Table 3.
Studies that examined epigenetic modifications in infertile males. Adapted with permission from Ref [43].
| Study | Type | Study Group (n) | Control Group (n) | Outcome Measures | Association |
|---|---|---|---|---|---|
| Hartmann et al., 2006 [141] | Pilot study | Men diagnosed with spermatogenic arrest at the level of spermatogonia (3) and spermatocytes (6) | None | H19 genomic DNA was obtained from different germ cell types derived from seminiferous tubules exhibiting impaired spermatogenesis | No abnormal H19 methylation in spermatogonia or spermatocytes in azoospermic men |
| Peng et al., 2018 [142] | Pilot experiment | Oligoasthenozoospermic men (OA:39) Asthenoteratozoospermic men (AT:36) |
Normozoospermic men (50) | Aberrant methylation of the imprinted genes H19 and SNRPN (small nuclear ribonucleoprotein polypeptide n) | The mean methylation level of H19-ICR in the OA group (78.66%) and the AT group (84.56%) was significantly lower than in the n group (88.51%, p < 0.001) Similarly, the mean methylation level of SNRPN-ICR in the OA group (8.36%) and the AT group (10.37%) was significantly higher than in the n group (6.32%, p < 0.001) |
| Kobayashi et al., 2007 [131] | Pilot experiment | Infertile couples with oligozoospermic men (18) | Infertile couples with normozoospermic men (79) | Genes studied: H19, GTL2, PEG1, LIT1, ZAC, PEG3, SNRPN Genomic DNA was obtained from sperm |
Abnormal paternal methylation (H19 and GTL2) imprint in 14 patients and abnormal maternal methylation (PEG1, LIT1, ZAC, PEG3, and SNRPN) in 20 patients. The occurrence of abnormal methylation at the H19 and GTL2 was significantly increased in oligozoospermic patients when compared with normozoospermic patients |
| Marques et al., 2008 [143] | Cohort | Oligozoospermic men (20) |
Normozoospermic men (5) | Genes studied: MEST, H19 Genomic DNA was obtained from sperm |
Infertile males with a sperm count below 10 × 106/mL displayed defective methylation of imprinted genes (H19 hypomethylation and MEST hypermethylation) |
| He et al., 2020 [144] | Cohort | Asthenospermic men (16) Oligozoospermic men (3) Oligoasthenospermic men (11) |
Normozoospermic men (8) | Differentially methylated regions (DMRs) of imprinted genes: H19, GNAS, MEG8, and SNRPN | DMRs of imprinted genes H19, GNAS, MEG8, and SNRPN, were different in the abnormal semen groups. MEG8 DMR methylation in the asthenospermic group was significantly increased |
| Kobayashi et al., 2009 [145] | Cohort | Aborted samples from women subjected to ART treatment and parental sperm (78) | Aborted samples from non-ART women and parental sperm (38) | Genes studied: H19, GTL2, PEG1, KCNQ1OT1, ZAC, PEG3, SNRPN, and XIST Genomic DNA from trophoblastic villi of aborted samples and parental sperm | Seventeen of 78 ART aborted samples presented abnormal DNA methylation at one or more imprinted gene. In 7 of these cases, the same imprinting errors were present in the parental sperm |
| Marques et al., 2010 [132] | Cohort | Azoospermic men (24) 5 with anejaculation, 5 with secondary obstructive azoospermia, 5 with primary obstructive azoospermia, 9 with nonobstructive azoospermia due to hypospermatogenesis |
None | Genes studied: H19, MEST/PEG1 Genomic DNA was obtained from human testicular sperm |
Methylation at H19 and IGF2 was significant reduced in nonobstructive azoospermic patients |
| Boissonnas et al., 2010 [146] | Cohort | Teratozoospermic men (19) Oligoasthenoteratozoo-spermic men (22) |
Normozoospermic men (17) | Genes studied: H19, IGF2 Genomic DNA was obtained from sperm |
In the teratozoospermia group, 11 of 19 patients presented a loss of methylation at variable CpG positions either in the IGF2 DMR2 or in both the IGF2 DMR2 and the 6th CTCF of the H19 DMR. In the oligoasthenoteratozoospermia group, 16 of 22 patients presented a severe loss of methylation of the 6th CTCF, which was associated with sperm concentration |
| Kobayashi et al., 2017 [147] | Cohort | Moderate oligozoospermic men (40) Severe oligozoospermic men (30) |
Normozoospermic men (151) | DNA methylation patterns of 3 paternally and 19 maternally methylated DMRs |
Aberrant methylation levels in 25 of the 151 patients (16.6%) with normozoospermia, 9 of the 40 patients (22.5%) with moderate oligozoospermia and 21 of the 30 patients (70.0%) with severe oligozoospermia |
| Song et al., 2021 [148] | Cohort | 80 cases showing impaired sperm DNA integrity | Normozoospermic men (86) | Methylation status of 257 CpG sites among H19 and SNRPN and four non-imprinted genes related to male infertility (MTHFR, GSTM1, DAZL, and CREM) | Differential methylation found in 43 CpG sites of 6 genes: H19, SNRPN, MTHFR, DAZL, GSTM1 and CREM The imprinting genes were associated with relatively higher rates of differentially methylated CpG sites (28.21% in H19 and 41.38% in SNRPN) than the non-imprinting genes |
| Khambata et al., 2021 [149] | Case-control study | Sperm collected from male partner of 112 couples with history of recurrent pregnancy loss (RPL) |
Normozoospermic prover fertile men (106) | DNA methylation status of selected imprinted genes such as IGF2-H19 DMR, IG-DMR, MEST, ZAC, KvDMR, PEG3, PEG10, and SNRPN | In the RPL group, a significant decrease in the global sperm 5mC levels and significant decrease in DNA methylation at three CpG sites in LINE1 promoter was found For IGF2-H19 DMR and IG-DMR, a significant decrease in sperm DNA methylation at specific CpG sites was observed in RPL group |
| Tang et al., 2018 [150] | Cohort | 135 men with idiopathic male infertility, including normozoospermia (n = 39), moderate oligozoospermia (n = 45), and severe oligozoospermia (n = 51) |
Fertile control Normozoospermic men (59) |
DNA methylation status of CpG sites within the differentially methylated regions (DMRs) of three imprinted genes, H19, GNAS, and DIRAS3 | Aberrant methylation patterns of imprinted genes were more prevalent in idiopathic infertile males, especially in patients with oligozoospermia Infertile males with aberrant methylation patterns of imprinted genes showed a lower global methylation levels, which was not statistical significance (p = 0.13) |