{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:55:43Z","timestamp":1790794543602,"version":"4.1.0"},"reference-count":50,"publisher":"The Company of Biologists","issue":"13","license":[{"start":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T00:00:00Z","timestamp":1625529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["FDN-148425"],"award-info":[{"award-number":["FDN-148425"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008762","name":"Genome Canada","doi-asserted-by":"crossref","award":["CEE-151619"],"award-info":[{"award-number":["CEE-151619"]}],"id":[{"id":"10.13039\/100008762","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Calcul Qu\u00e9bec"},{"DOI":"10.13039\/100013020","name":"Compute Canada","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013020","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"crossref","award":["BPF-156568"],"award-info":[{"award-number":["BPF-156568"]}],"id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008644","name":"McGill Faculty of Medicine","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008644","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>5,10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in the folate metabolic pathway with a key role in generating methyl groups. As MTHFR deficiency impacts male fertility and sperm DNA methylation, there is the potential for epimutations to be passed to the next generation. Here, we assessed whether the impact of MTHFR deficiency on testis morphology and sperm DNA methylation is exacerbated across generations in mouse. Although MTHFR deficiency in F1 fathers has only minor effects on sperm counts and testis weights and histology, F2 generation sons show further deterioration in reproductive parameters. Extensive loss of DNA methylation is observed in both F1 and F2 sperm, with &amp;gt;80% of sites shared between generations, suggestive of regions consistently susceptible to MTHFR deficiency. These regions are generally methylated during late embryonic germ cell development and are enriched in young retrotransposons. As retrotransposons are resistant to reprogramming of DNA methylation in embryonic germ cells, their hypomethylated state in the sperm of F1 males could contribute to the worsening reproductive phenotype observed in F2 MTHFR-deficient males, compatible with the intergenerational passage of epimutations.<\/jats:p>","DOI":"10.1242\/dev.199492","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T12:53:25Z","timestamp":1623761605000},"source":"Crossref","is-referenced-by-count":24,"title":["Paternal MTHFR deficiency leads to hypomethylation of young retrotransposons and reproductive decline across two successive generations"],"prefix":"10.1242","volume":"148","author":[{"given":"Gurbet","family":"Karahan","sequence":"first","affiliation":[{"name":"McGill University 1 Department of Human Genetics , , Montreal, QC H3A 0C7 , Canada"},{"name":"Child Health and Human Development Program, Research Institute of the McGill University Health Centre 2 , Montreal, QC H4A 3J1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donovan","family":"Chan","sequence":"additional","affiliation":[{"name":"Child Health and Human Development Program, Research Institute of the McGill University Health Centre 2 , Montreal, QC H4A 3J1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenjiro","family":"Shirane","sequence":"additional","affiliation":[{"name":"Life Sciences Institute, University of British Columbia 3 Department of Medical Genetics, Molecular Epigenetics Group , , Vancouver, BC V6T 1Z3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"McClatchie","sequence":"additional","affiliation":[{"name":"Chronic Disease Program, Ottawa Hospital Research Institute 4 , Ottawa, ON K1H 8L6 , Canada"},{"name":"University of Ottawa Faculty of Medicine 5 Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine , , Ottawa, ON K1H 8M5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne","family":"Janssen","sequence":"additional","affiliation":[{"name":"Life Sciences Institute, University of British Columbia 3 Department of Medical Genetics, Molecular Epigenetics Group , , Vancouver, BC V6T 1Z3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay M.","family":"Baltz","sequence":"additional","affiliation":[{"name":"Chronic Disease Program, Ottawa Hospital Research Institute 4 , Ottawa, ON K1H 8L6 , Canada"},{"name":"University of Ottawa Faculty of Medicine 5 Departments of Obstetrics and Gynecology and Cellular and Molecular Medicine , , Ottawa, ON K1H 8M5 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Lorincz","sequence":"additional","affiliation":[{"name":"Life Sciences Institute, University of British Columbia 3 Department of Medical Genetics, Molecular Epigenetics Group , , Vancouver, BC V6T 1Z3 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4830-042X","authenticated-orcid":false,"given":"Jacquetta","family":"Trasler","sequence":"additional","affiliation":[{"name":"McGill University 1 Department of Human Genetics , , Montreal, QC H3A 0C7 , Canada"},{"name":"Child Health and Human Development Program, Research Institute of the McGill University Health Centre 2 , Montreal, QC H4A 3J1 , Canada"},{"name":"McGill University 6 Department of Pharmacology and Therapeutics , , Montreal, QC H3A 1A3 , Canada"},{"name":"McGill University 7 Department of Pediatrics , , Montreal, QC H4A 3J1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,7,6]]},"reference":[{"key":"2024061306263079200_DEV199492C1","doi-asserted-by":"publisher","first-page":"R87","DOI":"10.1186\/gb-2012-13-10-r87","article-title":"methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles","volume":"13","author":"Akalin","year":"2012","journal-title":"Genome Biol."},{"key":"2024061306263079200_DEV199492C2","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1101\/gr.170167.113","article-title":"PRDM9 binding organizes hotspot nucleosomes and limits Holliday junction migration","volume":"24","author":"Baker","year":"2014","journal-title":"Genome Res."},{"key":"2024061306263079200_DEV199492C3","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1126\/science.aah5143","article-title":"The DNA methyltransferase DNMT3C protects male germ cells from transposon activity","volume":"354","author":"Barau","year":"2016","journal-title":"Science (80-.)"},{"key":"2024061306263079200_DEV199492C4","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1056\/NEJM200104123441517","article-title":"Homozygous Methylenetetrahydrofolate Reductase C677T Mutation and Male Infertility","volume":"344","author":"Bezold","year":"2001","journal-title":"N. 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