Epigenetics and its role in male infertility

Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India.
Journal of Assisted Reproduction and Genetics (Impact Factor: 1.72). 01/2012; 29(3):213-23. DOI: 10.1007/s10815-012-9715-0
Source: PubMed


Male infertility is a common and complex problem affecting 1 in 20 men. Despite voluminous research in this field, in many cases, the underlying causes are unknown. Epigenetic factors play an important role in male infertility and these have been studied extensively. Epigenetic modifications control a number of processes within the body, but this review will concentrate on male fertility and the consequences of aberrant epigenetic regulation/modification. Many recent studies have identified altered epigenetic profiles in sperm from men with oligozoospermia and oligoasthenoteratozoospermia. During gametogenesis and germ cell maturation, germ cells undergo extensive epigenetic reprogramming that involves the establishment of sex-specific patterns in the sperm and oocytes. Increasing evidence suggests that genetic and environmental factors can have negative effects on epigenetic processes controlling implantation, placentation and fetal growth. This review provides an overview of the epigenetic processes (histone-to-protamine exchange and epigenetic reprogramming post-fertilization), aberrant epigenetic reprogramming and its association with fertility, possible risks for ART techniques, testicular cancer and the effect of environmental factors on the epigenetic processes.

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    • "A similar study carried out by Kang and co-workers did not show either altered hatching rates of medaka couples or progeny malformations when exposing breeders to a range of BPA from 837 to 3129 mg/L BPA near the mating time (Kang et al., 2002). Taking into account that zebrafish spermatogenesis lasts 21 days at 20 C (Schulz et al., 2010), our period of exposure affected the early stages of spermatogenesis (from spermatogonia to spermatid) potentially compromising genome, epigenome and transcriptome of spermatozoa (Dada et al., 2012). The lack of impact on the progeny development of medaka when exposing after spermiogenesis has been completed is, therefore, another evidence of the stage-specific effects caused by BPA. "
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    ABSTRACT: Bisphenol A (BPA) is an endocrine disruptor used in manufacturing of plastic devices, resulting in an ubiquitous presence in the environment linked to human infertility, obesity or cardiovascular diseases. Both transcriptome and epigenome modifications lie behind these disorders that might be inherited transgenerationally when affecting germline. To assess potential effects of paternal exposure on offspring development, adult zebrafish males were exposed to BPA during spermatogenesis and mated with non-treated females. Results showed an increase in the rate of heart failures of progeny up to the F2, as well as downregulation of 5 genes involved in cardiac development in F1 embryos. Moreover, BPA causes a decrease in F0 and F1 sperm remnant mRNAs related to early development. Results reveal a paternal inheritance of changes in the insulin signaling pathway due to downregulation of insulin receptor β mRNAs, suggesting a link between BPA male exposure and disruption of cardiogenesis in forthcoming generations. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Environmental Pollution 08/2015; 206:667-678. DOI:10.1016/j.envpol.2015.08.016 · 4.14 Impact Factor
    • "Thus, the time taken from donating semen until its usage in assisted reproductive technology (ART) procedures is critical for their success. The quality of the male genetic material , which depends, among other things, on the degree of fragmentation of nuclear DNA, will have a direct impact on the embryo development and the health of future generations (Borini et al., 2006; Dada et al., 2012 "
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    ABSTRACT: Sperm DNA fragmentation varies between individuals and is more pronounced with increased patient age and time after sperm donation. The intensification of DNA fragmentation depends on the balance of the oxidoreductive system, which is regulated mainly by two enzymes – superoxide dismutase (SOD) and catalase. The objective of this study was to determine the relationship between sperm DNA fragmentation dynamics, fertility and seminal SOD and catalase activity. The study was conducted in 2013 and 2014 at the Non-Public Health Care Unit 'Ovum Reproduction and Andrology' in Lublin, Lublin, Poland, and covered 218 men aged 25–35 (85 fertile and 133 patients treated for infertility). Percentage of fragmented DNA was measured in a modified chromatin dispersion test at four time points after sperm donation (t = 0, 3, 6, 12 h). SOD and catalase activities were determined spectrophotometrically. We confirmed that the activity of SOD in the seminal plasma of men with reproductive disorders was lower compared with fertile men. Conversely, no significant correlations were found between fertility and catalase activity. Sperm DNA of infertile males was initially more fragmented than fertile male sperm DNA. SOD and catalase activity did not correlate with the degree of DNA fragmentation in fertile men. In men with reproductive disorders, the rate of DNA fragmentation was slow within first 3 h after sperm donation and then increased between 6 and 12 h. In this group of infertile men, those with higher SOD activity had a lower DNA fragmentation index (DFI) after 12 h, and a reduced rate of intensity of fragmentation from 6 to 12 h. Alternatively, higher catalase activity among men treated for infertility was accompanied by higher initial DFI and higher rate of DNA fragmentation from 6 to 12 h. These results highlight the importance of determining a proper time window between sperm donation and procedures of assisted reproductive technology.
