Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-5f56664f6-2gss9 Total loading time: 0 Render date: 2025-05-08T06:29:23.167Z Has data issue: false hasContentIssue false

Chapter 6 - Genomics, Epigenetics, and Male Reproduction

from Section 1 - Scientific Foundations of Male Infertility

Published online by Cambridge University Press:  08 July 2023

By
Millissia Ben Maamar  and
Michael K. Skinner
Edited by
Larry I. Lipshultz ,
Stuart S. Howards ,
Craig S. Niederberger  and
Dolores J. Lamb
Larry I. Lipshultz
Affiliation:
Baylor College of Medicine, Texas
Stuart S. Howards
Affiliation:
University of Virginia
Craig S. Niederberger
Affiliation:
University of Illinois, Chicago
Dolores J. Lamb
Affiliation:
Weill Cornell Medical College, New York
Get access

Summary

The definition of male infertility is the inability of a male to impregnate a fertile female. Infertility is a worldwide problem and, according to Sharlip et al., affects around 15 percent of couples [1]. Based on different studies, approximately 20–30 percent of infertility cases are due to male problems, 20–35 percent due to female problems, and 25–40 percent due to combined problems in both parts, while in 10–20 percent of cases, no causes are found (hence idiopathic infertility). Furthermore, nearly half of human infertility cases can be attributed to abnormal spermatogenesis [2]. Genetic causes for male infertility are related to a limited number of cases in which altered seminal parameters (motility, morphology, and concentration) are directly associated with a genetic mutation such as chromosome aberration or microdeletions at the Y chromosome [3]. The complexities to define the origin of this infertility have led researchers to suspect that both genetic and environmental factors contribute. The complex pathology and difficulty in identifying molecular abnormalities make it challenging to determine the etiology of male infertility. The molecular mechanisms and chromosomal variations associated with the infertility phenotype, consecutive pregnancy losses, or recurrent miscarriage, and idiopathic infertility cases remain to be elucidated [4, 5]. However, recent research indicates the presence of epigenetic alterations may provide further insights into the pathogenesis of male infertility [6]. The increased use of human assisted reproductive technology (ART) has created an enormous interest in identifying, diagnosing, and potentially treating male infertility. In recent years, advancements in the field of ART have provided indirect evidence for the role of epigenetic mechanisms in male infertility [2].

Type
Chapter
Information
Infertility in the Male , pp. 94 - 106
Publisher: Cambridge University Press
Print publication year: 2023

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Further Reading

Ben Maamar, M, Sadler-Riggleman, I, Skinner, MK. In: Skinner, MK, ed. Encyclopedia of Reproduction, 2nd ed, Vol. 5. Oxford: Academic Press, 2018; pp. 117–23.Google Scholar
Kubsad, D, Ben Maamar, M, Skinner, MK. Developmental epigenetic analysis of sperm. In: Skinner, MK, ed. Encyclopedia of Reproduction, 2nd ed, Vol. 5. Oxford: Academic Press, 2018; pp. 239–44.Google Scholar
Nilsson, EE, Sadler-Riggleman, I, Skinner, MK. Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenet 2018;4:dvy016.Google Scholar

