Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health

Key Points

  • 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.

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Figure 1: Epigenetic processes during male germ cell development.
Figure 2: Effects of diet on the main epigenetic processes.
Figure 3: Bioactive substances that can affect enzymes involved in epigenetic processes.
Figure 4: Key epigenetic events during human development.


  1. 1

    Esteves, S. C. A clinical appraisal of the genetic basis in unexplained male infertility. J. Hum. Reprod. Sci. 6, 176–182 (2013).

    PubMed  PubMed Central  Google Scholar 

  2. 2

    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).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    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).

    Google Scholar 

  4. 4

    Guerrero-Bosagna, C. & Skinner, M. K. Environmental epigenetics and effects on male fertility. Adv. Exp. Med. Biol. 791, 67–81 (2014).

    PubMed  Google Scholar 

  5. 5

    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).

    CAS  PubMed  Google Scholar 

  6. 6

    Lane, M., Robker, R. L. & Robertson, S. A. Parenting from before conception. Science 345, 756–760 (2014).

    CAS  PubMed  Google Scholar 

  7. 7

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Soubry, A. Epigenetic inheritance and evolution: a paternal perspective on dietary influences. Prog. Biophys. Mol. Biol. 118, 79–85 (2015).

    CAS  PubMed  Google Scholar 

  9. 9

    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).

    PubMed  PubMed Central  Google Scholar 

  10. 10

    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).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Dada, R. et al. Epigenetics and its role in male infertility. J. Assist. Reprod. Genet. 29, 213–223 (2012).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Schagdarsurengin, U., Paradowska, A. & Steger, K. Analysing the sperm epigenome: roles in early embryogenesis and assisted reproduction. Nat. Rev. Urol. 9, 609–619 (2012).

    CAS  PubMed  Google Scholar 

  13. 13

    Steger, K. et al. Expression of mRNA and protein of nucleoproteins during human spermiogenesis. Mol. Hum. Reprod. 4, 939–945 (1998).

    CAS  PubMed  Google Scholar 

  14. 14

    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).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    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).

  16. 16

    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).

    CAS  PubMed  Google Scholar 

  17. 17

    Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    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).

    CAS  PubMed  Google Scholar 

  19. 19

    Ward, W. S. Function of sperm chromatin structural elements in fertilization and development. Mol. Hum. Reprod. 16, 30–36 (2010).

    CAS  PubMed  Google Scholar 

  20. 20

    Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015).

    PubMed  Google Scholar 

  21. 21

    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).

    PubMed  Google Scholar 

  22. 22

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    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).

    CAS  PubMed  Google Scholar 

  24. 24

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Carone, B. R. et al. High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm. Dev. Cell 30, 11–22 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Carrell, D. T. & Hammoud, S. S. The human sperm epigenome and its potential role in embryonic development. Mol. Hum. Reprod. 16, 37–47 (2010).

    CAS  PubMed  Google Scholar 

  27. 27

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    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).

  29. 29

    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).

    CAS  PubMed  Google Scholar 

  30. 30

    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).

    CAS  PubMed  Google Scholar 

  31. 31

    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).

    CAS  PubMed  Google Scholar 

  32. 32

    Weaver, J. R., Susiarjo, M. & Bartolomei, M. S. Imprinting and epigenetic changes in the early embryo. Mamm. Genome 20, 532–543 (2009).

    PubMed  Google Scholar 

  33. 33

    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).

    CAS  PubMed  Google Scholar 

  34. 34

    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).

    CAS  PubMed  Google Scholar 

  35. 35

    Molaro, A. et al. Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell 146, 1029–1041 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    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).

    CAS  PubMed  Google Scholar 

  37. 37

    Benchaib, M. et al. Influence of global sperm DNA methylation on IVF results. Hum. Reprod. 20, 768–773 (2005).

    CAS  PubMed  Google Scholar 

  38. 38

    Grunewald, S., Paasch, U., Glander, H. J. & Anderegg, U. Mature human spermatozoa do not transcribe novel RNA. Andrologia 37, 69–71 (2005).

    CAS  PubMed  Google Scholar 

  39. 39

    Carrell, D. T. Contributions of spermatozoa to embryogenesis: assays to evaluate their genetic and epigenetic fitness. Reprod. Biomed. Online 16, 474–484 (2008).

    CAS  PubMed  Google Scholar 

  40. 40

    Lelancette, C., Miller, D., Li, Y. & Krawetz, S. A. Paternal contributions: new functional insights for spermatozoal RNA. J. Cell Biochem. 104, 1570–1579 (2008).

    Google Scholar 

  41. 41

    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).

