{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:27:25Z","timestamp":1788283645679,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T00:00:00Z","timestamp":1453161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Faculty of Life Sciences, University of Vienna"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Nutrition Food Res"],"published-print":{"date-parts":[[2016,4]]},"abstract":"<jats:sec><jats:title>Scope<\/jats:title><jats:p>Impaired folate metabolism increases the risk of birth defects, neurodegenerative and cardiovascular disease, osteoporosis and cancer. We used <jats:italic>Caenorhabditis elegans<\/jats:italic> to investigate impaired folate metabolism by RNA interference of key enzymes in the methionine synthase (MS) and thymidylate synthase (TS) cycle and by folate deficiency and over\u2010supplementation feeding studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Folate status is influenced by genetic variations (polymorphisms), folate deficiency and supplementation. Single RNAi of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) and MS revealed that gene regulation is largely affected in both folate cycles. Adaptation requires a close transcriptional connection between TS and MS cycle. Coupled DHFR and MS expression is required to balance both cycles, but seems to reduce the overall rate of folate conversion. Feeding studies showed that folate over\u2010supplementation to functioning metabolism inactivates MS and MTHFR expression and enhances TS activity, which favors DNA synthesis over methylation reactions. Folate deficiency disrupted homeostasis by favoring TS cycle and led to malformation in <jats:italic>C. elegans<\/jats:italic> offspring. Embryos show aneuploidy and are nonviable lacking DNA repair during meiotic stage of diakinesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Single gene silencing alters gene expression in both cycles and disrupts folate homeostasis. Folate over\u2010supplementation and deficiency favors TS over MS cycle and causes prophase DNA damage.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.201500819","type":"journal-article","created":{"date-parts":[[2015,12,21]],"date-time":"2015-12-21T09:10:56Z","timestamp":1450689056000},"page":"949-956","source":"Crossref","is-referenced-by-count":22,"title":["Folate deficiency and over\u2010supplementation causes impaired folate metabolism: Regulation and adaptation mechanisms in <i>Caenorhabditis elegans<\/i>"],"prefix":"10.1002","volume":"60","author":[{"given":"Martina","family":"Ortbauer","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Ripper","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Fuhrmann","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Vienna  Austria"},{"name":"Max Planck Institute of Immunobiology and Epigenetics  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Lassi","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Auernigg\u2010Haselmaier","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Stiegler","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Vienna  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,1,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/88.4.1149"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(87)90043-6"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/72.2.324"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20581"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-2115(00)00257-8"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2010.01.010"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2009.02.013"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201400280"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990543"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12032"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/128.7.1204"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.004"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwh066"},{"key":"e_1_2_8_15_1","first-page":"1089","article-title":"The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro","volume":"10","author":"Crott J. W.","year":"2001","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1590\/S1415-47572013005000035"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-407681-5.00001-5"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/01635581.2014.916326"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2011-000653"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-10-46"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00516.2006"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00047.2011"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi100"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-10-67"},{"key":"e_1_2_8_25_1","first-page":"304","article-title":"Folic acid in axenic cultivation of nematode Caenorhabditis briggsae","volume":"16","author":"Hansen E. L.","year":"1957","journal-title":"Fed. Proc."},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1986"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrc.20037"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063443"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)43186-3"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.7314\/APJCP.2014.15.14.5853"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.4238\/2014.July.24.24"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12263-014-0429-z"},{"key":"e_1_2_8_33_1","first-page":"2097","article-title":"The association between the C677T polymorphism in MTHFR gene and the risk of thyroid cancer: a meta\u2010analysis","volume":"18","author":"Yang Y. M.","year":"2014","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2014.04.048"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0595-111"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2003.017244"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062066299"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91743-8"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.07.016"}],"container-title":["Molecular Nutrition &amp; Food Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmnfr.201500819","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmnfr.201500819","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mnfr.201500819","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T12:59:30Z","timestamp":1696337970000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mnfr.201500819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,19]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2016,4]]}},"alternative-id":["10.1002\/mnfr.201500819"],"URL":"https:\/\/doi.org\/10.1002\/mnfr.201500819","archive":["Portico"],"relation":{},"ISSN":["1613-4125","1613-4133"],"issn-type":[{"value":"1613-4125","type":"print"},{"value":"1613-4133","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,19]]}}}