Sperm Epigenetics and Its Impact on Male Fertility, Pregnancy Loss, and Somatic Health of Future Offsprings

Abstract

Sperm epigenetic programming is tailored to meet the need of this specialized cell, which include its interaction with the oocyte during fertilization and early embryo development. The unique nature of the sperm epigenome has resulted in multiple studies investigating how perturbations in epigenetics might impact male fertility and early embryo development. In addition, sperm epigenetics appear to be altered by specific environmental exposures, which could provide a link for investigating the role of these triggers in somatic health of off springs produced. This has the potential of explaining otherwise missing heritability factors seen with several diseases. While this field of investigation is new and with limited validation, it is intriguing and further studies are warranted.

Keywords

epigenetics - male infertility - pregnancy loss - transgenerational effects - somatic health

• References

• 1 Consortium EP. ; ENCODE Project Consortium. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol 2011; 9 (04) e1001046
• 2 Jenkins TG, Carrell DT. The sperm epigenome and potential implications for the developing embryo. Reproduction 2012; 143 (06) 727-734
• 3 Zemach A, McDaniel IE, Silva P, Zilberman D. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 2010; 328 (5980): 916-919
• 4 Compere SJ, Palmiter RD. DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Cell 1981; 25 (01) 233-240
• 5 Berger SL. Histone modifications in transcriptional regulation. Curr Opin Genet Dev 2002; 12 (02) 142-148
• 6 Wright DE, Wang CY, Kao CF. Flickin' the ubiquitin switch: the role of H2B ubiquitylation in development. Epigenetics 2011; 6 (10) 1165-1175
• 7 Dion MF, Altschuler SJ, Wu LF, Rando OJ. Genomic characterization reveals a simple histone H4 acetylation code. Proc Natl Acad Sci U S A 2005; 102 (15) 5501-5506
• 8 Govin J, Caron C, Lestrat C, Rousseaux S, Khochbin S. The role of histones in chromatin remodelling during mammalian spermiogenesis. Eur J Biochem 2004; 271 (17) 3459-3469
• 9 Kouzarides T. Chromatin modifications and their function. Cell 2007; 128 (04) 693-705
• 10 Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 2005; 6 (11) 838-849
• 11 Imhof A, Yang XJ, Ogryzko VV, Nakatani Y, Wolffe AP, Ge H. Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 1997; 7 (09) 689-692
• 12 Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997; 389 (6649): 349-352
• 13 Shirakata Y, Hiradate Y, Inoue H, Sato E, Tanemura K. Histone h4 modification during mouse spermatogenesis. J Reprod Dev 2014; 60 (05) 383-387
• 14 Wilkinson KD. The discovery of ubiquitin-dependent proteolysis. Proc Natl Acad Sci U S A 2005; 102 (43) 15280-15282
• 15 Chandrasekharan MB, Huang F, Sun ZW. Histone H2B ubiquitination and beyond: Regulation of nucleosome stability, chromatin dynamics and the trans-histone H3 methylation. Epigenetics 2010; 5 (06) 460-468
• 16 Kuo MH, Allis CD. Roles of histone acetyltransferases and deacetylases in gene regulation. BioEssays 1998; 20 (08) 615-626
• 17 Trojer P, Reinberg D. Histone lysine demethylases and their impact on epigenetics. Cell 2006; 125 (02) 213-217
• 18 Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell 2002; 108 (04) 475-487
• 19 Fan HY, He X, Kingston RE, Narlikar GJ. Distinct strategies to make nucleosomal DNA accessible. Mol Cell 2003; 11 (05) 1311-1322
• 20 Hammoud SS, Nix DA, Zhang H, Purwar J, Carrell DT, Cairns BR. Distinctive chromatin in human sperm packages genes for embryo development. Nature 2009; 460 (7254): 473-478
• 21 James E, Jenkins TG. Epigenetics, infertility, and cancer: future directions. Fertil Steril 2018; 109 (01) 27-32
• 22 Oliva R. Protamines and male infertility. Hum Reprod Update 2006; 12 (04) 417-435
• 23 Carrell DT, Emery BR, Hammoud S. Altered protamine expression and diminished spermatogenesis: what is the link?. Hum Reprod Update 2007; 13 (03) 313-327
• 24 Benchaib M, Braun V, Ressnikof D. , et al. Influence of global sperm DNA methylation on IVF results. Hum Reprod 2005; 20 (03) 768-773
