Epigenetic Risk Factors for Diseases: A Transgenerational Perspective

  • Johannes Bohacek
  • Isabelle M. MansuyEmail author
Part of the Epigenetics and Human Health book series (EHH)


Each individual is determined by a combination of genetic and non-genetic factors that together shape physiological and biological functions during development and adulthood. While genetic features are embedded in the DNA sequence inherited from parents, non-genetic features (which include epigenetic modifications) are acquired through experiences and environmental exposure across life. However, it is now acknowledged that non-genetic features can also be inherited from parents and propagate across generations. This chapter discusses the concept of non-genetic germline inheritance in mammals and examines possible routes of transmission of non-genetic information involving germline-dependent and germline-independent modes of transfer. It reviews current evidence that environmental factors can induce non-genetic alterations in the germline that can impact behavioral and physiological features in the offspring. This chapter also addresses the underlying molecular mechanisms, provides initial insight into the implication of epigenetic marks and non-coding RNAs in male germ cells, and questions the way non-genetic modifications can be induced and maintained in germ cells. It highlights promising areas of current research and reflects on evolutionary perspectives and future challenges.


Non-genetic germline inheritance Epigenetics Transgenerational Sperm DNA methylation Histone posttranslational modifications ncRNAs 


  1. Adalsteinsson B, Ferguson-Smith A (2014) Epigenetic control of the genome – lessons from genomic imprinting. Genes (Basel) 5:635–655Google Scholar
  2. Adeoya-Osiguwa SA, Gibbons R, Fraser LR (2006) Identification of functional alpha2- and beta-adrenergic receptors in mammalian spermatozoa. Hum Reprod 21:1555–1563PubMedCrossRefGoogle Scholar
  3. Aitken RJ, Koopman P, Lewis SEM (2004) Seeds of concern. Nature 432:48–52PubMedCrossRefGoogle Scholar
  4. Arai JA, Li S, Hartley DM, Feig LA (2009) Transgenerational rescue of a genetic defect in long-term potentiation and memory formation by juvenile enrichment. J Neurosci 29:1496–1502PubMedPubMedCentralCrossRefGoogle Scholar
  5. Aravin AA, Sachidanandam R, Girard A et al (2007) Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 316:744–747PubMedCrossRefGoogle Scholar
  6. Aravin AA, Sachidanandam R, Bourc’his D et al (2008) A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol Cell 31:785–799PubMedPubMedCentralCrossRefGoogle Scholar
  7. Arpanahi A, Brinkworth M, Iles D et al (2009) Endonuclease-sensitive regions of human spermatozoal chromatin are highly enriched in promoter and CTCF binding sequences. Genome Res 19:1338–1349PubMedPubMedCentralCrossRefGoogle Scholar
  8. Arroyo JD, Chevillet JR, Kroh EM et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108:5003–5008PubMedPubMedCentralCrossRefGoogle Scholar
  9. Babb JA, Carini LM, Spears SL, Nephew BC (2014) Transgenerational effects of social stress on social behavior, corticosterone, oxytocin, and prolactin in rats. Horm Behav 65:386–393PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bartolomei MS (2009) Genomic imprinting: employing and avoiding epigenetic processes. Genes Dev 23:2124–2133PubMedPubMedCentralCrossRefGoogle Scholar
  11. Beaujean N (2014) Histone post-translational modifications in preimplantation mouse embryos and their role in nuclear architecture. Mol Reprod Dev 81:100–112PubMedCrossRefGoogle Scholar
  12. Behrman JR, Calderon MC, Preston SH et al (2009) Nutritional supplementation in girls influences the growth of their children: prospective study in Guatemala. Am J Clin Nutr 90:1372–1379PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bennett-Baker PE, Wilkowski J, Burke DT (2003) Age-associated activation of epigenetically repressed genes in the mouse. Genetics 165:2055–2062PubMedPubMedCentralGoogle Scholar
  14. Bohacek J, Mansuy IM (2013) Epigenetic inheritance of disease and disease risk. Neuropsychopharmacology 38:220–236PubMedCrossRefGoogle Scholar
