title: Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation.
abstract: Metabolism of folate is essential for proper cellular function. Within the folate pathway, methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a methyl donor for remethylation of homocysteine to methionine, the precursor of S-adenosylmethionine. S-adenosylmethionine is the methyl donor for numerous cellular reactions. In adult male mice, MTHFR levels are highest in the testis; this finding, in conjunction with recent clinical evidence, suggest an important role for MTHFR in spermatogenesis. Indeed, we show here that severe MTHFR deficiency in male mice results in abnormal spermatogenesis and infertility. Maternal oral administration of betaine, an alternative methyl donor, throughout pregnancy and nursing, resulted in improved testicular histology in Mthfr-/- offspring at Postnatal Day 6, but not at 8 mo of age. However, when betaine supplementation was maintained postweaning, testicular histology improved, and sperm numbers and fertility increased significantly. We postulate that the adverse effects of MTHFR deficiency on spermatogenesis, may, in part, be mediated by alterations in the transmethylation pathway and suggest that betaine supplementation may provide a means to bypass MTHFR deficiency and its adverse effects on spermatogenesis by maintaining normal methylation levels within male germ cells.
authors.affiliation: Department of Pediatrics, McGill University and the Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
authors.forename: Tamara L J
authors.initials: TL
authors.lastname: Kelly
authors.forename: Oana R
authors.initials: OR
authors.lastname: Neaga
authors.forename: Bernd C
authors.initials: BC
authors.lastname: Schwahn
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
authors.forename: Jacquetta M
authors.initials: JM
authors.lastname: Trasler
mesh_terms: D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2) / Q000172:deficiency* / Q000378:metabolism*; D000818:Animals; D001622:Betaine / Q000008:administration & dosage*; D019587:Dietary Supplements; D004334:Drug Administration Schedule; D005298:Fertility / Q000187:drug effects / Q000502:physiology; D005303:Fertility Agents, Male / Q000008:administration & dosage; D005492:Folic Acid / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007248:Infertility, Male / Q000178:diet therapy* / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013076:Sperm Count; D013091:Spermatogenesis / Q000187:drug effects* / Q000502:physiology; D018709:Statistics, Nonparametric; D013737:Testis / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
chemical_list: D005303:Fertility Agents, Male; D001622:Betaine; D005492:Folic Acid; D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2)