{"doi":"10.1093/molehr/gaae008","title":"Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase <i>677C&amp;gt;T</i> variant and correction with moderate dose folic acid supplementation","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C&amp;gt;T) results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2 mg folic acid/kg diet) and assess the effects of folic acid supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing and whole-genome bisulfite sequencing (WGBS). Reproductive parameters and locus-specific imprinted gene methylation were unaffected by genotype or diet. Using WGBS, sperm from 677TT mice had 360 differentially methylated tiles as compared to 677CC mice, predominantly hypomethylation (60% of tiles). Folic acid supplementation mostly caused hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.</jats:p>","journal":"Molecular Human Reproduction","year":2024,"id":650154,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1695153,"name":"Donovan Chan","orcid":"0000-0002-6860-8384","position":1,"is_corresponding":false},{"id":1695154,"name":"Karen E Christensen","orcid":null,"position":2,"is_corresponding":false},{"id":1695155,"name":"Alaina M Reagan","orcid":null,"position":3,"is_corresponding":false},{"id":1695157,"name":"Gareth R Howell","orcid":null,"position":4,"is_corresponding":false},{"id":881231,"name":"Rima Rozen","orcid":"0000-0003-3516-6329","position":5,"is_corresponding":false},{"id":1695159,"name":"Jacquetta Trasler","orcid":"0000-0002-4830-042X","position":6,"is_corresponding":false},{"id":1695152,"name":"Edgar Martínez Duncker Rebolledo","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Sperm DNA methylation defects in a new mouse model of the 5,10-methylenetetrahydrofolate reductase <i>677C&amp;gt;T</i> variant and correction with moderate dose folic acid supplementation","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>5,10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays a key role in providing methyl groups for DNA methylation, including during spermatogenesis. A common genetic variant in humans (MTHFR 677C&amp;gt;T) results in reduced enzyme activity and has been linked to various disorders, including male infertility. A new animal model has been created by reproducing the human equivalent of the polymorphism in mice using CRISPR/Cas9. Biochemical parameters in the Mthfr 677TT mice recapitulate alterations found in MTHFR 677TT men. Our aims were to characterize the sperm DNA methylome of the Mthfr 677CC and TT mice on a control diet (2 mg folic acid/kg diet) and assess the effects of folic acid supplementation (10 mg/kg diet) on the sperm DNA methylome. Body and reproductive organ weights, testicular sperm counts, and histology were examined. DNA methylation in sperm was assessed using bisulfite pyrosequencing and whole-genome bisulfite sequencing (WGBS). Reproductive parameters and locus-specific imprinted gene methylation were unaffected by genotype or diet. Using WGBS, sperm from 677TT mice had 360 differentially methylated tiles as compared to 677CC mice, predominantly hypomethylation (60% of tiles). Folic acid supplementation mostly caused hypermethylation in sperm of males of both genotypes and was found to partially correct the DNA methylation alterations in sperm associated with the TT genotype. The new mouse model will be useful in understanding the role of MTHFR deficiency in male fertility and in designing folate supplementation regimens for the clinic.</jats:p>","is_dataset_classified":null,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38366926","pmcid":"PMC10980591","openalex_id":"https://openalex.org/W4391896905","authors":[],"funders":[{"funder_name":"Canadian Institutes of Health Research","grant_id":"FND-148425","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"unidentified","title":"unidentified"}],"total_grants":2,"fwci":2.595,"citation_percentile":0.89262233,"influential_citations":0,"citation_trend":[{"year":2024,"count":3},{"year":2025,"count":5}],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://academic.oup.com/molehr/advance-article-pdf/doi/10.1093/molehr/gaae008/56695481/gaae008.pdf","host_type":"journal"},{"url":"https://academic.oup.com/molehr/advance-article-pdf/doi/10.1093/molehr/gaae008/56695481/gaae008.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/molehr/article-pdf/30/4/gaae008/57122678/gaae008.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/molehr/gaae008","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38366926","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10980591","host_type":"repository"},{"url":"https://mouseion.jax.org/stfb2024/66","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10980591","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10980591?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1093/molehr/gaae008","host_type":""},{"url":"https://doi.org/https://doi.org/10.1093/molehr/gaae008","host_type":""}],"fields_of_study":["Folate and B Vitamins Research","Epigenetics and DNA Methylation","Genetic Syndromes and Imprinting","0301 basic medicine","0303 health sciences","03 medical and health sciences","Male","Humans","Animals","Mice","DNA Methylation","Methylenetetrahydrofolate Reductase (NADPH2)","Semen","Spermatozoa","Folic Acid","Genotype","Dietary Supplements","Sulfites"],"mesh_terms":["Animals","Folic Acid","Genotype","Humans","Male","Semen","Spermatozoa","Sulfites","DNA Methylation","Dietary Supplements","Methylenetetrahydrofolate Reductase (NADPH2)","Mice"],"keywords":["Methylenetetrahydrofolate reductase","Biology","DNA methylation","Sperm","Methylation","Genotype","Spermatogenesis","Genetics","Andrology","Endocrinology","Gene","Medicine","Gene expression","Epigenetics","Folate Metabolism","5,10-Methylenetetrahydrofolate Reductase","Folic Acid Supplement","Male","570","610","Spermatozoa","Mice","Folic Acid","Semen","Dietary Supplements","Humans","Animals","Sulfites","Methylenetetrahydrofolate Reductase (NADPH2)","JMG","Original Research"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T04:56:31.289277Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}