References

Sharlip, ID, Jarow, JP, Belker, AM, et al. Best practice policies for male infertility. Fertil Steril 2002;77:873–82.Google Scholar
Kitamura, A, Miyauchi, N, Hamada, H, et al. Epigenetic alterations in sperm associated with male infertility. Congenit Anom (Kyoto) 2015;55:133–44.Google Scholar
Jodar, M, Selvaraju, S, Sendler, E, Diamond, MP, Krawetz, SA. The presence, role and clinical use of spermatozoal RNAs. Hum Reprod Update 2013;19:604–24.Google Scholar
Minocherhomji, S, Athalye, AS, Madon, PF, Kulkarni, D,Uttamchandani, SA, Parikh, FR. A case-control study identifying chromosomal polymorphic variations as forms of epigenetic alterations associated with the infertility phenotype. Fertil Steril 2009;92:88–95.Google Scholar
Rull, K, Nagirnaja, L, Laan, M. Genetics of recurrent miscarriage: challenges, current knowledge, future directions. Front Genet 2012;3:34.Google Scholar
Jenkins, TG, Aston, KI, James, ER, Carrell, DT. Sperm epigenetics in the study of male fertility, offspring health, and potential clinical applications. Syst Biol Reprod Med 2017;63:69–76.Google Scholar
Holliday, R, Pugh, JE. DNA modification mechanisms and gene activity during development. Science 1975;187:226–32.Google Scholar
Singer, J, Roberts-Ems, J, Riggs, AD. Methylation of mouse liver DNA studied by means of the restriction enzymes msp I and hpa II. Science 1979;203:1019–21.CrossRefGoogle ScholarPubMed
Liu, MY, DeNizio, JE, Schutsky, EK, Kohli, RM. The expanding scope and impact of epigenetic cytosine modifications. Curr Opin Chem Biol 2016;33:67–73.Google Scholar
Loidl, P. Histone acetylation: facts and questions. Chromosoma 1994;103:441–9.CrossRefGoogle ScholarPubMed
Davie, JR. Covalent modifications of histones: expression from chromatin templates. Curr Opin Genet Dev 1998;8:173–8.Google Scholar
Kornfeld, JW, Bruning, JC. Regulation of metabolism by long, non-coding RNAs. Front Genet 2014;5:57.Google Scholar
Yaniv, M. Chromatin remodeling: from transcription to cancer. Cancer Genet 2014;207:352–7.Google Scholar
Reik, W, Surani, MA. Germline and pluripotent stem cells. Cold Spring Harb Perspect Biol 2015;7:a019422.Google Scholar
Nilsson, E, Sadler-Riggleman, I, Skinner, MK. Environmentally induced epigenetic transgenerational inheritance of disease. Environ Epigenet 2018;4:dvy016.Google Scholar
Guerrero-Bosagna, C, Skinner, J. Environmentally induced epigenetic transgenerational inheritance of male infertility. Curr Opin Genet Dev 2014;26:79–88.Google Scholar
Anway, MD, Cupp, AS, Uzumcu, M, Skinner, MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005;308:1466–9.Google Scholar
Oliva, R, Castillo, J. Proteomics and the genetics of sperm chromatin condensation. Asian J Androl 2011;13:24–30.Google Scholar
Murphy, KE, Murphy, PJ, Carrell, JT. Epigenetic changes in the paternal germline. In: Tollefsbol, T, ed. Transgenerational Epigenetics. London: Academic Press, 2014; pp. 43–55.CrossRefGoogle Scholar
Gunes, S, Kulac, T. The role of epigenetics in spermatogenesis. Turk J Urol 2013;39:181–7.Google Scholar
Portela, A, Esteller, M. Epigenetic modifications and human disease. Nat Biotechnol 2010;28:1057–68.Google Scholar
Kim, YZ. Altered histone modifications in gliomas. Brain Tumor Res Treat 2014;2:7–21.Google Scholar
Campos, E, Reinberg, D. Histones: annotating chromatin. Annu Rev Genet 2009;43:559–99.Google Scholar
Godde, JS, Ura, K. Dynamic alterations of linker histone variants during development. Int J Dev Biol 2009;53:215–24.Google Scholar
Govin, J, Caron, C, Lestrat, C, Rousseaux, S, Khochbin, S. The role of histones in chromatin remodelling during mammalian spermiogenesis. Eur J Biochem 2004;271:3459–69.Google Scholar
