"6","author":"S Fabris","year":"2011","unstructured":"Fabris S, Bollati V, Agnelli L, et al. Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia. Epigenetics. 2011;6(2):188\u201394.","journal-title":"Epigenetics"},{"issue":"7","key":"586_CR42","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1164\/rccm.200807-1097OC","volume":"179","author":"A Baccarelli","year":"2009","unstructured":"Baccarelli A, Wright RO, Bollati V, et al. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med. 2009;179(7):572\u20138.","journal-title":"Am J Respir Crit Care Med"},{"key":"586_CR43","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1289\/ehp.0901429","volume":"118","author":"RO Wright","year":"2010","unstructured":"Wright RO, Schwartz J, Wright RJ, et al. Biomarkers of lead exposure and DNA methylation within retrotransposons. Environ Health Perspect. 2010;118:790\u20135.","journal-title":"Environ Health Perspect"},{"key":"586_CR44","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1743-8977-10-28","volume":"10","author":"HM Byun","year":"2013","unstructured":"Byun HM, Motta V, Panni T, et al. Evolutionary age of repetitive element subfamilies and sensitivity of DNA methylation to airborne pollutants. Part Fibre Toxicol. 2013;10:28.","journal-title":"Part Fibre Toxicol"},{"key":"586_CR45","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/35057062","volume":"409","author":"ES Lander","year":"2001","unstructured":"Lander ES, Linton LM, Birren B, Nusbaum C, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860\u2013921.","journal-title":"Nature"},{"issue":"10","key":"586_CR46","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1101\/gr.388902","volume":"12","author":"P Medstrand","year":"2002","unstructured":"Medstrand P, van de Lagemaat LN, Mager DL. Retroelement distributions in the human genome: variations associated with age and proximity to genes. Genome Res. 2002;12(10):1483\u201395.","journal-title":"Genome Res"},{"key":"586_CR47","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1006\/abbi.1998.0757","volume":"356","author":"NS Millian","year":"1998","unstructured":"Millian NS, Garrow TA. Human betaine-homocysteine methyltransferase is a zinc metalloenzyme. Arch Biochem Biophys. 1998;356:93\u20138.","journal-title":"Arch Biochem Biophys"},{"key":"586_CR48","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.ymgme.2008.03.013","volume":"94","author":"F Li","year":"2008","unstructured":"Li F, Feng Q, Lee C, et al. Human betaine-homocysteinemethyltransferase (BHMT) and BHMT2: common gene sequence variation and functional characterization. Mol Genet Metab. 2008;94:326\u201335.","journal-title":"Mol Genet Metab"},{"key":"586_CR49","doi-asserted-by":"publisher","first-page":"4685","DOI":"10.1007\/s11033-013-2563-x","volume":"40","author":"MR Amorim","year":"2013","unstructured":"Amorim MR, Moura CM, Gomes AD, et al. Betaine-homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population. Mol Biol Rep. 2013;40:4685\u20139.","journal-title":"Mol Biol Rep"},{"key":"586_CR50","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/ejcn.2016.190","volume":"71","author":"SK Jaiswal","year":"2017","unstructured":"Jaiswal SK, Sukla KK, Chauhan A, Lakhotia AR, Kumar A, Rai AK. Choline metabolic pathway gene polymorphisms and risk for Down syndrome: an association study in a population with folate-homocysteine metabolic impairment. Eur J Clin Nutr. 2017;71:45\u201350.","journal-title":"Eur J Clin Nutr"},{"key":"586_CR51","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/S0083-6729(00)59012-8","volume":"59","author":"B Seetharam","year":"2000","unstructured":"Seetharam B, Li N. Transcobalamin II and its cell surface receptor. Vitam Horm. 2000;59:337\u201366.","journal-title":"Vitam Horm"},{"key":"586_CR52","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.3945\/ajcn.117.156349","volume":"106","author":"A Oussalah","year":"2017","unstructured":"Oussalah A, Levy J, Filhine-Tr\u00e9sarrieu P, Namour F, Gu\u00e9ant JL. Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies. Am J Clin Nutr. 2017;106:1142\u201356.","journal-title":"Am J Clin Nutr"},{"key":"586_CR53","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/517504","author":"D Balduino Victorino","year":"2014","unstructured":"Balduino Victorino D, de Godoy MF, Goloni-Bertollo EM, Pavarino \u00c9C. Genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome: a meta-analysis. Dis Markers. 2014. https:\/\/doi.org\/10.1155\/2014\/517504.","journal-title":"Dis Markers"},{"key":"586_CR54","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.1111\/cas.12013","volume":"103","author":"H Ono","year":"2012","unstructured":"Ono H, Iwasaki M, Kuchiba A, et al. Association of dietary and genetic factors related to one-carbon metabolism with global methylation level of leukocyte DNA. Cancer Sci. 2012;103:2159\u201364.","journal-title":"Cancer Sci"},{"key":"586_CR55","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1093\/ajcn\/nqz031","volume":"110","author":"PR Mandaviya","year":"2019","unstructured":"Mandaviya PR, Joehanes R, Brody J, et al. Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals. Am J Clin Nutr. 2019;110:437\u201350.","journal-title":"Am J Clin Nutr"},{"key":"586_CR56","doi-asserted-by":"publisher","first-page":"55008","DOI":"10.1074\/jbc.M410818200","volume":"279","author":"HF Nijhout","year":"2004","unstructured":"Nijhout HF, Reed MC, Budu P, Ulrich CM. A mathematical model of the folate cycle: new insights into folate homeostasis. J Biol Chem. 2004;279:55008\u201316.","journal-title":"J Biol Chem"},{"key":"586_CR57","doi-asserted-by":"publisher","first-page":"646","DOI":"10.3945\/ajcn.114.086603","volume":"101","author":"KE Christensen","year":"2015","unstructured":"Christensen KE, Mikael LG, Leung K-Y, et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015;101:646\u201358.","journal-title":"Am J Clin Nutr"},{"issue":"7","key":"586_CR58","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1093\/hmg\/ddy021","volume":"27","author":"M Aarabi","year":"2018","unstructured":"Aarabi M, Christensen KE, Chan D, et al. Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation. Hum Mol Genet. 2018;27(7):1123\u201335.","journal-title":"Hum Mol Genet"},{"issue":"Suppl 3","key":"586_CR59","doi-asserted-by":"publisher","first-page":"941S","DOI":"10.1093\/jn\/133.3.941S","volume":"133","author":"JB Mason","year":"2003","unstructured":"Mason JB. Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism. J Nutr. 2003;133(Suppl 3):941S-S947.","journal-title":"J Nutr"},{"key":"586_CR60","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1007\/s12263-015-0480-4","volume":"10","author":"A Agodi","year":"2015","unstructured":"Agodi A, Barchitta M, Quattrocchi A, et al. Low fruit consumption and folate deficiency are associated with LINE-1 hypomethylation in women of a cancer-free population. Genes Nutr. 2015;10:480.","journal-title":"Genes Nutr"},{"key":"586_CR61","doi-asserted-by":"publisher","first-page":"606","DOI":"10.4161\/epi.20236","volume":"7","author":"FF Zhang","year":"2012","unstructured":"Zhang FF, Santella RM, Wolff M, Kappil MA, Markowitz SB, Morabia A. White blood cell global methylation and IL-6 promoter methylation in association with diet and lifestyle risk factors in a cancer-free population. Epigenetics. 2012;7:606\u201314.","journal-title":"Epigenetics"},{"key":"586_CR62","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1093\/ajcn\/nqy119","volume":"108","author":"JA Chamberlain","year":"2018","unstructured":"Chamberlain JA, Dugu\u00e9 PA, Bassett JK, et al. Dietary intake of one-carbon metabolism nutrients and DNA methylation in peripheral blood. Am J Clin Nutr. 2018;108:611\u201321.","journal-title":"Am J Clin Nutr"},{"key":"586_CR63","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1093\/carcin\/19.7.1163","volume":"19","author":"M Fenech","year":"1998","unstructured":"Fenech M, Aitken C, Rinaldi J. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis. 1998;19:1163\u201371.","journal-title":"Carcinogenesis"},{"key":"586_CR64","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.numecd.2013.11.011","volume":"24","author":"W Perng","year":"2014","unstructured":"Perng W, Villamor E, Shroff MR, et al. Dietary intake, plasma homocysteine, and repetitive element DNA methylation in the multi-ethnic study of atherosclerosis (MESA). Nutr Metab Cardiovasc Dis. 2014;24:614\u201322.","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"586_CR65","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/s00439-002-0779-2","volume":"111","author":"BN Trinh","year":"2002","unstructured":"Trinh BN, Ong CN, Coetzee GA, Yu MC, Laird PW. Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels. Hum Genet. 2002;111:299\u2013302.","journal-title":"Hum Genet"},{"key":"586_CR66","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.mrfmmm.2004.03.008","volume":"551","author":"X Wang","year":"2004","unstructured":"Wang X, Thomas P, Xue J, Fenech M. Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21. Mutat Res. 2004;551:167\u201380.","journal-title":"Mutat Res"},{"key":"586_CR67","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.neulet.2008.10.074","volume":"449","author":"F Copped\u00e8","year":"2009","unstructured":"Copped\u00e8 F, Migheli F, Bargagna S, et al. Association of maternal polymorphisms in folate metabolizing genes with chromosome damage and risk of Down syndrome offspring. Neurosci Lett. 2009;449:15\u20139.","journal-title":"Neurosci Lett"},{"key":"586_CR68","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/1755-8794-3-42","volume":"3","author":"F Copped\u00e8","year":"2010","unstructured":"Copped\u00e8 F, Grossi E, Migheli F, Migliore L. Polymorphisms in folate-metabolizing genes, chromosome damage, and risk of Down syndrome in Italian women: identification of key factors using artificial neural networks. BMC Med Genomics. 2010;3:42.","journal-title":"BMC Med Genomics"},{"key":"586_CR69","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1002\/ijc.25190","volume":"127","author":"L Hou","year":"2010","unstructured":"Hou L, Wang H, Sartori S, et al. Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population. Int J Cancer. 2010;127:1866\u201374.","journal-title":"Int J Cancer"},{"key":"586_CR70","doi-asserted-by":"publisher","first-page":"623","DOI":"10.4161\/epi.6.5.15335","volume":"6","author":"FF Zhang","year":"2011","unstructured":"Zhang FF, Cardarelli R, Carroll J, et al. Significant differences in global genomic DNA methylation by gender and race\/ethnicity in peripheral blood. Epigenetics. 2011;6:623\u20139.","journal-title":"Epigenetics"},{"key":"586_CR71","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052570","author":"MVM Gomes","year":"2012","unstructured":"Gomes MVM, Toffoli LV, Arruda DW, et al. Age-related changes in the global DNA methylation profile of leukocytes are linked to nutrition but are not associated with the MTHFR C677T genotype or to functional capacities. PLoS ONE. 2012. https:\/\/doi.org\/10.1371\/journal.pone.0052570.","journal-title":"PLoS ONE"},{"key":"586_CR72","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.1096\/fj.11-197251","volume":"26","author":"X Xu","year":"2012","unstructured":"Xu X, Gammon MD, Hernandez-Vargas H, et al. DNA methylation in peripheral blood measured by LUMA is associated with breast cancer in a population-based study. FASEB J. 2012;26:2657\u201366.","journal-title":"FASEB J"},{"key":"586_CR73","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1289\/ehp.1206068","volume":"121","author":"SM Tajuddin","year":"2013","unstructured":"Tajuddin SM, Amaral AFS, Fern\u00e1ndez AF, et al. Genetic and non-genetic predictors of LINE-1 methylation in leukocyte DNA. Environ Health Perspect. 