    CAS  PubMed  Google Scholar 

  42. 42

    Krawetz, S. A. A survey of small RNAs in human sperm. Hum. Reprod. 26, 3401–3412 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Song, R. et al. Male germ cells express abundant endogenous siRNAs. Proc. Natl Acad. Sci. USA 108, 13159–13164 (2011).

    CAS  PubMed  Google Scholar 

  44. 44

    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).

    CAS  PubMed  Google Scholar 

  45. 45

    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).

    PubMed  Google Scholar 

  46. 46

    Miller, D. Ensuring continuity of the paternal genome: potential roles for spermatozoal RNA in mammalian embryogenesis. Soc. Reprod. Fertil. Suppl. 65, 373–389 (2007).

    CAS  PubMed  Google Scholar 

  47. 47

    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).

    CAS  PubMed  Google Scholar 

  48. 48

    Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).

    CAS  PubMed  Google Scholar 

  50. 50

    Voisin, S., Eynon, N., Yan, X. & Bishop, D. J. Exercise training and DNA methylation in humans. Acta Physiol. (Oxf.) 213, 39–59 (2015).

    CAS  Google Scholar 

  51. 51

    Shenderov, B. A. Gut indigenous microbiota and epigenetics. Microb. Ecol. Health Dis. 28, 23 (2012).

    Google Scholar 

  52. 52

    Canani, R. B., Costanzo, M. D. & Leone, L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin. Epigenetics 4, 4 (2012).

    CAS  Google Scholar 

  53. 53

    Pompei, A. et al. Folate production by bifidobacteria as a potential probiotic property. Appl. Environ. Microbiol. 73, 179–185 (2007).

    CAS  PubMed  Google Scholar 

  54. 54

    Paul, B. et al. Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin. Epigenetics 7, 112 (2015).

    PubMed  PubMed Central  Google Scholar 

  55. 55

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Radford, E. J. et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. 57

    Heller, C. G. & Clermont, Y. Spermatogenesis in man: an estimate on its duration. Science 140, 184–186 (1963).

    CAS  PubMed  Google Scholar 

  58. 58

    Rexhaj, E. et al. Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span. J. Clin. Invest. 123, 5052–5060 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Chen, M. et al. Altered glucose metabolism in mouse and humans conceived by IVF. Diabetes 63, 3189–3198 (2014).

    CAS  PubMed  Google Scholar 

  60. 60

    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).

    PubMed  PubMed Central  Google Scholar 

  61. 61

    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).

    CAS  PubMed  Google Scholar 

  62. 62

    Flanangan, J. M. et al. Intra- and inter-individual epigenetic variation in human germ cells. Am. J. Hum. Genet. 79, 67–84 (2006).

    Google Scholar 

  63. 63

    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).

    Google Scholar 

  64. 64

    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).

    CAS  PubMed  Google Scholar 

  65. 65

    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).

    CAS  PubMed  Google Scholar 

  66. 66

    Jones, P. L. et al. Methylated DNA and MeCP2 recruits histone demethylase to repress transcription. Nat. Genet. 19, 187–191 (1998).

    CAS  PubMed  Google Scholar 

  67. 67

    Baylin, S. B. DNA methylation and gene silencing in cancer. Nat. Clin. Pract. Oncol. 2, S4–S11 (2005).

    CAS  PubMed  Google Scholar 

  68. 68

    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).

    CAS  PubMed  Google Scholar 

  69. 69

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Rice, J. C. & Allis, C. D. Histone methylation versus histone acetylation: new insights into epigenetic regulation. Curr. Opin. Cell Biol. 13, 263–273 (2001).

    CAS  PubMed  Google Scholar 

  71. 71

    Roth, S. Y., Denu, J. M. & Allis, C. D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81–120 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).

    CAS  PubMed  Google Scholar 

  73. 73

    Upadhyay, A. K. & Chen, X. Dynamics of histone lysine methylation: structures of methyl writers and erasers. Prog. Drug Res. 62, 107–124 (2011).

    Google Scholar 

  74. 74

    Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).

    CAS  PubMed  Google Scholar 

  75. 75

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Sonnack, V., Failing, K., Bergmann, M. & Steger, K. Expression of hyperacetylated histone H4 during normal and impaired human spermatogenesis. Andrologia 34, 384–390 (2002).

    CAS  PubMed  Google Scholar 

  77. 77

    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).

    CAS  PubMed  Google Scholar 

  78. 78

    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).

    CAS  PubMed  Google Scholar 

  79. 79

    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).

    PubMed  PubMed Central  Google Scholar 

  80. 80

    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).

    CAS  PubMed  Google Scholar 

  81. 81

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Shankar, S., Kumar, D. & Srivastava, R. K. Epigenetic modifications by dietary phytochemicals: implications for personalized nutrition. Pharmacol. Ther. 138, 1–17 (2013).