Montellier, E, Boussouar, F, Rousseaux, S, et al. Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B. Genes Dev 2013;27:1680–92.CrossRefGoogle ScholarPubMed
Samson, M, Jow, MM, Wong, CC, et al. The specification and global reprogramming of histone epigenetic marks during gamete formation and early embryo development in C. elegans. PLoS Genet 2014;10:e1004588.Google Scholar
Skinner, MK. Endocrine disruptor induction of epigenetic transgenerational inheritance of disease. Mol Cell Endocrinol 2014;398:4–12.Google Scholar
Skinner, MK. Endocrine disruptors in 2015: epigenetic transgenerational inheritance. Nat Rev Endocrinol 2016;12:68–70.Google Scholar
Layman, LC. The genetic basis of female reproductive disorders: etiology and clinical testing. Mol Cell Endocrinol 2013;370:138–48.Google Scholar
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:e1289.CrossRefGoogle ScholarPubMed
Hartmann, S, Bergmann, M, Bohle, RM, Weidner, W, Steger, K. Genetic imprinting during impaired spermatogenesis. Mol Hum Reprod 2006;12:407–11.Google Scholar
Montjean, D, Ravel, C, Benkhalifa, M, et al. Methylation changes in mature sperm deoxyribonucleic acid from oligozoospermic men: assessment of genetic variants and assisted reproductive technology outcome. Fertil Steril 2013;100:1241–7.CrossRefGoogle ScholarPubMed
Manipalviratn, S, DeCherney, A, Segars, J. Imprinting disorders and assisted reproductive technology. Fertil Steril 2009;91:305–15.Google Scholar
DeAngelis, AM, Martini, AE, Owen, CM. Assisted reproductive technology and epigenetics. Semin Reprod Med 2018;36: 221–32.CrossRefGoogle ScholarPubMed
Das, L, Parbin, S, Pradhan, N, Kausar, C, Patra, SK. Epigenetics of reproductive infertility. Front Biosci (Schol Ed) 2017;9:509–35.Google Scholar
Marques, CJ, Costa, P, Vaz, B, et al. Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia. Mol Hum Reprod 2008; 14:67–74.CrossRefGoogle ScholarPubMed
Li, B, Li, JB, Xiao, XF, et al. Altered DNA methylation patterns of the H19 differentially methylated region and the DAZL gene promoter are associated with defective human sperm. PLoS ONE 2013;8:e71215.Google Scholar
Stuppia, L, Franzago, M, Ballerini, P, Gatta, V, Antonucci, I. Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics 2015;7:120.Google Scholar
Aston, KI, Uren, PJ, Jenkins, TG, et al. Aberrant sperm DNA methylation predicts male fertility status and embryo quality. Fertil Steril 2015;104:1388–97.Google Scholar
Bannister, AJ, Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res 2011;21:381–95.Google Scholar
Hazzouri, M, Pivot-Pajot, C, Faure, AK, et al. Regulated hyperacetylation of core histones during mouse spermatogenesis: involvement of histone deacetylases. Eur J Cell Biol 2000;79:950–60.Google Scholar
Steilmann, C, Cavalcanti, MC, Bartkuhn, M, et al. The interaction of modified histones with the bromodomain testis-specific (BRDT) gene and its mRNA level in sperm of fertile donors and subfertile men. Reproduction 2010;140:435–43.Google Scholar
Okada, Y, Scott, G, Ray, MK, Mishina, Y, Zhang, Y. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 2007;450:119–23.Google Scholar
Sonnack, V, Failing, K, Bergmann, M, Steger, K. Expression of hyperacetylated histone H4 during normal and impaired human spermatogenesis. Andrologia 2002;34:384–90.Google Scholar
Paradowska, AS, Miller, D, Spiess, AN, et al. Genome wide identification of promoter binding sites for H4K12ac in human sperm and its relevance for early embryonic development. Epigenetics 2012;7:1057–70.CrossRefGoogle ScholarPubMed
Lee, MG, Wynder, C, Cooch, N, Shiekhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 2005;437:432–5.Google Scholar
