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Infertility in 5,10-Methylenetetrahydrofolate Reductase (MTHFR)-Deficient Male Mice Is Partially Alleviated by Lifetime Dietary Betaine Supplementation¹

Departments of Pediatrics,⁴ Human Genetics,⁵ Biology,⁶ Pharmacology & Therapeutics,⁷ McGill University and the Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada H3H 1P3

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.

¹ Supported by grants from the Canadian Institutes of Health Research to J.M.T. and R.R.

² Correspondence: Jacquetta M. Trasler, McGill University-Montreal Children's Hospital, Research Institute, 2300 Tupper Street Montreal, Quebec, Canada H3H 1P3. FAX: 514 412 4331; jacquetta.trasler{at}mcgill.ca

³ Current address: Metabolic Unit, University Children's Hospital, Düsseldorf, Germany

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