2013;121:650\u20136.","journal-title":"Environ Health Perspect"},{"key":"586_CR74","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1080\/15592294.2015.1006505","volume":"10","author":"S Karami","year":"2015","unstructured":"Karami S, Andreotti G, Liao LM, et al. LINE1 methylation levels in pre-diagnostic leukocyte DNA and future renal cell carcinoma risk. Epigenetics. 2015;10:282\u201392.","journal-title":"Epigenetics"},{"key":"586_CR75","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1289\/ehp.0901131","volume":"118","author":"KY Kim","year":"2010","unstructured":"Kim KY, Kim DS, Lee SK, et al. Association of low-dose exposure to persistent organic pollutants with global DNA hypomethylation in healthy Koreans. Environ Health Perspect. 2010;118:370\u20134.","journal-title":"Environ Health Perspect"},{"key":"586_CR76","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1093\/ije\/dyq154","volume":"41","author":"ZZ Zhu","year":"2012","unstructured":"Zhu ZZ, Hou L, Bollati V, et al. Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis. Int J Epidemiol. 2012;41:126\u201339.","journal-title":"Int J Epidemiol"},{"key":"586_CR77","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1289\/ehp.11338","volume":"116","author":"JA Rusiecki","year":"2008","unstructured":"Rusiecki JA, Baccarelli A, Bollati V, Tarantini L, Moore LE, Bonefeld-Jorgensen EC. Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ Health Perspect. 2008;116:1547\u201352.","journal-title":"Environ Health Perspect"},{"key":"586_CR78","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/1471-2350-11-77","volume":"11","author":"L Mirabello","year":"2010","unstructured":"Mirabello L, Savage SA, Korde L, Gadalla SM, Greene MH. LINE-1 methylation is inherited in familial testicular cancer kindreds. BMC Med Genet. 2010;11:77.","journal-title":"BMC Med Genet"},{"key":"586_CR79","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1093\/ije\/dys020","volume":"41","author":"MS Pearce","year":"2012","unstructured":"Pearce MS, McConnell JC, Potter C, et al. Global LINE-1 DNA methylation is associated with blood glycaemic and lipid profiles. Int J Epidemiol. 2012;41:210\u20137.","journal-title":"Int J Epidemiol"},{"key":"586_CR80","doi-asserted-by":"publisher","first-page":"467","DOI":"10.14348\/molcells.2014.0073","volume":"37","author":"YK Na","year":"2014","unstructured":"Na YK, Hong HS, Lee DH, Lee WK, Kim DS. Effect of body mass index on global DNA methylation in healthy Korean women. Mol Cells. 2014;37:467\u201372.","journal-title":"Mol Cells"},{"issue":"1","key":"586_CR81","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1017\/S0007114519002526","volume":"123","author":"J Steluti","year":"2019","unstructured":"Steluti J, Palchetti CZ, Miranda AM, Fisberg RM, Marchioni DM. DNA methylation and one-carbon metabolism related nutrients and polymorphisms: analysis after mandatory flour fortification with folic acid. Br J Nutr. 2019;123(1):23\u20139.","journal-title":"Br J Nutr"}],"container-title":["Human Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13577-021-00586-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13577-021-00586-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13577-021-00586-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T14:48:35Z","timestamp":1633445315000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13577-021-00586-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,19]]},"references-count":81,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["586"],"URL":"https:\/\/doi.org\/10.1007\/s13577-021-00586-0","relation":{},"ISSN":["1749-0774"],"issn-type":[{"value":"1749-0774","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,19]]},"assertion":[{"value":"24 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study protocol was approved by the Research Ethics Committee of the School of Medicine of Sao Jose do Rio Preto (CEP-FAMERP, 222\/2011).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The participants were dispensed from informed written consent because previously collected samples were used.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}