title: High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism.
abstract: Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR.
authors: Department of Human Genetics, Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1.
authors: Mahmoud
authors: M
authors: Aarabi
authors: Division of Urology, Department of Surgery and, Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1.
authors: Maria C
authors: MC
authors: San Gabriel
authors: Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1.
authors: Donovan
authors: D
authors: Chan
authors: Nutrition Research Division, Health Canada, Ottawa, ON, Canada K1A 0K9 and.
authors: Nathalie A
authors: NA
authors: Behan
authors: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada H3A 1A4.
authors: Maxime
authors: M
authors: Caron
authors: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada H3A 1A4.
authors: Tomi
authors: T
authors: Pastinen
authors: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada H3A 1A4.
authors: Guillaume
authors: G
authors: Bourque
authors: Nutrition Research Division, Health Canada, Ottawa, ON, Canada K1A 0K9 and.
authors: Amanda J
authors: AJ
authors: MacFarlane
authors: Division of Urology, Department of Surgery and, Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1.
authors: Armand
authors: A
authors: Zini
authors: Department of Human Genetics, Departments of Pediatrics and Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada H4A 3J1, Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, QC, Canada H4A 3J1, jacquetta.trasler@mcgill.ca.
authors: Jacquetta
authors: J
authors: Trasler
mesh_terms: D000328:Adult; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D019587:Dietary Supplements; D044127:Epigenesis, Genetic / Q000187:drug effects; D005492:Folic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D005809:Genes, Regulator; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic; D013094:Spermatozoa / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D055517:snRNP Core Proteins / Q000235:genetics
chemical_list: D055517:snRNP Core Proteins; D004247:DNA; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)