Document Type : Original Article

Authors

Personalized Medicine Research Center of AmitisGen, Tehran, Iran

10.21859/pmj01023

Abstract

Methylenetetrahydrofolate reductase (MTHFR) has a critical role in spermatogenesis process and altered expression level of this gene may leads to male infertility. In the present study, the assocaitions of gene expression and promoter methylation of MTHFR with risk of oligozoospermia was assessed. Sperm DNA and RNA were extracted from 20 oligozoospermia men and 20 controls consisting of healthy fertile men. Following the modification of DNAs by sodium bisulfite treatment, the methylation status of the MTHFR gene promoter was quantified by methyl specific PCR. MTHFR expression evaluated by Quantitative PCR, or real-time PCR, (qPCR). Our data revealed a significant association of CpG island promoter methylation and MTHFR expression with risk of oligospermia (P = 0.031). The prevalence of methylation in promoter region of MTHFR can be a useful molecular biomarker to predict the predisposition of male infertility.

Keywords

1.Nuti F, Krausz C. Gene polymorphisms/mutations relevant
to abnormal spermatogenesis. Reprod BioMed Online.
2008;16(4):504-13. doi: 10.1016/s1472-6483(10)60457-9
2. Klaver R, Tuttelmann F, Bleiziffer A, Haaf T, Kliesch S,
Gromoll J. DNA methylation in spermatozoa as a prospective
marker in andrology. Andrology. 2013;1(5):731-40. doi:
10.1111/j.2047-2927.2013.00118.x pmid: 23970452
3. Liu K, Zhao R, Shen M, Ye J, Li X, Huang Y, et al. Role of
genetic mutations in folate-related enzyme genes on Male
Infertility. Sci Rep. 2015;5:15548. doi: 10.1038/srep15548
pmid: 26549413
4. Montjean D, Benkhalifa M, Dessolle L, Cohen-Bacrie P, Belloc
S, Siffroi JP, et al. Polymorphisms in MTHFR and MTRR
genes associated with blood plasma homocysteine
concentration and sperm counts. Fertil Steril. 2011;95(2):635-
40. doi: 10.1016/j.fertnstert.2010.08.054 pmid: 20888556
5. Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis
and male infertility. Mutat Res. 2011;727(3):62-71. doi:
10.1016/j.mrrev.2011.04.002 pmid: 21540125
6. Richardson ME, Bleiziffer A, Tuttelmann F, Gromoll J,
Wilkinson MF. Epigenetic regulation of the RHOX homeobox
gene cluster and its association with human male infertility.
Hum Mol Genet. 2014;23(1):12-23. doi:
10.1093/hmg/ddt392 pmid: 23943794.WHO. Global report on disabilities World Health Organization:
Geneva; 2018. Available from:
https://www.who.int/disabilities/world_report/2011/report.pdf
8. Rotondo JC, Selvatici R, Di Domenico M, Marci R, Vesce F,
Tognon M, et al. Methylation loss at H19 imprinted gene
correlates with methylenetetrahydrofolate reductase gene
promoter hypermethylation in semen samples from infertile
males. Epigenetics. 2013;8(9):990-7. doi: 10.4161/epi.25798
pmid: 23975186
9. Urdinguio RG, Bayon GF, Dmitrijeva M, Torano EG, Bravo C,
Fraga MF, et al. Aberrant DNA methylation patterns of
spermatozoa in men with unexplained infertility. Hum Reprod.
2015; 30(5):1014-28. doi: 10.1093/humrep/dev053 pmid:
25753583
10. Houshdaran S, Cortessis VK, Siegmund K, Yang A, Laird PW,
Sokol RZ. Widespread epigenetic abnormalities suggest a
broad DNA methylation erasure defect in abnormal human
sperm. PLoS One. 2007;2(12):e1289. doi:
10.1371/journal.pone.0001289 pmid: 18074014
11. Ciapa B, Arnoult C. Could modifications of signalling
pathways activated after ICSI induce a potential risk of
epigenetic defects? Int J Dev Biol. 2011;55(2):143-52. doi:
10.1387/ijdb.103122bc pmid: 21671220
12. Wu W, Shen O, Qin Y, Niu X, Lu C, Xia Y, et al. Idiopathi c
male infertility is strongly associated with aberran t
promoter methylation of methylenetetrahydrofol ate
reductase (MTHFR). PLoS One. 2010;5(11):e 13 88 4.
doi: 10.1371/journal .pone.0013884 pmid: 21085488