Bao, J, Bedford, MT. Epigenetic regulation of the histone-to-protamine transition during spermiogenesis. Reproduction 2016;151:R55–70.Google Scholar
Shi, Y, Lan, F, Matson, C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004;119:941–53.Google Scholar
Waterland, RA, Michels, KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007;27:363–88.Google Scholar
Liu, Z, Zhou, S, Liao, L, Chen, X, Meistrich, M, Xu, J. Jmjd1a demethylase-regulated histone modification is essential for cAMP-response element modulator-regulated gene expression and spermatogenesis. J Biol Chem 2010;285:2758–70.Google Scholar
Gomes, AQ, Nolasco, S, Soares, H. Non-coding RNAs: multi-tasking molecules in the cell. Int J Mol Sci 2013;14:16010–39.Google Scholar
Saxe, JP, Lin, H. Small noncoding RNAs in the germline. Cold Spring Harb Perspect Biol 2011;3:a002717.Google Scholar
Gou, LT, Dai, P, Liu, MF. Small noncoding RNAs and male infertility. Wiley Interdiscip Rev RNA 2014;5:733-45.Google Scholar
Khazaie, Y, Nasr Esfahani, MH. MicroRNA and male infertility: a potential for diagnosis. Int J Fertil Steril 2014;8:113–18.Google Scholar
Luk, AC, Chan, WY, Rennert, OM, Lee, TL. Long noncoding RNAs in spermatogenesis: insights from recent high-throughput transcriptome studies. Reproduction 2014;147:R131–41.Google Scholar
Sharma, R, Biedenharn, KR, Fedor, JM, Agarwal, A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol 2013;11:66.Google Scholar
Cloonan, YK, Holt, VL, Goldberg, J. Male factor infertility: a twin study. Paediatr Perinat Epidemiol 2007;21:229–34.Google Scholar
Cortessis, VK, Thomas, DC, Levine, AJ, et al. Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships. Hum Genet 2012;131:1565–89.Google Scholar
Mirbahai, L, Chipman, JK. Epigenetic memory of environmental organisms: a reflection of lifetime stressor exposures. Mutat Res Genet Toxicol Environ Mutagen 2014;764–5:10–17.Google Scholar
Wei, Y, Schatten, H, Sun, QY. Environmental epigenetic inheritance through gametes and implications for human reproduction. Hum Reprod Update 2015;21:194–208.Google Scholar
Baccarelli, A, Bollati, V. Epigenetics and environmental chemicals. Curr Opin Pediatr 2009;21:243–51.Google Scholar
Wilhelm-Benartzi, CS, Houseman, EA, Maccani, MA, et al. In utero exposures, infant growth, and DNA methylation of repetitive elements and developmentally related genes in human placenta. Environ Health Perspect 2012;120:296–302.Google Scholar
Martinez-Arguelles, DB, Campioli, E, Culty, M, Zirkin, BR, Papadopoulos, V. Fetal origin of endocrine dysfunction in the adult: the phthalate model. J Steroid Biochem Mol Biol 2013;137:5–17.Google Scholar
Skinner, MK, Manikkam, M, Guerrero-Bosagna, C. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 2010;21:214–22.Google Scholar
Uzumcu, M, Suzuki, H, Skinner, MK. Effect of the anti-androgenic endocrine disruptor vinclozolin on embryonic testis cord formation and postnatal testis development and function. Reprod Toxicol 2004;18:765–74.Google Scholar
LaRocca, J, Boyajian, A, Brown, C, Smith, SD, Hixon, M. Effects of in utero exposure to bisphenol A or diethylstilbestrol on the adult male reproductive system. Birth Defects Res B Dev Reprod Toxicol 2011;92:526–33.Google Scholar
Park, CJ, Nah, WH, Lee, JE, Oh, YS, Gye, MC. Butyl paraben-induced changes in DNA methylation in rat epididymal spermatozoa. Andrologia 2012;44 Suppl 1:187–93.Google Scholar
Stouder, C, Paoloni-Giacobino, A. Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes. Reproduction 2011;141:207–16.Google Scholar
Skinner, MK, Ben Maamar, M, Sadler-Riggleman, I, et al. Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease. Epigenetics Chromatin 2018;11:8.Google Scholar
