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INFERTILITY AND TESTICULAR DEFECTS IN MALE MICE DEFICIENT IN METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR).
Dell'Api, Melissa1,2,3,4,5, Kelly, Tamara1,2,3,4,5, Chen, Zhoutao1,2,3,4,5, Rozen, Rima1,2,3,4,5, Trasler, Jacquetta1,2,3,4,5, 1 2 3 4 5
ABSTRACT- MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a methyl donor for homocysteine remethylation to methionine, the precursor of S-adenosyl methionine (SAM). SAM is the methyl donor for many reactions including DNA methylation. Since Mthfr is present at high levels in the testes of normal mice, we hypothesized that the enzyme may play a role in the establishment of DNA methylation patterns in male germ cells. To better understand the role of MTHFR in spermatogenesis, the fertility and testicular histology of inbred Mthfr-deficient male mice were examined. Fertility was not affected in heterozygous males. In contrast, about one-third of male homozygotes were infertile. Testis weight was unaffected in heterozygotes but significantly decreased in most homozygotes. Paired testis weights (mg) for 6 month old mice of each genotype were: Mthfr+/+: 196±12 (n=5), Mthfr+/-: 191±9 (n=8), Mthfr-/-: 99±22 (n=8). A few Mthfr-/- mice had approximately normal testis weights; upon morphological examination, testes of these mice lacked elongated spermatids, but all other germ cells appeared and were present in their proper cellular associations. The majority of the Mthfr-/- mice showed paired testis weights in the 100-140 mg range; such decreases in testis weight were associated with numerous seminiferous tubule abnormalities, including germ cell disorganization, sloughing of pachytene spermatocytes, large Sertoli cell processes and absence of elongated spermatids. Testicular histology in Mthfr-/- mice with paired testis weights below 100 mg showed an almost complete absence of all germ cells. Our results indicate that MTHFR is important for male germ cell development. The basis for the heterogeneity in the testicular phenotype in the Mthfr-deficient mice is being pursued. We suggest that the adverse effects on spermatogenesis may be due to alterations in DNA methylation. (Supported by CIHR, FRSQ ,FCAR)
KEY WORDS: spermatogenesis, MTHFR, DNA methylation, infertility