  15. Bohacek J, Mansuy IM (2015) Molecular insights into transgenerational non-genetic inheritance of acquired behaviours. Nat Rev Genet 16:641–652PubMedCrossRefGoogle Scholar
  16. Bohacek J, Gapp K, Saab BJ, Mansuy IM (2012) Transgenerational epigenetic effects on brain functions. Biol Psychiatry 73:313–320PubMedCrossRefGoogle Scholar
  17. Bohacek J, Farinelli M, Mirante O et al (2015) Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress. Mol Psychiatry 20:621–631PubMedCrossRefGoogle Scholar
  18. Bohacek J, von Werdt S, Mansuy IM (2016) Probing the germline-dependence of epigenetic inheritance using artificial insemination in mice. Environmental Epigenetics 2:1–10Google Scholar
  19. Borgel J, Guibert S, Li Y et al (2010) Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet 42:1093–1100PubMedCrossRefGoogle Scholar
  20. Bostick M, Kim JK, Estève P-O et al (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317:1760–1764PubMedCrossRefGoogle Scholar
  21. Bourguiba S, Genissel C, Lambard S et al (2003) Regulation of aromatase gene expression in Leydig cells and germ cells. J Steroid Biochem Mol Biol 86:335–343PubMedCrossRefGoogle Scholar
  22. Boyko A, Kathiria P, Zemp FJ et al (2007) Transgenerational changes in the genome stability and methylation in pathogen-infected plants: (virus-induced plant genome instability). Nucleic Acids Res 35:1714–1725PubMedPubMedCentralCrossRefGoogle Scholar
  23. Brunner AM, Nanni P, Mansuy IM (2014) Epigenetic marking of sperm by post-translational modification of histones and protamines. Epigenetics Chromatin 7:2PubMedPubMedCentralCrossRefGoogle Scholar
  24. Brykczynska U, Hisano M, Erkek S et al (2010) Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat Struct Mol Biol 17:679–687PubMedCrossRefGoogle Scholar
  25. Byrnes JJ, Babb JA, Scanlan VF, Byrnes EM (2011) Adolescent opioid exposure in female rats: transgenerational effects on morphine analgesia and anxiety-like behavior in adult offspring. Behav Brain Res 218:200–205PubMedCrossRefGoogle Scholar
  26. Byrnes JJ, Johnson NL, Carini LM, Byrnes EM (2013) Multigenerational effects of adolescent morphine exposure on dopamine D2 receptor function. Psychopharmacology 227:263–272PubMedPubMedCentralCrossRefGoogle Scholar
  27. Cacciola G, Chioccarelli T, Altucci L et al (2013) Low 17beta-estradiol levels in CNR1 knock-out mice affect spermatid chromatin remodeling by interfering with chromatin reorganization. Biol Reprod 88:152PubMedCrossRefGoogle Scholar
  28. Carmell MA, Girard A, van de Kant HJG et al (2007) MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev Cell 12:503–514PubMedCrossRefGoogle Scholar
  29. Carone BR, Fauquier L, Habib N et al (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143:1084–1096PubMedPubMedCentralCrossRefGoogle Scholar
  30. Carone BR, Hung J-H, Hainer SJ et al (2014) High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm. Dev Cell 30:11–22PubMedPubMedCentralCrossRefGoogle Scholar
  31. Carr MS, Yevtodiyenko A, Schmidt CL, Schmidt JV (2007) Allele-specific histone modifications regulate expression of the Dlk1-Gtl2 imprinted domain. Genomics 89:280–290PubMedCrossRefGoogle Scholar
  32. Casas E, Vavouri T (2014) Sperm epigenomics: challenges and opportunities. Front Genet 5:1–7CrossRefGoogle Scholar
  33. Champagne FA (2008) Epigenetic mechanisms and the transgenerational effects of maternal care. Front Neuroendocrinol 29:386–397PubMedPubMedCentralCrossRefGoogle Scholar
  34. Chen TH-H, Chiu Y-H, Boucher BJ (2006) Transgenerational effects of betel-quid chewing on the development of the metabolic syndrome in the Keelung Community-based Integrated Screening Program. Am J Clin Nutr 83:688–692PubMedGoogle Scholar
  35. Cossetti C, Lugini L, Astrologo L et al (2014) Soma-to-germline transmission of RNA in mice xenografted with human tumour cells: possible transport by exosomes. PLoS One 9:e101629PubMedPubMedCentralCrossRefGoogle Scholar
  36. Court F, Tayama C, Romanelli V et al (2014) Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. Genome Res 24:554–569PubMedPubMedCentralCrossRefGoogle Scholar