    CAS  PubMed  Google Scholar 

  83. 83

    Heerboth, S. et al. Use of epigenetic drugs in disease: an overview. Genet. Epigenetics 6, 9–19 (2014).

    CAS  Google Scholar 

  84. 84

    Shukla, S., Meeran, S. M. & Katiyar, S. K. Epigenetic regulation by selected dietary phytochemicals in cancer prevention. Cancer Lett. 355, 9–17 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Bishop, K. S. & Ferguson, L. R. The interaction between epigenetics, nutrition and the development of cancer. Nutrients 30, 922–947 (2015).

    Google Scholar 

  86. 86

    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).

  87. 87

    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).

    CAS  PubMed  Google Scholar 

  88. 88

    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).

    CAS  PubMed  Google Scholar 

  89. 89

    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).

    PubMed  Google Scholar 

  90. 90

    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).

    CAS  PubMed  Google Scholar 

  91. 91

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    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).

    CAS  PubMed  Google Scholar 

  94. 94

    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).

    CAS  PubMed  Google Scholar 

  95. 95

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    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).

    CAS  PubMed  Google Scholar 

  98. 98

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Marcu, M. G. et al. Curcumin is an inhibitor of p300 histone acetylatransferase. Med. Chem. 2, 169–174 (2006).

    CAS  PubMed  Google Scholar 

  100. 100

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    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).

    CAS  PubMed  Google Scholar 

  102. 102

    Schmid, T. E. et al. Micronutrients intake is associated with improved sperm DNA quality in older men. Fertil. Steril. 98, 1130–1137 (2012).

    CAS  PubMed  Google Scholar 

  103. 103

    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).

    CAS  PubMed  Google Scholar 

  104. 104

    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).

    CAS  PubMed  Google Scholar 

  105. 105

    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).

    CAS  PubMed  Google Scholar 

  106. 106

    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).

    CAS  PubMed  Google Scholar 

  107. 107

    Karlic, H. & Varga, F. Impact of vitamin D metabolism on clinical epigenetics. Clin. Epigenetics 2, 55–61 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Pereira, F. et al. Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle 11, 1081–1089 (2012).

    CAS  PubMed  Google Scholar 

  109. 109

    Fetahu, I. S., Höbaus, J. & Kállay, E. Vitamin D and the epigenome. Front. Physiol. 5, 164 (2014).

    PubMed  PubMed Central  Google Scholar 

  110. 110

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Balhorn, R., Reed, S. & Tanphaichitr, N. Aberrant protamine 1/protamine 2 ratios in sperm of infertile human males. Experientia 1, 52–55 (1988).

    Google Scholar 

  113. 113

    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).

    CAS  PubMed  Google Scholar 

  114. 114

    Aoki, V. W. et al. DNA integrity is compromised in protamine-deficient human sperm. J. Androl. 26, 741–748 (2005).

    CAS  PubMed  Google Scholar 

  115. 115

    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).

    CAS  PubMed  Google Scholar 

  116. 116

    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).

    PubMed  Google Scholar 

  117. 117

    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).

    CAS  PubMed  Google Scholar 

  118. 118

    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).

    CAS  PubMed  Google Scholar 

  119. 119

    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).

    CAS  PubMed  Google Scholar 

  120. 120

    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).

    CAS  PubMed  Google Scholar 

  121. 121

    Menezo, Y., Evenson, D., Cohen, M. & Dale, B. Effect of antioxidants on sperm DNA damage. Adv. Exp. Med. Biol. 791, 173–189 (2014).

    PubMed  Google Scholar 

  122. 122

    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).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Showell, M. G. et al. Antioxidants for male subfertility. Cochrane Database Syst. Rev. 12, CD007411 (2014).

    Google Scholar 

  124. 124

    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).

    PubMed  Google Scholar 

  125. 125

    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).

    PubMed  Google Scholar 

  126. 126

    Agbaje, I. M. et al. Insulin dependent diabetes mellitus: implications for male reproductive function. Hum. Reprod. 22, 1871–1877 (2007).

    CAS  PubMed  Google Scholar 

  127. 127

    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).

    CAS  PubMed  Google Scholar 

  128. 128

    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).

    PubMed  PubMed Central  Google Scholar 

  129. 129

    Eslamian, B. et al. Antioxidant intake is associated with semen quality in healthy men. Hum. Reprod. 20, 1006–1012 (2005).

    Google Scholar 

  130. 130

    Dupont, C. et al. Obesity leads to higher risk of sperm DNA damage in infertile patients. Asian J. Androl. 15, 622–625 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    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).

    CAS  PubMed  Google Scholar 

  132. 132

    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).

    CAS  PubMed  Google Scholar 

  133. 133

    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).

    CAS  PubMed  Google Scholar 

  134. 134

    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).

    PubMed  Google Scholar 

  135. 135

    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).

    PubMed  PubMed Central  Google Scholar 

  136. 136

    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).

    CAS  PubMed  Google Scholar 

  137. 137

    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).

    CAS  PubMed  Google Scholar 

  138. 138

    Ng, S. F. et al. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467, 963–966 (2010).

    CAS  PubMed  Google Scholar 

  139. 139

    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).

    CAS  PubMed  Google Scholar 

  140. 140

    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).

    CAS  PubMed  Google Scholar 

  141. 141

    Tunc, O. & Tremellen, K. Oxidative DNA damage impaires global sperm DNA methylation in infertile men. J. Assist. Reprod. Genet. 26, 537–544 (2009).

    PubMed  PubMed Central  Google Scholar 

  142. 142

    Soubry, A. et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int. J. Obes. (Lond.) 39, 650–657 (2015).

    CAS  Google Scholar 

  143. 143

    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).

    CAS  PubMed  Google Scholar 

  144. 144

    Lumey, L. H. et al. Cohort profile: the Dutch Hunger Winter families study. Int. J. Epidemiol. 36, 1196–1204 (2007).

    CAS  PubMed  Google Scholar 

  145. 145

    Jiménez-Chillarón, J. C. et al. The role of nutrition for epigenetic modifications and their implications on health. Biochimie 94, 2242–2263 (2012).

    PubMed  Google Scholar 

  146. 146

    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).

    CAS  PubMed  Google Scholar 

  147. 147

    Bygren, L. O., Kaati, G. & Edvinsson, S. Longevity determined by paternal ancestors' nutrition during their slow growth period. Acta Biotheor. 49, 53–59 (2001).

    CAS  PubMed  Google Scholar 

  148. 148

    Pembrey, M. E. et al. Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14, 159–166 (2006).

    PubMed  Google Scholar 

  149. 149

    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).

    CAS  PubMed  Google Scholar 

  150. 150

    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).

    CAS  PubMed  Google Scholar 

  151. 151

    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).

    CAS  PubMed  Google Scholar 

  152. 152

    Waterland, R. A. & Jirtle, R. L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 15, 5293–5300 (2003).

    Google Scholar 

  153. 153

    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).

    CAS  PubMed  Google Scholar 

  154. 154

    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).

    CAS  PubMed  Google Scholar 

  155. 155

    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).

    CAS  PubMed  Google Scholar 

  156. 156

    Bestor, T. H. Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain. EMBO J. 11, 2611–2617 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    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).

    CAS  PubMed  Google Scholar 

  158. 158

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Daxinger, L. & Whitelaw, E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13, 153–162 (2012).

    CAS  PubMed  Google Scholar 

  161. 161

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Soubry, A. et al. Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin. Epigenetics 8, 51 (2016).

    PubMed  PubMed Central  Google Scholar 

  163. 163

    Carone, B. R. et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    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).

    CAS  PubMed  Google Scholar 

  165. 165

    Wei, Y. et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc. Natl Acad. Sci. USA 111, 1873–1878 (2014).

    CAS  PubMed  Google Scholar 

  166. 166

    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).

    CAS  PubMed  Google Scholar 

  167. 167

    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).

    CAS  PubMed  Google Scholar 

  168. 168

    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).

    CAS  PubMed  Google Scholar 

  169. 169

    Smallwood, S. A. & Kelsey, G. de novo DNA methylation: a germ cell perspective. Trends Genet. 28, 33–42 (2012).

    CAS  PubMed  Google Scholar 

  170. 170

    Smith, Z. D. et al. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484, 339–344 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    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).

    CAS  PubMed  Google Scholar 

  174. 174

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    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).

    CAS  PubMed  Google Scholar 

  176. 176

    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).

    CAS  PubMed  Google Scholar 

  177. 177

    Seisenberger, S. et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849–862 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    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).

    CAS  PubMed  Google Scholar 

  179. 179

    Arnaud, P. Genomic imprinting in germ cells: imprints are under control. Reproduction 140, 411–423 (2010).

    CAS  PubMed  Google Scholar 

  180. 180

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181

    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).

    CAS  PubMed  Google Scholar 

  182. 182

    Sachs, M. et al. Bivalent chromatin marks developmental regulatory genes in the mouse embryonic germline in vivo. Cell Rep. 3, 1777–1784 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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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).

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All authors researched data for the article, made a substantial contribution to discussion of content, wrote and reviewed and/or edited the article before submission.

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Correspondence to Klaus Steger.

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PowerPoint slides



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.


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).

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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

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