Ben Maamar, M, Sadler-Riggleman, I, Beck, D, et al. Alterations in sperm DNA methylation, non-coding RNA expression, and histone retention mediate vinclozolin-induced epigenetic transgenerational inheritance of disease. Environ Epigenet 2018;4:dvy010.Google Scholar
Sadler-Riggleman, I, Klukovich, R, Nilsson, E, et al. Epigenetic Transgenerational inheritance of testis pathology and Sertoli cell epimutations: generational origins of male infertility. Environ Epigenet 2019;5:dvz013.Google Scholar
Skakkebaek, NE, Rajpert-De Meyts, E, Jorgensen, N, et al. Testicular cancer trends as ‘whistle blowers’ of testicular developmental problems in populations. Int J Androl 2007;30:198–204; discussion 204–5.Google Scholar
Singh, KP, Kumari, R, Pevey, C, Jackson, D, DuMond, JW. Long duration exposure to cadmium leads to increased cell survival, decreased DNA repair capacity, and genomic instability in mouse testicular Leydig cells. Cancer Lett 2009;279:84–92.Google Scholar
Dubrova, YE. Radiation-induced transgenerational instability. Oncogene 2003;22:7087–93.Google Scholar
Merrifield, M, Kovalchuk, O. Epigenetics in radiation biology: a new research frontier. Front Genet 2013;4:40.Google Scholar
Skinner, MK. Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability. Epigenetics 2011;6:838–42.Google Scholar
Skinner, MK. What is an epigenetic transgenerational phenotype? F3 or F2. Reprod Toxicol 2008;25:2–6.Google Scholar
Guerrero-Bosagna, C, Savenkova, M, Haque, MM, Nilsson, E, Skinner, MK. Environmentally induced epigenetic transgenerational inheritance of altered Sertoli cell transcriptome and epigenome: molecular etiology of male infertility. PLoS ONE 2013;8:e59922.Google Scholar
Anway, MD, Memon, MA, Uzumcu, M, Skinner, MK. Transgenerational effect of the endocrine disruptor vinclozolin on male spermatogenesis. J Androl 2006;27:868–79.Google Scholar
Manikkam, M, Guerrero-Bosagna, C, Tracey, R, Haque, MM, Skinner, MK. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS ONE 2012;7:e31901.Google Scholar
Pastuszak, AW, Lamb, DJ. The genetics of male fertility – from basic science to clinical evaluation. J Androl 2012;33:1075–84.Google Scholar
Matzuk, MM, Lamb, DJ. The biology of infertility: research advances and clinical challenges. Nat Med 2008;14:1197–213.Google Scholar
Sanabria, M, Cucielo, MS, Guerra, MT, et al. Sperm quality and fertility in rats after prenatal exposure to low doses of TCDD: a three-generation study. Reprod Toxicol 2016;65:29–38.Google Scholar
Skakkebaek, NE, Rajpert-De Meyts, E, Buck Louis, GM, et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev 2016;96:55–97.Google Scholar
Jensen, TK, Jacobsen, R, Christensen, K, Nielsen, NC, Bostofte, E. Good semen quality and life expectancy: a cohort study of 43,277 men. Am J Epidemiol 2009;170:559–65.Google Scholar
Eisenberg, ML, Li, S, Cullen, MR, Baker, LC. Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data. Fertil Steril 2016;105:629–36.Google Scholar
Levine, H, Jorgensen, N, Martino-Andrade, A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update 2017;23:646–59.Google Scholar
Marieb, EN, Hoehn, K. The reproductive system. In: Marieb, EN, Hoehn, K, eds. Human Anatomy and Physiology, 9th ed. Pearson, 2012; p. 1264.Google Scholar
Jirtle, RL, Skinner, MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet 2007;8:253–62.Google Scholar
Tortora, GJ, Derrickson, BH. The cellular level of organization. In: Tortora, GJ, Derrickson, BH, eds. Principles of Anatomy and Physiology, 14th ed. Hoboken, NJ: John Wiley & Sons, 2014; pp. 59–105.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×