  37. Crean AJ, Kopps AM, Bonduriansky R (2014) Revisiting telegony: offspring inherit an acquired characteristic of their mother’s previous mate. Ecol Lett 17:1545–1552PubMedPubMedCentralCrossRefGoogle Scholar
  38. Crews D, Gore AC, Hsu TS et al (2007) Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci U S A 104:5942–5946PubMedPubMedCentralCrossRefGoogle Scholar
  39. Curley JP, Mashoodh R, Champagne FA (2011) Epigenetics and the origins of paternal effects. Horm Behav 59:306–314PubMedCrossRefGoogle Scholar
  40. Das S, Bryan K, Buckley PG et al (2013) Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs. Oncogene 32:2927–2936PubMedCrossRefGoogle Scholar
  41. Daxinger L, Whitelaw E (2012) Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet 13:153–162PubMedCrossRefGoogle Scholar
  42. De Kloet ER, Karst H, Joëls M (2008) Corticosteroid hormones in the central stress response: quick-and-slow. Front Neuroendocrinol 29:268–272PubMedCrossRefGoogle Scholar
  43. Debiec J, Sullivan RM (2014) Intergenerational transmission of emotional trauma through amygdala-dependent mother-to-infant transfer of specific fear. Proc Natl Acad Sci 111:12222–12227PubMedPubMedCentralCrossRefGoogle Scholar
  44. Denomme MM, Mann MRW (2012) Genomic imprints as a model for the analysis of epigenetic stability during assisted reproductive technologies. Reproduction 144:393–409PubMedCrossRefGoogle Scholar
  45. Dias BG, Ressler KJ (2014) Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 17:89–96PubMedCrossRefGoogle Scholar
  46. Dietz DM, Laplant Q, Watts EL et al (2011) Paternal transmission of stress-induced pathologies. Biol Psychiatry 70:408–414PubMedPubMedCentralCrossRefGoogle Scholar
  47. Dunn GA, Bale TL (2009) Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice. Endocrinology 150:4999–5009PubMedPubMedCentralCrossRefGoogle Scholar
  48. Dunn GA, Bale TL (2011) Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology 152:2228–2236PubMedPubMedCentralCrossRefGoogle Scholar
  49. Eichler EE, Flint J, Gibson G et al (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11:446–450PubMedPubMedCentralCrossRefGoogle Scholar
  50. Engel SM, Berkowitz GS, Wolff MS, Yehuda R (2005) Psychological trauma associated with the World Trade Center attacks and its effect on pregnancy outcome. Paediatr Perinat Epidemiol 19:334–341PubMedCrossRefGoogle Scholar
  51. Erkek S, Hisano M, Liang C-Y et al (2013) Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nat Struct Mol Biol 20:868–875PubMedCrossRefGoogle Scholar
  52. Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33PubMedCrossRefGoogle Scholar
  53. Finegersh A, Homanics GE (2014) Paternal alcohol exposure reduces alcohol drinking and increases behavioral sensitivity to alcohol selectively in male offspring. PLoS One 9:e99078PubMedPubMedCentralCrossRefGoogle Scholar
  54. Franklin TB, Russig H, Weiss IC et al (2010) Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68:408–415PubMedCrossRefGoogle Scholar
  55. Franklin TB, Linder N, Russig H et al (2011) Influence of early stress on social abilities and serotonergic functions across generations in mice. PLoS One 6:e21842PubMedPubMedCentralCrossRefGoogle Scholar
  56. Frésard L, Morisson M, Brun J-M et al (2013) Epigenetics and phenotypic variability: some interesting insights from birds. Genet Sel Evol 45:16PubMedPubMedCentralCrossRefGoogle Scholar
  57. Fullston T, Ohlsson Teague EMC, Palmer NO et al (2013) 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 27:4226–4243PubMedCrossRefGoogle Scholar
  58. Galler JR (1980) Home-orienting behavior in rat pups surviving postnatal or intergenerational malnutrition. Dev Psychobiol 13:563–572PubMedCrossRefGoogle Scholar
  59. Galler JR (1981) Visual discrimination in rats: the effects of rehabilitation following intergenerational malnutrition. Dev Psychobiol 14:229–236PubMedCrossRefGoogle Scholar
  60. Galler JR, Seelig C (1981) Home-orienting behavior in rat pups: the effect of 2 and 3 generations of rehabilitation following intergenerational malnutrition. Dev Psychobiol 14:541–548PubMedCrossRefGoogle Scholar
