Strain-specific defects in testicular development and sperm epigenetic patterns in 5,10-methylenetetrahydrofolate reductase-deficient mice.
Methylenetetrahydrofolate reductase (MTHFR) is a crucial folate pathway enzyme that contributes to the maintenance of cellular pools of S-adenosylmethionine, the universal methyl donor for several reactions including DNA methylation. Whereas Mthfr(-/-) BALB/c mice show growth retardation, developmental delay, and spermatogenic defects and infertility, C57BL/6 mice appear to have a less severe phenotype. In the present study, we investigated the effects of MTHFR deficiency on early germ cell development in both strains and assessed whether MTHFR deficiency results in DNA methylation abnormalities in sperm. The reproductive phenotype associated with MTHFR deficiency differed strikingly between the two strains, with BALB/c mice showing an early postnatal loss of germ cell number and proliferation that was not evident in the C57BL/6 mice. As a result, the BALB/c MTHFR-deficient mice were infertile, whereas the C57BL/6 mice had decreased sperm numbers and altered testicular histology but showed normal fertility. Imprinted genes and sequences that normally become methylated during spermatogenesis were unaffected by MTHFR deficiency in C57BL/6 mice. In contrast, a genome-wide restriction landmark genomic scanning approach revealed a number of sites of hypo- and hypermethylation in the sperm of this mouse strain. These results showing strain-specific defects in MTHFR-deficient mice may help to explain population differences in infertility among men with common MTHFR polymorphisms.
Chan
Donovan
D
Montréal Children's Hospital Research Institute, 2300 Tupper Street, Montréal, Québec, Canada H3H 1P3.
Cushnie
Duncan W
DW
Neaga
Oana R
OR
Lawrance
Andrea K
AK
Rozen
Rima
R
Trasler
Jacquetta M
JM
D000818:Animals; D019175:DNA Methylation; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology*; D013094:Spermatozoa / Q000166:cytology* / Q000378:metabolism*; D013737:Testis / Q000166:cytology* / Q000378:metabolism
D042965:Methylenetetrahydrofolate Reductase (NADPH2)