    Andrology 07/2015; 3(4):748-55. DOI:10.1111/andr.12061 · 2.30 Impact Factor
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    • "Interestingly, hypomethylated promoters in the mature sperm are the promoters of developmental transcription and signalling factors. In mammals, correct sperm DNA methylation is suggested to be essential for both fertilization and early embryo viability (Li et al., 1992; Okano et al., 1999; Bourc'his and Bestor, 2004; Anway et al., 2005; Yaman and Grandjean, 2006; Carrell and Hammoud, 2010; Romero et al., 2011; Dada et al., 2012; Jenkins and Carrell, 2012) and therefore improved knowledge of the epigenetics of sperm is not only necessary to understand these processes, but may also provide clues to the potential causes of male infertility of unknown origin. Early studies of sperm DNA methylation analysis were specifically performed in imprinted genes as an increased risk of congenital imprinting diseases in children conceived through assisted reproductive technologies (ART) had been suggested. "
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    ABSTRACT: Are there DNA methylation alterations in sperm that could explain the reduced biological fertility of male partners from couples with unexplained infertility? DNA methylation patterns, not only at specific loci but also at Alu Yb8 repetitive sequences, are altered in infertile individuals compared with fertile controls. Aberrant DNA methylation of sperm has been associated with human male infertility in patients demonstrating either deficiencies in the process of spermatogenesis or low semen quality. Case and control prospective study. This study compares 46 sperm samples obtained from 17 normospermic fertile men and 29 normospermic infertile patients. Illumina Infinium HD Human Methylation 450K arrays were used to identify genomic regions showing differences in sperm DNA methylation patterns between five fertile and seven infertile individuals. Additionally, global DNA methylation of sperm was measured using the Methylamp Global DNA Methylation Quantification Ultra kit (Epigentek) in 14 samples, and DNA methylation at several repetitive sequences (LINE-1, Alu Yb8, NBL2, D4Z4) measured by bisulfite pyrosequencing in 44 sperm samples. A sperm-specific DNA methylation pattern was obtained by comparing the sperm methylomes with the DNA methylomes of differentiated somatic cells using data obtained from methylation arrays (Illumina 450 K) of blood, neural and glial cells deposited in public databases. In this study we conduct, for the first time, a genome-wide study to identify alterations of sperm DNA methylation in individuals with unexplained infertility that may account for the differences in their biological fertility compared with fertile individuals. We have identified 2752 CpGs showing aberrant DNA methylation patterns, and more importantly, these differentially methylated CpGs were significantly associated with CpG sites which are specifically methylated in sperm when compared with somatic cells. We also found statistically significant (P < 0.001) associations between DNA hypomethylation and regions corresponding to those which, in somatic cells, are enriched in the repressive histone mark H3K9me3, and between DNA hypermethylation and regions enriched in H3K4me1 and CTCF, suggesting that the relationship between chromatin context and aberrant DNA methylation of sperm in infertile men could be locus-dependent. Finally, we also show that DNA methylation patterns, not only at specific loci but also at several repetitive sequences (LINE-1, Alu Yb8, NBL2, D4Z4), were lower in sperm than in somatic cells. Interestingly, sperm samples at Alu Yb8 repetitive sequences of infertile patients showed significantly lower DNA methylation levels than controls. Our results are descriptive and further studies would be needed to elucidate the functional effects of aberrant DNA methylation on male fertility. Overall, our data suggest that aberrant sperm DNA methylation might contribute to fertility impairment in couples with unexplained infertility and they provide a promising basis for future research. This work has been financially supported by Fundación Cientifica de la AECC (to R.G.U.); IUOPA (to G.F.B.); FICYT (to E.G.T.); the Spanish National Research Council (CSIC; 200820I172 to M.F.F.); Fundación Ramón Areces (to M.F.F); the Plan Nacional de I+D+I 2008-2011/2013-2016/FEDER (PI11/01728 to AF.F., PI12/01080 to M.F.F. and PI12/00361 to S.L.); the PN de I+D+I 2008-20011 and the Generalitat de Catalunya (2009SGR01490). A.F.F. is sponsored by ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (CP11/00131). S.L. is sponsored by the Researchers Stabilization Program from the Spanish National Health System (CES09/020). The IUOPA is supported by the Obra Social Cajastur, Spain. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Reproduction 03/2015; 30(5). DOI:10.1093/humrep/dev053 · 4.57 Impact Factor
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