  61. Gapp K, Jawaid A, Sarkies P et al (2014a) Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 17:667–669PubMedPubMedCentralCrossRefGoogle Scholar
  62. Gapp K, Soldado-Magraner S, Alvarez-Sánchez M et al (2014b) Early life stress in fathers improves behavioural flexibility in their offspring. Nat Commun 5:5466PubMedCrossRefGoogle Scholar
  63. Gapp K, von Ziegler L, Tweedie-Cullen RY, Mansuy IM (2014c) Early life epigenetic programming and transmission of stress-induced traits in mammals: how and when can environmental factors influence traits and their transgenerational inheritance? Bioessays 36:491–502PubMedCrossRefGoogle Scholar
  64. Ghildiyal M, Zamore PD (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10:94–108PubMedPubMedCentralCrossRefGoogle Scholar
  65. Gillette R, Miller-Crews I, Nilsson EE et al (2014) Sexually dimorphic effects of ancestral exposure to vinclozolin on stress reactivity in rats. Endocrinology 155:3853–3866PubMedPubMedCentralCrossRefGoogle Scholar
  66. Girardot M, Feil R, Llères D (2013) Epigenetic deregulation of genomic imprinting in humans: causal mechanisms and clinical implications. Epigenomics 5:715–728PubMedCrossRefGoogle Scholar
  67. Govorko D, Bekdash RA, Zhang C, Sarkar DK (2012) Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations. Biol Psychiatry 72:378–388PubMedPubMedCentralCrossRefGoogle Scholar
  68. Grandjean V, Gounon P, Wagner N et al (2009) The miR-124-Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth. Development 136:3647–3655PubMedCrossRefGoogle Scholar
  69. Guerrero-Bosagna C, Skinner MK (2012) Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Mol Cell Endocrinol 354:3–8PubMedCrossRefGoogle Scholar
  70. Guerrero-Bosagna C, Settles M, Lucker B, Skinner MK (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS One 5:e13100PubMedPubMedCentralCrossRefGoogle Scholar
  71. Guerrero-Bosagna C, Savenkova M, Haque MM et al (2013) Environmentally induced epigenetic transgenerational inheritance of altered Sertoli cell transcriptome and epigenome: molecular etiology of male infertility. PLoS One 8:e59922PubMedPubMedCentralCrossRefGoogle Scholar
  72. Guerrero-Bosagna C, Weeks S, Skinner MK (2014) Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations. PLoS One 9:e100194PubMedPubMedCentralCrossRefGoogle Scholar
  73. Hackett JA, Sengupta R, Zylicz JJ et al (2013) Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339:448–452PubMedCrossRefGoogle Scholar
  74. Haddad JJ (2004) Alcoholism and neuro-immune-endocrine interactions: physiochemical aspects. Biochem Biophys Res Commun 323:361–371PubMedCrossRefGoogle Scholar
  75. Haeussler S, Claus R (2007) Expression of the glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase 2 in pig testes cells along fetal development. Reprod Fertil Dev 19:664PubMedCrossRefGoogle Scholar
  76. Hammoud SS, Nix DA, Zhang H et al (2009) Distinctive chromatin in human sperm packages genes for embryo development. Nature 460:473–478PubMedPubMedCentralGoogle Scholar
  77. Harper LV (2005) Epigenetic inheritance and the intergenerational transfer of experience. Psychol Bull 131:340–360PubMedCrossRefGoogle Scholar
  78. Hazra R, Upton D, Jimenez M et al (2014) In vivo actions of the Sertoli cell glucocorticoid receptor. Endocrinology 155:1120–1130PubMedCrossRefGoogle Scholar
  79. Heijmans BT, Tobi EW, Stein AD et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049PubMedPubMedCentralCrossRefGoogle Scholar
  80. Heller EA, Cates HM, Peña CJ et al (2014) Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat Neurosci 17:1720–1727PubMedPubMedCentralCrossRefGoogle Scholar
  81. Hergenreider E, Heydt S, Tréguer K et al (2012) Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14:249–256PubMedCrossRefGoogle Scholar
  82. Hermo L, Pelletier R-M, Cyr DG, Smith CE (2010) Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia, and spermatocytes. Microsc Res Tech 73:241–278PubMedCrossRefGoogle Scholar
  83. Hess RA, Renato de Franca L (2008) Spermatogenesis and cycle of the seminiferous epithelium. Adv Exp Med Biol 636:1–15PubMedCrossRefGoogle Scholar