• 25 Aston KI, Punj V, Liu L, Carrell DT. Genome-wide sperm deoxyribonucleic acid methylation is altered in some men with abnormal chromatin packaging or poor in vitro fertilization embryogenesis. Fertil Steril 2012; 97 (02) 285-292
• 26 Aston KI, Uren PJ, Jenkins TG. , et al. Aberrant sperm DNA methylation predicts male fertility status and embryo quality. Fertil Steril 2015; 104 (06) 1388-97.e1 , 5
• 27 Urdinguio RG, Bayón GF, Dmitrijeva M. , et al. Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility. Hum Reprod 2015; 30 (05) 1014-1028
• 28 Camprubí C, Salas-Huetos A, Aiese-Cigliano R. , et al. Spermatozoa from infertile patients exhibit differences of DNA methylation associated with spermatogenesis-related processes: an array-based analysis. Reprod Biomed Online 2016; 33 (06) 709-719
• 29 Du Y, Li M, Chen J. , et al. Promoter targeted bisulfite sequencing reveals DNA methylation profiles associated with low sperm motility in asthenozoospermia. Hum Reprod 2016; 31 (01) 24-33
• 30 Jenkins TG, Aston KI, Hotaling JM, Shamsi MB, Simon L, Carrell DT. Teratozoospermia and asthenozoospermia are associated with specific epigenetic signatures. Andrology 2016; 4 (05) 843-849
• 31 Santi D, De Vincentis S, Magnani E, Spaggiari G. Impairment of sperm DNA methylation in male infertility: a meta-analytic study. Andrology 2017; 5 (04) 695-703
• 32 Schmauss C, Brines ML, Lerner MR. The gene encoding the small nuclear ribonucleoprotein-associated protein N is expressed at high levels in neurons. J Biol Chem 1992; 267 (12) 8521-8529
• 33 Zhang Y, Tycko B. Monoallelic expression of the human H19 gene. Nat Genet 1992; 1 (01) 40-44
• 34 Dong H, Wang Y, Zou Z. , et al. Abnormal methylation of imprinted genes and cigarette smoking: assessment of their association with the risk of male infertility. Reprod Sci 2017; 21 (01) 114-123
• 35 Mayer W, Hemberger M, Frank HG. , et al. Expression of the imprinted genes MEST/Mest in human and murine placenta suggests a role in angiogenesis. Dev Dyn 2000; 217 (01) 1-10
• 36 Jung H, Lee SK, Jho EH. Mest/Peg1 inhibits Wnt signalling through regulation of LRP6 glycosylation. Biochem J 2011; 436 (02) 263-269
• 37 Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 2005; 437 (7057): 432-435
• 38 Glaser S, Lubitz S, Loveland KL. , et al. The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenetics Chromatin 2009; 2 (01) 5
• 39 Fenic I, Sonnack V, Failing K, Bergmann M, Steger K. In vivo effects of histone-deacetylase inhibitor trichostatin-A on murine spermatogenesis. J Androl 2004; 25 (05) 811-818
• 40 Fenic I, Hossain HM, Sonnack V. , et al. In vivo application of histone deacetylase inhibitor trichostatin-a impairs murine male meiosis. J Androl 2008; 29 (02) 172-185
• 41 Balhorn R, Reed S, Tanphaichitr N. Aberrant protamine 1/protamine 2 ratios in sperm of infertile human males. Experientia 1988; 44 (01) 52-55
• 42 Hecht NB. Regulation of ‘haploid expressed genes’ in male germ cells. J Reprod Fertil 1990; 88 (02) 679-693
• 43 Oliva R, Dixon GH. Vertebrate protamine gene evolution I. Sequence alignments and gene structure. J Mol Evol 1990; 30 (04) 333-346
• 44 Aoki VW, Liu L, Carrell DT. Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males. Hum Reprod 2005; 20 (05) 1298-1306
• 45 Aoki VW, Liu L, Jones KP. , et al. Sperm protamine 1/protamine 2 ratios are related to in vitro fertilization pregnancy rates and predictive of fertilization ability. Fertil Steril 2006; 86 (05) 1408-1415
• 46 Zhang X, San Gabriel M, Zini A. Sperm nuclear histone to protamine ratio in fertile and infertile men: evidence of heterogeneous subpopulations of spermatozoa in the ejaculate. J Androl 2006; 27 (03) 414-420
• 47 Arpanahi A, Brinkworth M, Iles D. , et al. Endonuclease-sensitive regions of human spermatozoal chromatin are highly enriched in promoter and CTCF binding sequences. Genome Res 2009; 19 (08) 1338-1349
• 48 El Hajj N, Zechner U, Schneider E. , et al. Methylation status of imprinted genes and repetitive elements in sperm DNA from infertile males. Sex Dev 2011; 5 (02) 60-69
• 49 Eden S, Cedar H. Role of DNA methylation in the regulation of transcription. Curr Opin Genet Dev 1994; 4 (02) 255-259
• 50 Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 1992; 69 (06) 915-926
• 51 Panning B, Jaenisch R. DNA hypomethylation can activate Xist expression and silence X-linked genes. Genes Dev 1996; 10 (16) 1991-2002
• 52 Walsh CP, Chaillet JR, Bestor TH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 1998; 20 (02) 116-117
• 53 Seifertová M, Veselý J, Cihák A. Enhanced mortality in offsprings of male mice treated with 5-azacytidine prior to mating. Morphological changes in testes. Neoplasma 1976; 23 (01) 53-60
• 54 Oakes CC, Kelly TL, Robaire B, Trasler JM. Adverse effects of 5-aza-2′-deoxycytidine on spermatogenesis include reduced sperm function and selective inhibition of de novo DNA methylation. J Pharmacol Exp Ther 2007; 322 (03) 1171-1180
• 55 Rogenhofer N, Ott J, Pilatz A. , et al. Unexplained recurrent miscarriages are associated with an aberrant sperm protamine mRNA content. Hum Reprod 2017; 32 (08) 1574-1582
• 56 Donkin I, Barrès R. Sperm epigenetics and influence of environmental factors. Mol Metab 2018; 14: 1-11
• 57 Noble D, Jablonka E, Joyner MJ, Müller GB, Omholt SW. Evolution evolves: physiology returns to centre stage. J Physiol 2014; 592 (11) 2237-2244
• 58 Carone BR, Fauquier L, Habib N. , et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 2010; 143 (07) 1084-1096
• 59 Ng SF, Lin RC, Maloney CA, Youngson NA, Owens JA, Morris MJ. Paternal high-fat diet consumption induces common changes in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female rat offspring. FASEB J 2014; 28 (04) 1830-1841
• 60 Radford EJ, Ito M, Shi H. , et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 2014; 345 (6198): 1255903
• 61 de Castro Barbosa T, Ingerslev LR, Alm PS. , et al. High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol Metab 2015; 5 (03) 184-197
• 62 Denham J, O'Brien BJ, Harvey JT, Charchar FJ. Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans. Epigenomics 2015; 7 (05) 717-731
• 63 Donkin I, Versteyhe S, Ingerslev LR. , et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab 2016; 23 (02) 369-378
• 64 Ingerslev LR, Donkin I, Fabre O. , et al. Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots. Clin Epigenetics 2018; 10: 12
• 65 Jenkins TG, James ER, Alonso DF. , et al. Cigarette smoking significantly alters sperm DNA methylation patterns. Andrology 2017; 5 (06) 1089-1099
• 66 Chang JS, Selvin S, Metayer C, Crouse V, Golembesky A, Buffler PA. Parental smoking and the risk of childhood leukemia. Am J Epidemiol 2006; 163 (12) 1091-1100
• 67 Lee KM, Ward MH, Han S. , et al. Paternal smoking, genetic polymorphisms in CYP1A1 and childhood leukemia risk. Leuk Res 2009; 33 (02) 250-258
• 68 Secretan B, Straif K, Baan R. , et al; WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens--Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009; 10 (11) 1033-1034
• 69 Laqqan M, Tierling S, Alkhaled Y, LoPorto C, Hammadeh ME. Alterations in sperm DNA methylation patterns of oligospermic males. Reprod Biol 2017; 17 (04) 396-400
• 70 Laqqan M, Tierling S, Alkhaled Y, Porto CL, Solomayer EF, Hammadeh ME. Aberrant DNA methylation patterns of human spermatozoa in current smoker males. Reprod Toxicol 2017; 71: 126-133
• 71 Laqqan M, Tierling S, Alkhaled Y, Lo Porto C, Solomayer EF, Hammadeh M. Spermatozoa from males with reduced fecundity exhibit differential DNA methylation patterns. Andrology 2017; 5 (05) 971-978
• 72 Montjean D, Zini A, Ravel C. , et al. Sperm global DNA methylation level: association with semen parameters and genome integrity. Andrology 2015; 3 (02) 235-240
• 73 Kuhtz J, Schneider E, El Hajj N. , et al. Epigenetic heterogeneity of developmentally important genes in human sperm: implications for assisted reproduction outcome. Epigenetics 2014; 9 (12) 1648-1658
• 74 Francis S, Yelumalai S, Jones C, Coward K. Aberrant protamine content in sperm and consequential implications for infertility treatment. Hum Fertil (Camb) 2014; 17 (02) 80-89
• 75 Rajender S, Avery K, Agarwal A. Epigenetics, spermatogenesis and male infertility. Mutat Res 2011; 727 (03) 62-71