Spermatozoa have a unique epigenetic signature, consisting of their DNA methylation profile, DNA-associated proteins, protamine 1:protamine 2 ratio, nucleosome distribution pattern, post-translational histone modifications, stored RNA and nonhistone and nonprotamine proteins
Dietary compounds, especially phytochemicals, minerals and vitamins, can effect changes in epigenetic signatures of somatic as well as germ cells by influencing enzymes and other proteins responsible for epigenetic modifications
Modifications of the epigenetic landscape by dietary compounds can affect overall health but also the reproductive health of both sexes
Studies in animal models and human epidemiological data point toward a transgenerational effect of parental nutrition on offspring health
Male germ cell development can be divided into distinct stages, each representing a time window of susceptibility to epigenetic alterations, resulting in specific epigenetic changes in descendants and their phenotypes
Epigenetic inheritance and its underlying molecular mechanisms are among the most intriguing areas of current biological and medical research. To date, studies have shown that both female and male germline development follow distinct paths of epigenetic events and both oocyte and sperm possess their own unique epigenomes. Fertilizing male and female germ cells deliver not only their haploid genomes but also their epigenomes, which contain the code for preimplantation and postimplantation reprogramming and embryonal development. For example, in spermatozoa, DNA methylation profile, DNA-associated proteins, protamine 1:protamine 2 ratio, nucleosome distribution pattern, histone modifications and other properties make up a unique epigenetic landscape. However, epigenetic factors and mechanisms possess certain plasticity and are affected by environmental conditions. Paternal and maternal lifestyle, including physical activity, nutrition and exposure to hazardous substances, can alter the epigenome and, moreover, can affect the health of their children. In male reproductive health, data are emerging on epigenetically mediated effects of a man's diet on sperm quality, for example through phytochemicals, minerals and vitamins, and nutritional support for subfertile men is already being used. In addition, studies in animal models and human epidemiological data point toward a transgenerational effect of the paternally contributed sperm epigenome on offspring health.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Predicting male fertility from the sperm methylome: application to 120 bulls with hundreds of artificial insemination records
Clinical Epigenetics Open Access 27 April 2022
Transcriptome-wide m6A profiling reveals mRNA post-transcriptional modification of boar sperm during cryopreservation
BMC Genomics Open Access 03 August 2021
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Esteves, S. C. A clinical appraisal of the genetic basis in unexplained male infertility. J. Hum. Reprod. Sci. 6, 176–182 (2013).
Sharma, R., Biedenharn, K. R., Fedor, J. M. & Agarwal, A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod. Biol. Endocrinol. 11, 66–80 (2013).
El Hajj, N., Schneider, E., Lehnen, H. & Haaf, T. Epigenetics and life-long consequences of an adverse nutritional and diabetic intrauterine environment. Reproduction 148, 111–120 (2014).
Guerrero-Bosagna, C. & Skinner, M. K. Environmental epigenetics and effects on male fertility. Adv. Exp. Med. Biol. 791, 67–81 (2014).
Hughes, V. The sins of the father: the roots of inheritance may extend beyond the genome, but the mechanisms remain a puzzle. Nature 507, 22–24 (2014).
Lane, M., Robker, R. L. & Robertson, S. A. Parenting from before conception. Science 345, 756–760 (2014).
Soubry, A., Hoyo, C., Jirtle, R. L. & Murphy, S. K. A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays 36, 359–371 (2014).
Soubry, A. Epigenetic inheritance and evolution: a paternal perspective on dietary influences. Prog. Biophys. Mol. Biol. 118, 79–85 (2015).
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 7, 120–134 (2015).
Wu, H., Hauser, R., Krawetz, S. A. & Pilsner, J. R. Environmental susceptibility of the sperm epigenome during windows of male germ cell development. Curr. Environ. Health Rep. 2, 356–366 (2015).
Dada, R. et al. Epigenetics and its role in male infertility. J. Assist. Reprod. Genet. 29, 213–223 (2012).
Schagdarsurengin, U., Paradowska, A. & Steger, K. Analysing the sperm epigenome: roles in early embryogenesis and assisted reproduction. Nat. Rev. Urol. 9, 609–619 (2012).
Steger, K. et al. Expression of mRNA and protein of nucleoproteins during human spermiogenesis. Mol. Hum. Reprod. 4, 939–945 (1998).
Brunner, A. M., Nanni, P. & Mansuy, I. M. Epigenetic marking of sperm by post-translational modification of histones and protamines. Epigenetics Chromatin 7, 2 (2014).
Ni, K., Spiess, A. N., Schuppe, H. C. & Steger, K. The impact of sperm protamine deficiency and sperm DNA damage on human male fertility: a systematic review and meta-analysis. Andrology http://dx.doi.org/10.1111/andr.12216 (2016).
Hammoud, S. S., Purwar, J., Pflueger, C., Cairns, B. R. & Carrell, D. T. Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil. Steril. 94, 1728–1733 (2010).
Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).
Samans, B. et al. Uniformity of nucleosome preservation pattern in mammalian sperm and its connection to repetitive DNA elements. Dev. Cell 30, 23–35 (2014).
Ward, W. S. Function of sperm chromatin structural elements in fertilization and development. Mol. Hum. Reprod. 16, 30–36 (2010).
Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015).
Gannon, J. R., Emery, B. R., Jenkins, T. G. & Carrell, D. T. The sperm epigenome: implications for the embryo. Adv. Exp. Med. Biol. 791, 53–66 (2014).
Arpanahi, A. et al. Endonuclease-sensitive regions of human spermatozoal chromatin are highly enriched in promoter and CTCF binding sequences. Genome Res. 19, 1338–1349 (2009).
Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat. Struct. Mol. Biol. 17, 679–687 (2010).
Hammoud, S. S. et al. Genome-wide analysis identifies changes in histone retention and epigenetic modifications at developmental and imprinted gene loci in the sperm of infertile men. Hum. Reprod. 26, 2558–2569 (2011).
Carone, B. R. et al. High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm. Dev. Cell 30, 11–22 (2014).
Carrell, D. T. & Hammoud, S. S. The human sperm epigenome and its potential role in embryonic development. Mol. Hum. Reprod. 16, 37–47 (2010).
Vavouri, T. & Lehner, B. Chromatin organization in sperm may be the major functional consequence of base composition variation in the human genome. PLoS Genet. 7, e1002036 (2011).
Schagdarsurengin, U., Western, P., Steger, K. & Meinhardt, A. Developmental origins of male subfertility: role of infection, inflammation, and environmental factors. Semin. Immunopathol. http://dx.doi.org/10.1007/s00281-016-0576-y (2016).
Davis, T. L., Yang, G. J., McCarrey, J. R. & Bartolomei, M. S. The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development. Hum. Mol. Genet. 9, 2885–2894 (2000).
Ueda, T. et al. The paternal methylation imprint of the mouse H19 locus is acquired in the gonocyte stage during foetal testis development. Genes Cells 5, 649–659 (2000).
Li, J. Y., Lees-Murdock, D. J., Xu, G. L. & Walsh, C. P. Timing of establishment of paternal methylation imprints in the mouse. Genomics 84, 952–960 (2004).
Weaver, J. R., Susiarjo, M. & Bartolomei, M. S. Imprinting and epigenetic changes in the early embryo. Mamm. Genome 20, 532–543 (2009).
Oakes, C. C., La Salle, S., Smiraglia, D. J., Robaire, B. & Trasler, J. M. Developmental acquisition of genome-wide DNA methylation occurs prior to meiosis in male germ cells. Dev. Biol. 307, 368–379 (2007).
Oakes, C. C., La Salle, S., Smiraglia, D. J., Robaire, B. & Trasler, J. M. A unique configuration of genome-wide DNA methylation patterns in the testis. Proc. Natl Acad. Sci. USA 104, 228–233 (2007).
Molaro, A. et al. Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell 146, 1029–1041 (2011).
Nanassy, L. & Carrell, D. T. Abnormal methylation of the promoter of CREM is broadly associated with male factor infertility and poor sperm quality but is improved in sperm selected by density gradient cengtrifugation. Fertil. Steril. 95, 2310–2314 (2011).
Benchaib, M. et al. Influence of global sperm DNA methylation on IVF results. Hum. Reprod. 20, 768–773 (2005).
Grunewald, S., Paasch, U., Glander, H. J. & Anderegg, U. Mature human spermatozoa do not transcribe novel RNA. Andrologia 37, 69–71 (2005).
Carrell, D. T. Contributions of spermatozoa to embryogenesis: assays to evaluate their genetic and epigenetic fitness. Reprod. Biomed. Online 16, 474–484 (2008).
Lelancette, C., Miller, D., Li, Y. & Krawetz, S. A. Paternal contributions: new functional insights for spermatozoal RNA. J. Cell Biochem. 104, 1570–1579 (2008).
Yan, W. et al. Birth of mice after intracytoplasmic injection of single purified sperm nuclei and detection of messenger RNAs and microRNAs in the sperm nuclei. Biol. Reprod. 78, 896–902 (2008).
Krawetz, S. A. A survey of small RNAs in human sperm. Hum. Reprod. 26, 3401–3412 (2011).
Song, R. et al. Male germ cells express abundant endogenous siRNAs. Proc. Natl Acad. Sci. USA 108, 13159–13164 (2011).
Frost, R. J. et al. MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs. Proc. Natl Acad. Sci. USA 107, 11847–11852 (2010).
Lim, S. L. et al. Conservation and expression of PIWI-interacting RNA pathway genes in male and female adult gonad of amniotes. Biol. Reprod. 89, 136 (2013).
Miller, D. Ensuring continuity of the paternal genome: potential roles for spermatozoal RNA in mammalian embryogenesis. Soc. Reprod. Fertil. Suppl. 65, 373–389 (2007).
Liu, W. M. et al. Sperm-borne microRNA-34c is required for the first cleavage division in mouse. Proc. Natl Acad. Sci. USA 109, 490–494 (2012).
Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2015).
Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).
Voisin, S., Eynon, N., Yan, X. & Bishop, D. J. Exercise training and DNA methylation in humans. Acta Physiol. (Oxf.) 213, 39–59 (2015).
Shenderov, B. A. Gut indigenous microbiota and epigenetics. Microb. Ecol. Health Dis. 28, 23 (2012).
Canani, R. B., Costanzo, M. D. & Leone, L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin. Epigenetics 4, 4 (2012).
Pompei, A. et al. Folate production by bifidobacteria as a potential probiotic property. Appl. Environ. Microbiol. 73, 179–185 (2007).
Paul, B. et al. Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin. Epigenetics 7, 112 (2015).
Lambrot, R. et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat. Commun. 4, 2889 (2013).
Radford, E. J. et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).
Heller, C. G. & Clermont, Y. Spermatogenesis in man: an estimate on its duration. Science 140, 184–186 (1963).
Rexhaj, E. et al. Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span. J. Clin. Invest. 123, 5052–5060 (2013).
Chen, M. et al. Altered glucose metabolism in mouse and humans conceived by IVF. Diabetes 63, 3189–3198 (2014).
Feuer, S. K. et al. Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis. Endocrinology 155, 1956–1969 (2014).
Ceelen, M., van Weissenbruch, M. M., Vermeiden, J. P., van Leeuwen, F. E. & Delemarre-van de Waal, H. A. Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J. Clin. Endocrinol. Metab. 93, 1682–1688 (2008).
Flanangan, J. M. et al. Intra- and inter-individual epigenetic variation in human germ cells. Am. J. Hum. Genet. 79, 67–84 (2006).
Yodar, J. A., Soman, N. S., Verdine, G. L. & Bestor, T. H. DNA (cytosine-5)-methyltransferase in mouse cells and tissue. Studies with a mechanism-based probe. J. Mol. Biol. 270, 385–395 (1997).
Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
Watt, F. & Molloy, P. L. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late protein. Genes Dev. 2, 1136–1143 (1988).
Jones, P. L. et al. Methylated DNA and MeCP2 recruits histone demethylase to repress transcription. Nat. Genet. 19, 187–191 (1998).
Baylin, S. B. DNA methylation and gene silencing in cancer. Nat. Clin. Pract. Oncol. 2, S4–S11 (2005).
Takumi, S. et al. The effect of a methyl-deficient diet on the global DNA methylation and the DNA methylation regulatory pathways. J. Appl. Toxicol. 35, 1550–1556 (2015).
Pogribny, I. P. et al. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J. Hepatol. 51, 176–186 (2009).
Rice, J. C. & Allis, C. D. Histone methylation versus histone acetylation: new insights into epigenetic regulation. Curr. Opin. Cell Biol. 13, 263–273 (2001).
Roth, S. Y., Denu, J. M. & Allis, C. D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81–120 (2001).
Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).
Upadhyay, A. K. & Chen, X. Dynamics of histone lysine methylation: structures of methyl writers and erasers. Prog. Drug Res. 62, 107–124 (2011).
Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).
Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003).
Sonnack, V., Failing, K., Bergmann, M. & Steger, K. Expression of hyperacetylated histone H4 during normal and impaired human spermatogenesis. Andrologia 34, 384–390 (2002).
Fenic, I., Sonnack, V., Failing, K., Bergmann, M. & Steger, K. In vivo effects of histone-deacetylase inhibitor trichostatin-A on murine spermatogenesis. J. Androl. 25, 811–818 (2004).
Palmer, N. O., Fullston, T., Mitchell, M., Setchell, B. P. & Lane, M. SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity. Reprod. Fertil. Dev. 23, 929–939 (2011).
Nettersheim, D. et al. Analysis of TET expression/activity and 5 mC oxidation during normal and malignant germ cell development. PLoS ONE 8, e82881 (2013).
Ni, K. et al. TET enzymes are successively expressed during human spermatogenesis and their expression level is pivotal for male fertility. Hum. Reprod. 31, 1411–1424 (2016).
Ho, E., Beaver, L. M., Williams, D. E. & Dashwood, R. H. Dietary factors and epigenetic regulation for prostate cancer prevention. Adv. Nutr. 2, 497–510 (2011).
Shankar, S., Kumar, D. & Srivastava, R. K. Epigenetic modifications by dietary phytochemicals: implications for personalized nutrition. Pharmacol. Ther. 138, 1–17 (2013).
Heerboth, S. et al. Use of epigenetic drugs in disease: an overview. Genet. Epigenetics 6, 9–19 (2014).
Shukla, S., Meeran, S. M. & Katiyar, S. K. Epigenetic regulation by selected dietary phytochemicals in cancer prevention. Cancer Lett. 355, 9–17 (2014).
Bishop, K. S. & Ferguson, L. R. The interaction between epigenetics, nutrition and the development of cancer. Nutrients 30, 922–947 (2015).
Shankar, E., Kanwal, R., Candamo, M. & Gipta, S. Dietary phytochemicals as epigenetic modifiers in cancer: promise and challenges. Semin. Cancer Biol. http://dx.doi.org/10.1016/j.semcancer.2016.04.002 (2016).
Fang, M. Z. et al. Tea polyphenol(–)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63, 7563–7570 (2003).
Lee, W. J., Shim, J. Y. & Zhu, B. T. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol. Pharmacol. 68, 1018–1030 (2005).
Navarro-Perán, E., Cabezas-Herrera, J., Campo, L. S. & Rodríguez-López, J. N. Effects of folate cycle disruption by the green tea polyphenol epigallocatechin-3-gallate. Int. J. Biochem. Cell Biol. 39, 2215–2225 (2007).
Choi, K. C. et al. Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. Cancer Res. 69, 583–592 (2009).
Pandey, M., Shukla, S. & Gupta, S. Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells. Int. J. Cancer 126, 2520–2533 (2010).
Balasubramanian, S., Scharadin, T. M., Han, B., Xu, W. & Eckert, R. L. The Bmi-1 helix-turn and ring finger domains are required for Bmi-1 antagonism of (–) epigallocatechin-3-gallate suppression of skin cancer cell survival. Cell. Signal. 27, 1336–1344 (2015).
Tsang, W. P. & Kwok, T. T. Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis in human cancer cells. J. Nutr. Biochem. 21, 140–146 (2010).
Stefanska, B., Rudnicka, K., Bednarek, A. & Fabianowska-Majewska, K. Hypomethylation and induction of retinoic acid receptor β2 by concurrent action of adenosine analogues and natural compounds in breast cancer cells. Eur. J. Pharmacol. 638, 47–53 (2010).
Roy, S. K., Chen, Q., Fu, J., Shankar, S. & Srivastava, R. K. Resveratrol inhibits growth of orthotopic pancreatic tumors through activation of FOXO transcription factors. PLoS ONE 6, e25166 (2011).
Tili, E. et al. Resveratrol modulates the levels of microRNAs targeting genes encoding tumor-suppressors and effectors of TGFβ signaling pathway in SW480 cells. Biochem. Pharmacol. 80, 2057–2065 (2010).
Medina-Franco, J. L., López-Vallejo, F., Kuck, D. & Lyko, F. Natural products as DNA methyltransferase inhibitors: a computer-aided discovery approach. Mol. Divers. 15, 293–304 (2011).
Rajendran, P., Ho, E., Williams, D. E. & Dashwood, R. H. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. Clin. Epigenetics 3, 4 (2011).
Marcu, M. G. et al. Curcumin is an inhibitor of p300 histone acetylatransferase. Med. Chem. 2, 169–174 (2006).
Eustache, F. et al. Chronic dietary exposure to a low-dose mixture of genistein and vinclozolin modifies the reproductive axis, testis transcriptome, and fertility. Environ. Health Perspect. 117, 1272–1279 (2009).
Mendiola, J. et al. A low intake of antioxidant nutrients is associated with poor semen quality in patients attending fertility clinics. Fertil. Steril. 93, 1128–1133 (2010).
Schmid, T. E. et al. Micronutrients intake is associated with improved sperm DNA quality in older men. Fertil. Steril. 98, 1130–1137 (2012).
Minguez-Alarcon, L. et al. Dietary intake of antioxidant nutrients is associated with semen quality in young university students. Hum. Reprod. 27, 2807–2814 (2012).
Blomberg-Jensen, M. et al. Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa. Hum. Reprod. 26, 1307–1317 (2011).
Yang, B. et al. Associations between testosterone, bone mineral density, vitamin D and semen quality in fertile and infertile Chinese men. Int. J. Androl. 35, 783–792 (2012).
Pike, J. W., Meyer, M. B. & Bishop, K. A. Regulation of target gene expression by the vitamin D receptor — an update on mechanisms. Rev. Endocr. Metab. Disord. 13, 45–55 (2012).
Karlic, H. & Varga, F. Impact of vitamin D metabolism on clinical epigenetics. Clin. Epigenetics 2, 55–61 (2011).
Pereira, F. et al. Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle 11, 1081–1089 (2012).
Fetahu, I. S., Höbaus, J. & Kállay, E. Vitamin D and the epigenome. Front. Physiol. 5, 164 (2014).
Crider, K. S., Yang, T. P., Berry, R. J. & Bailey, L. B. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate´s role. Adv. Nutr. 3, 21–38 (2012).
Mejos, K. K., Kim, H. W., Lim, E. M. & Chang, N. Effects of parental folate deficiency on the folate content, global DNA methylation, and expressions of FRα, IGF-2 and IGF-1R in the postnatal rat liver. Nutr. Res. Pract. 7, 281–286 (2013).
Balhorn, R., Reed, S. & Tanphaichitr, N. Aberrant protamine 1/protamine 2 ratios in sperm of infertile human males. Experientia 1, 52–55 (1988).
Rogenhofer, N. et al. The sperm protamine mRNA ratio as a clinical parameter to estimate the fertilizing potential of men taking part in an ART programme. Hum. Reprod. 28, 969–978 (2013).
Aoki, V. W. et al. DNA integrity is compromised in protamine-deficient human sperm. J. Androl. 26, 741–748 (2005).
Castillo, J., Simon, L., de Mateo, S., Lewis, S. & Oliva, R. Protamine/DNA ratios and DNA damage in native and density gradient centrifuged sperm from infertile patients. J. Androl. 32, 324–332 (2011).
García-Peiró, A. et al. Protamine 1 to protamine 2 ratio correlates with dynamic aspects of DNA fragmentation in human sperm. Fertil. Steril. 95, 105–109 (2011).
Noblanc, A. et al. DNA oxidative damage in mammalian spermatozoa: where and why is the male nucleus affected? Free Radic. Biol. Med. 65, 719–723 (2013).
Aitken, R. J., Smith, T. B., Jobling, M. S., Baker, M. A. & De Iuliis, G. N. Oxidative stress and male reproductive health. Asian J. Androl. 16, 31–38 (2014).
Wright, C., Milne, S. & Leeson, H. Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility. Reprod. Biomed. Online 28, 684–703 (2014).
McPherson, N. O., Fullston, T., Aitken, R. J. & Lane, M. Paternal obesity, interventions, and mechanistic pathways to impaired health in offspring. Ann. Nutr. Metab. 64, 231–238 (2014).
Menezo, Y., Evenson, D., Cohen, M. & Dale, B. Effect of antioxidants on sperm DNA damage. Adv. Exp. Med. Biol. 791, 173–189 (2014).
Dattilo, M., Cornet, D., Amar, E., Cohen, M. & Menezo, Y. The importance of the one carbon cycle nutritional support in human male fertility: a preliminary clinical report. Reprod. Biol. Endocrinol. 12, 71 (2014).
Showell, M. G. et al. Antioxidants for male subfertility. Cochrane Database Syst. Rev. 12, CD007411 (2014).
Sinclair, K. D. & Watkins, A. J. Parental diet, pregnancy outcomes and offspring health: metabolic determinants in developing oocytes and embryos. Reprod. Fertil. Dev. 26, 99–114 (2013).
Eisenberg, M. L. et al. The relationship between male BMI and waist circumference on semen quality: data from the LIFE study. Hum. Reprod. 29, 193–200 (2014).
Agbaje, I. M. et al. Insulin dependent diabetes mellitus: implications for male reproductive function. Hum. Reprod. 22, 1871–1877 (2007).
Chavarro, J. E. et al. Trans-fatty acid levels in sperm are associated with sperm concentration among men from an infertility clinic. Fertil. Steril. 95, 1794–1797 (2011).
Colaci, D. S. et al. Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization. Fertil. Steril. 98, 1193–1199.e1 (2012).
Eslamian, B. et al. Antioxidant intake is associated with semen quality in healthy men. Hum. Reprod. 20, 1006–1012 (2005).
Dupont, C. et al. Obesity leads to higher risk of sperm DNA damage in infertile patients. Asian J. Androl. 15, 622–625 (2013).
Bakos, H. W., Thompson, J. P., Feil, D. & Lane, M. Sperm DNA damage is associated with assisted reproductive technology pregnancy. Int. J. Androl. 31, 518–526 (2008).
Ghanayem, B. I., Bai, R., Kissling, G. E., Travlos, G. & Hoffler, U. Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity. Biol. Reprod. 82, 96–104 (2010).
Sermondade, N. et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum. Reprod. Update 19, 221–231 (2013).
Campbell, J. M., Lane, M., Owens, J. A. & Bakos, H. W. Paternal obesity negatively affects male fertility and assisted reproductive outcomes: a systematic review and meta-analysis. Reprod. Biomed. Online 31, 593–604 (2015).
Hakonsen, L. B. et al. Does weight loss improve sperm quality and reproductive hormones? Results from a cohort of severely obese men. Reprod. Health 8, 24 (2011).
Palmer, N. O., Bakos, H. W., Owens, J. A., Setchell, B. P. & Lane, M. Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function. Am. J. Physiol. Endocrinol. Metab. 302, E768–E780 (2012).
Figueroa-Colon, R., Arani, R. B., Goran, M. I. & Weinsier, R. L. Paternal body fat is a longitudinal predictor of changes in body fat in premenarcheal girls. Am. J. Clin. Nutr. 71, 829–834 (2000).
Ng, S. F. et al. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467, 963–966 (2010).
Fullston, T. et al. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J. 27, 4226–4243 (2013).
Fullston, T. et al. Diet-induced paternal obesity in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice. Hum. Reprod. 27, 1391–1400 (2012).
Tunc, O. & Tremellen, K. Oxidative DNA damage impaires global sperm DNA methylation in infertile men. J. Assist. Reprod. Genet. 26, 537–544 (2009).
Soubry, A. et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int. J. Obes. (Lond.) 39, 650–657 (2015).
Lumey, L. H. et al. The Dutch famine birth cohort study: design, validation of exposure, and selected characteristics of subjects after 43 years follow-up. Paediatr. Perinat. Epidemiol. 7, 354–367 (1993).
Lumey, L. H. et al. Cohort profile: the Dutch Hunger Winter families study. Int. J. Epidemiol. 36, 1196–1204 (2007).
Jiménez-Chillarón, J. C. et al. The role of nutrition for epigenetic modifications and their implications on health. Biochimie 94, 2242–2263 (2012).
Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046–17049 (2008).
Bygren, L. O., Kaati, G. & Edvinsson, S. Longevity determined by paternal ancestors' nutrition during their slow growth period. Acta Biotheor. 49, 53–59 (2001).
Pembrey, M. E. et al. Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14, 159–166 (2006).
Kaati, G., Bygren, L. O. & Edvinsson, S. Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur. J. Hum. Genet. 10, 682–688 (2002).
Kaati, G., Bygren, L. O., Pembrey, M. & Sjostrom, M. Transgenerational response to nutrition, early life circumstances and longevity. Eur. J. Hum. Genet. 15, 784–790 (2007).
Duhl, D. M., Vrieling, H., Miller, K. A., Wolff, G. L. & Barsh, G. S. Neomorphic agouti mutations in obese yellow mice. Nat. Genet. 8, 59–65 (1994).
Waterland, R. A. & Jirtle, R. L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 15, 5293–5300 (2003).
Yen, T. T., Gill, A. M., Frigeri, L. G., Barsh, G. S. & Wolff, G. L. Obesity, diabetes, and neoplasia in yellow A(vy)/–mice: ectopic expression of the agouti gene. FASEB J. 8, 479–488 (1994).
Wolff, G. L., Kodell, R. L., Moore, S. R. & Cooney, C. A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12, 949–957 (1998).
Cooney, C. A. Are somatic cells inherently deficient in methylation metabolism? A proposed mechanism for DNA methylation loss, senescence and aging. Growth Dev. Aging 57, 261–273 (1993).
Bestor, T. H. Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain. EMBO J. 11, 2611–2617 (1992).
Jirtle, R. L. The agouti mouse: a biosensor for environmental epigenomics studies investigating the developmental origins of health and disease. Epigenomics 6, 447–450 (2014).
Dolinoy, D. C., Weidmann, J. R., Waterland, R. A. & Jirtle, L. R. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ. Health Perspect. 114, 567–572 (2006).
Dolinoy, D. C., Weinhouse, C., Jones, T. R., Rozek, L. S. & Jirtle, R. L. Variable histone modifications at the Avy metastable allele. Epigenetics 5, 637–644 (2010).
Daxinger, L. & Whitelaw, E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13, 153–162 (2012).
Soubry, A. et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med. 11, 29 (2013).
Soubry, A. et al. Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin. Epigenetics 8, 51 (2016).
Carone, B. R. et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010).
Martinez, D. et al. In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. Cell Metab. 19, 941–951 (2014).
Wei, Y. et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc. Natl Acad. Sci. USA 111, 1873–1878 (2014).
Kagiwada, S., Kurimoto, K., Hirota, T., Yamaji, M. & Saitou, M. Replication-coupled passive DNA demethylation for the erasure of genome imprints in mice. EMBO J. 32, 340–353 (2013).
Hill, P. W., Amouroux, R. & Hajkova, P. DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: an emerging complex story. Genomics 104, 324–333 (2014).
Gkountela, S. et al. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat. Cell Biol. 15, 113–122 (2013).
Smallwood, S. A. & Kelsey, G. de novo DNA methylation: a germ cell perspective. Trends Genet. 28, 33–42 (2012).
Smith, Z. D. et al. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484, 339–344 (2012).
Niles, K. M., Chan, D., La Salle, S., Oakes, C. C. & Trasler, J. M. Critical period of nonpromoter DNA methylation acquisition during prenatal male germ cell development. PLoS ONE 6, e24156 (2011).
Kobayashi, H. et al. Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks. PLoS Genet. 8, e1002440 (2012).
Jones, E. L., Zalensky, A. O. & Zalenskaya, I. A. Protamine withdrawal from human sperm nuclei following heterologous ICSI into hamster oocytes. Protein Pept. Lett. 18, 811–816 (2011).
Jodar, M., Selvaraju, S., Sendler, E., Diamond, M. P. & Krawetz, S. A. The presence, role and clinical use of spermatozoal RNAs. Hum. Reprod. Update 19, 604–624 (2013).
Ying, Y., Qi, X. Zhao, G. Q. Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc. Natl Acad. Sci. USA 98, 7858–7862 (2001).
Gaskell, T. L., Esnal, A., Robinson, L. L., Anderson, R. A. & Saunders, P. T. Immunohistochemical profiling of germ cells within the human fetal testis: identification of three subpopulations. Biol. Reprod. 71, 2012–2021 (2004).
Seisenberger, S. et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849–862 (2012).
Seki, Y. et al. Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev. Biol. 278, 440–458 (2005).
Arnaud, P. Genomic imprinting in germ cells: imprints are under control. Reproduction 140, 411–423 (2010).
Mochizuki, K., Tachibana, M., Saitou, M., Tokitake, Y. & Matsui, Y. Implication of DNA demethylation and bivalent histone modification for selective gene regulation in mouse primordial germ cells. PLoS ONE 7, e46036 (2012).
Lesch, B. J., Dokshin, G. A., Young, R. A., McCarrey, J. R. & Page, D. C. A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis. Proc. Natl Acad. Sci. USA 110, 16061–16066 (2013).
Sachs, M. et al. Bivalent chromatin marks developmental regulatory genes in the mouse embryonic germline in vivo. Cell Rep. 3, 1777–1784 (2013).
The authors wish to acknowledge grant support from the German Research Foundation (DFG), Clinical Research Unit KFO181 and the University Medical Center Giessen and Marburg (UKGM; 29/2015GI).
The authors declare no competing financial interests.
The study of mechanisms that regulate gene expression without changing the underlying DNA sequence, for example, gene silencing through addition of methyl groups to DNA and/or to histones.
In haploid male germ cells, histones are replaced by arginine-rich proteins termed protamines, resulting in high-order nuclear chromatin compaction.
- Imprinted genes
Genes that are expressed in a parent-of-origin-dependent manner depending on genomic imprinting. For example, if the paternally inherited allele is imprinted (for example, silenced due to methylated cytosines within the gene promoter) only the maternal allele is expressed.
A 147 bp DNA sequence wound around a histone octamere that consists of two molecules each of histones H2A, H2B, H3 and H4.
- LINES and SINEs
In repetitive DNA, short interspersed nuclear elements (SINEs, containing 100–500 bp) and long interspersed nuclear elements (LINEs, containing 6–8 kbp) make up ∼52% of all known repeat elements, which are mainly localized in heterochromatin.
- Epigenetic tagging
Addition of methyl or acetyl groups to DNA and/or histones by specialized enzymes results in specific epigenetic signatures that can act as a 'cellular memory' when inherited by offspring.
- Restriction landmark genomic scanning
A method to visualize differences in DNA methylation levels across the genome, consisting of DNA digestion by restriction enzymes followed by radioactive labelling and 2D electrophoresis.
The sum of all microorganisms hosted by an individual in an environmental niche.
- One-carbon metabolism
Folate and methionine cycles constitute a one-carbon metabolism, as only one carbon group is transferred, for example, a methyl group via S-adenosylmethionine.
- Polycomb group protein complexes
Cluster of proteins belonging to one family that are involved in chromatin remodelling to facilitate epigenetic gene silencing.
- DNA fragmentation
A hallmark of apoptosis during which endonucleases cleave chromatin into nucleosomal units representing multiples of ∼180 bp.
- Reactive oxygen species
Highly reactive chemical species (radicals) formed as a natural byproduct of oxygen metabolism. During oxidative stress, levels of reactive oxygen species can increase and effect cell damage.
- Transgenerational epigenetics
Transmission of parental epigenetic signatures and their effects further than the first generation of children (F1 generation; classified as intergenerational epigenetics) to grandchildren and subsequent offspring (F2 and following generations).
- Agouti-viable-yellow (Avy) mouse
In this model, expression of the metastable Avy allele depends on the methylation status of an intracisternal A particle located upstream of the Asip transcription start site. Low methylation levels of CpG sites result in high agouti-signalling protein expression from Asip and the agouti phenotype (yellow coat colour), whereas methylated CpG sites result in low expression levels and the pseudoagouti phenotype (brown coat colour).
Rights and permissions
About this article
Cite this article
Schagdarsurengin, U., Steger, K. Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health. Nat Rev Urol 13, 584–595 (2016). https://doi.org/10.1038/nrurol.2016.157
This article is cited by
Predicting male fertility from the sperm methylome: application to 120 bulls with hundreds of artificial insemination records
Clinical Epigenetics (2022)
A Review on Epigenetic Inheritance of Experiences in Humans
Biochemical Genetics (2022)
Umweltfaktoren, Lebensstil und männliche Fertilität
Die Urologie (2022)
Parental high-fat high-sugar diet programming and hypothalamus adipose tissue axis in male Wistar rats
European Journal of Nutrition (2022)
Future Offspring Costs in Economic Evaluation