  84. Hilton IB, D’Ippolito AM, Vockley CM et al (2015) Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. doi: 10.1038/nbt.3199 PubMedPubMedCentralGoogle Scholar
  85. Hoeffer CA, Wong H, Cain P et al (2013) Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment. J Neurosci 33:16930–16944PubMedPubMedCentralCrossRefGoogle Scholar
  86. Holland ML, Rakyan VK (2013) Transgenerational inheritance of non-genetically determined phenotypes. Biochem Soc Trans 41:769–776PubMedCrossRefGoogle Scholar
  87. Holliday R (1987) Epigenetic defects. Science 238:163–170PubMedCrossRefGoogle Scholar
  88. Hulf T, Sibbritt T, Wiklund ED et al (2013) Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer. Oncogene 32:2891–2899PubMedCrossRefGoogle Scholar
  89. Jablonka E (2012) Epigenetic variations in heredity and evolution. Clin Pharmacol Ther 92:683–688PubMedCrossRefGoogle Scholar
  90. Jablonka E, Raz G (2009) Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution. Q Rev Biol 84:131–176PubMedCrossRefGoogle Scholar
  91. Jenkins TG, Carrell DT (2012) The sperm epigenome and potential implications for the developing embryo. Reproduction 143:727–734PubMedCrossRefGoogle Scholar
  92. Jia H, Morris CD, Williams RM et al (2014) HDAC inhibition imparts beneficial transgenerational effects in Huntington’s disease mice via altered DNA and histone methylation. Proc Natl Acad Sci U S A 112:E56–E64PubMedPubMedCentralCrossRefGoogle Scholar
  93. Jimenez-Chillaron JC, Isganaitis E, Charalambous M et al (2009) Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58:460–468PubMedPubMedCentralCrossRefGoogle Scholar
  94. Jodar M, Selvaraju S, Sendler E et al (2013) The presence, role and clinical use of spermatozoal RNAs. Hum Reprod Update 19:604–624PubMedPubMedCentralCrossRefGoogle Scholar
  95. Johnson GD, Lalancette C, Linnemann AK et al (2011) The sperm nucleus: chromatin, RNA, and the nuclear matrix. Reproduction 141:21–36PubMedCrossRefGoogle Scholar
  96. Kaati G, Bygren LO, Pembrey M, Sjostrom M (2007) Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 15:784–790PubMedCrossRefGoogle Scholar
  97. Kaufmann SH, Wright WW, Okret S et al (1992) Evidence that rodent epididymal sperm contain the Mr approximately 94,000 glucocorticoid receptor but lack the Mr approximately 90,000 heat shock protein. Endocrinology 130:3074–3084PubMedGoogle Scholar
  98. Kiani J, Grandjean V, Liebers R et al (2013) RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS Genet 9:e1003498PubMedPubMedCentralCrossRefGoogle Scholar
  99. Kim DH, Saetrom P, Snove O Jr, Rossi JJ (2008) MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc Natl Acad Sci U S A 105:16230–16235PubMedPubMedCentralCrossRefGoogle Scholar
  100. Kinnally EL, Feinberg C, Kim D et al (2013) Transgenerational effects of variable foraging demand stress in female bonnet macaques. Am J Primatol 75:509–517PubMedPubMedCentralCrossRefGoogle Scholar
  101. Krawetz SA, Kruger A, Lalancette C et al (2011) A survey of small RNAs in human sperm. Hum Reprod 26:3401–3412PubMedPubMedCentralCrossRefGoogle Scholar
  102. Kyle UG, Pichard C (2006) The Dutch Famine of 1944–1945: a pathophysiological model of long-term consequences of wasting disease. Curr Opin Clin Nutr Metab Care 9:388–394PubMedCrossRefGoogle Scholar
  103. Lane N, Dean W, Erhardt S, Hajkova P, Surani A, Walter J, Reik W (2003) Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35:88–93Google Scholar
  104. Law JA, Jacobsen SE (2010) Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet 11:204–220PubMedPubMedCentralCrossRefGoogle Scholar
  105. Lee JS, Smith E, Shilatifard A (2010) The language of histone crosstalk. Cell 142:682–685PubMedPubMedCentralCrossRefGoogle Scholar
  106. Lee HJ, Hore TA, Reik W (2014) Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14:710–719PubMedPubMedCentralCrossRefGoogle Scholar
  107. Leshem M, Schulkin J (2012) Transgenerational effects of infantile adversity and enrichment in male and female rats. Dev Psychobiol 54:169–186PubMedCrossRefGoogle Scholar
  108. Li Y-F, Langholz B, Salam MT, Gilliland FD (2005) Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest 127:1232–1241PubMedGoogle Scholar
  109. Li C-Q, Luo Y-W, Bi F-F et al (2014) Development of anxiety-like behavior via Hippocampal IGF-2 signaling in the offspring of parental morphine exposure: effect of enriched environment. Neuropsychopharmacology 39:1–11CrossRefGoogle Scholar
  110. Liu W-M, Pang RTK, Chiu PCN et al (2012) Sperm-borne microRNA-34c is required for the first cleavage division in mouse. Proc Natl Acad Sci 109:490–494PubMedCrossRefGoogle Scholar
  111. Liu B, Zupan B, Laird E et al (2014) Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory. Nat Neurosci 17:97–105PubMedCrossRefGoogle Scholar
  112. Llamas B, Holland ML, Chen K et al (2012) High-resolution analysis of cytosine methylation in ancient DNA. PLoS One 7:e30226PubMedPubMedCentralCrossRefGoogle Scholar
  113. Lumey LH, Stein AD (1997) Offspring birth weights after maternal intrauterine undernutrition: a comparison within sibships. Am J Epidemiol 146:810–819PubMedCrossRefGoogle Scholar
  114. Lumey LH, Stein AD, Susser E (2011) Prenatal famine and adult health. Annu Rev Public Health 32:237–262PubMedCrossRefGoogle Scholar
  115. Ma J, Flemr M, Stein P et al (2010) MicroRNA activity is suppressed in mouse oocytes. Curr Biol 20:265–270PubMedPubMedCentralCrossRefGoogle Scholar
  116. Majdic G, Millar MR, Saunders PT (1995) Immunolocalisation of androgen receptor to interstitial cells in fetal rat testes and to mesenchymal and epithelial cells of associated ducts. J Endocrinol 147:285–293PubMedCrossRefGoogle Scholar
  117. Manikkam M, Guerrero-Bosagna C, Tracey R et al (2012) Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 7:e31901PubMedPubMedCentralCrossRefGoogle Scholar
  118. Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK (2013) Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One 8:e55387PubMedPubMedCentralCrossRefGoogle Scholar
  119. Manolio TA, Collins FS, Cox NJ et al (2009) Finding the missing heritability of complex diseases. Nature 461:747–753PubMedPubMedCentralCrossRefGoogle Scholar
  120. Markel AL, Trut LN (2011) Behavior, stress, and evolution in light of the Novosibirsk selection experiments. In: Jablonka E, Gissis SB (eds) Transformations of Lamarckism: from subtle fluids to molecular biology. The MIT Press, Cambridge, MA, pp 171–180CrossRefGoogle Scholar
  121. Market-Velker BA, Zhang L, Magri LS et al (2009) Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner. Hum Mol Genet 19:36–51CrossRefGoogle Scholar
  122. Marques CJ, João Pinho M, Carvalho F et al (2011) DNA methylation imprinting marks and DNA methyltransferase expression in human spermatogenic cell stages. Epigenetics 6:1354–1361PubMedCrossRefGoogle Scholar
  123. Martínez D, Pentinat T, Ribó S et al (2014) In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered lxra DNA methylation. Cell Metab 19:941–951PubMedCrossRefGoogle Scholar
  124. Mashoodh R, Franks B, Curley JP, Champagne FA (2012) Paternal social enrichment effects on maternal behavior and offspring growth. Proc Natl Acad Sci U S A 109(Suppl):17232–17238PubMedPubMedCentralCrossRefGoogle Scholar
  125. Maze I, Noh K-M, Soshnev AA, Allis CD (2014) Every amino acid matters: essential contributions of histone variants to mammalian development and disease. Nat Rev Genet 15:259–271PubMedPubMedCentralCrossRefGoogle Scholar
  126. Meikar O, Da Ros M, Korhonen H, Kotaja N (2011) Chromatoid body and small RNAs in male germ cells. Reproduction 142:195–209PubMedCrossRefGoogle Scholar
  127. Merikangas KR, Stolar M, Stevens DE et al (1998) Familial transmission of substance use disorders. Arch Gen Psychiatry 55:973–979PubMedCrossRefGoogle Scholar
  128. Mital P, Hinton BT, Dufour JM (2011) The blood-testis and blood-epididymis barriers are more than just their tight junctions. Biol Reprod 84:851–858PubMedPubMedCentralCrossRefGoogle Scholar
  129. Moisiadis VG, Matthews SG (2014) Glucocorticoids and fetal programming part 1: outcomes. Nat Rev Endocrinol 10:391–402PubMedCrossRefGoogle Scholar
  130. Morgan CP, Bale TL (2011) Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage. J Neurosci 31:11748–11755PubMedPubMedCentralCrossRefGoogle Scholar
  131. Morgan HD, Sutherland HG, Martin DI, