Idiopathic male infertility is strongly associated with aberrant DNA methylation of imprinted loci in sperm: a case-control study

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Abstract

Background

Male infertility is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. Abnormal epigenetic programming has been proposed as a possible mechanism compromising male fertility. Recent studies suggest that aberrant imprinting in spermatozoa in a subset of infertile men is a risk factor for congenital diseases in children conceived via assisted reproduction techniques. In this study, we examined the DNA methylation status of CpG sites within the differentially methylated regions (DMRs) of three imprinted genes, H19, GNAS, and DIRAS3, using combined bisulfite PCR restriction analysis and bisulfite sequencing in sperm obtained from 135 men with idiopathic male infertility, including normozoospermia ( n = 39), moderate oligozoospermia ( n = 45), and severe oligozoospermia ( n = 51), and fertile controls ( n = 59). The percentage of global methylation was compared between fertile controls and infertile patients displaying abnormal DNA methylation status of imprinted loci. Moreover, we also analyzed whether the DNA methyltransferases (DNMTs) polymorphisms impact upon the methylation patterns of imprinted genes in idiopathic infertile males.

Results

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 displayed a tendency of lower global methylation levels, although not reaching statistical significance ( P = 0.13). In the genotype-epigenotype correlation analysis, no significant association was observed between aberrant methylation patterns of the three imprinted genes and genotypes of the four DNA methyltransferase (DNMT) genes.

Conclusion

We conclude that abnormalities of DMR within imprinted genes may be associated with idiopathic male infertility. Disruption in methylation pattern of the three imprinted genes does not occur in high-risk genotypes of DNMTs.

Electronic supplementary material

The online version of this article (10.1186/s13148-018-0568-y) contains supplementary material, which is available to authorized users.

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Most cited references 34

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Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.

Masahiro Kaneda, Masaki Okano, Kenichiro Hata … (2004)

Imprinted genes are epigenetically marked during gametogenesis so that they are exclusively expressed from either the paternal or the maternal allele in offspring. Imprinting prevents parthenogenesis in mammals and is often disrupted in congenital malformation syndromes, tumours and cloned animals. Although de novo DNA methyltransferases of the Dnmt3 family are implicated in maternal imprinting, the lethality of Dnmt3a and Dnmt3b knockout mice has precluded further studies. We here report the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology. Offspring from Dnmt3a conditional mutant females die in utero and lack methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males show impaired spermatogenesis and lack methylation at two of three paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring show no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice, except for the discrepancy in methylation at one locus. These results indicate that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but also suggest the involvement of other factors.

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Chromosomal instability and tumors promoted by DNA hypomethylation.

Amir Eden, François Gaudet, Alpana Waghmare … (2003)

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Induction of tumors in mice by genomic hypomethylation.

François Gaudet, J Hodgson, Amir Eden … (2003)

Genome-wide DNA hypomethylation occurs in many human cancers, but whether this epigenetic change is a cause or consequence of tumorigenesis has been unclear. To explore this phenomenon, we generated mice carrying a hypomorphic DNA methyltransferase 1 (Dnmt1) allele, which reduces Dnmt1 expression to 10% of wild-type levels and results in substantial genome-wide hypomethylation in all tissues. The mutant mice were runted at birth, and at 4 to 8 months of age they developed aggressive T cell lymphomas that displayed a high frequency of chromosome 15 trisomy. These results indicate that DNA hypomethylation plays a causal role in tumor formation, possibly by promoting chromosomal instability.

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Author and article information

Contributors

Wei Wu:

ORCID: http://orcid.org/0000-0002-0267-1284

wwu@njmu.edu.cn

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 29 October 2018

Publication date PMC-release: 29 October 2018

Publication date Collection: 2018

Volume: 10

Electronic Location Identifier: 134

Affiliations

[1 ]ISNI 0000 0004 1757 7869, GRID grid.459791.7, Department of Obstetrics, , The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, ; Nanjing, China

[2 ]ISNI 0000 0004 1757 7869, GRID grid.459791.7, Department of Urology, , The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, ; Nanjing, China

[3 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, State Key Laboratory of Reproductive Medicine, Institute of Toxicology, , Nanjing Medical University, ; 101 Longmian Avenue, Nanjing, 211166 China

[4 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, , Nanjing Medical University, ; Nanjing, China

[5 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, National Toxicology Program Laboratory, Division of the National Toxicology Program, , National Institute of Environmental Health Sciences, ; Research Triangle Park, NC USA

[6 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Department of Health and Human Services, National Institute of Environmental Health Sciences, , National Institutes of Health, ; Research Triangle Park, USA

Author information

Wei Wu http://orcid.org/0000-0002-0267-1284

Article

Publisher ID: 568

DOI: 10.1186/s13148-018-0568-y

PMC ID: 6206675

PubMed ID: 30373665

SO-VID: cb8e8241-e0df-4994-bc46-30249d1b589f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 4 July 2018

Date accepted : 14 October 2018

Funding

Funded by: National Natural Science Foundation of China

Award ID: 81673217

Award Recipient : Wei Wu

Funded by: Jiangsu Overseas Visiting Scholar Program for University Prominent Young & Middle-aged Teachers and Presidents

Funded by: Priority Academic Program for the Development of Jiangsu Higher Education Institutions

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ScienceOpen disciplines: Genetics

Keywords: dna methylation,dnmt,global methylation,imprinted gene,male infertility,polymorphism,sperm

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ScienceOpen disciplines: Genetics

Keywords: dna methylation, dnmt, global methylation, imprinted gene, male infertility, polymorphism, sperm

Idiopathic male infertility is strongly associated with aberrant DNA methylation of imprinted loci in sperm: a case-control study

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Electronic supplementary material

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G3: Genes|Genomes|Genetics

Most cited references 34

Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.

Chromosomal instability and tumors promoted by DNA hypomethylation.

Induction of tumors in mice by genomic hypomethylation.

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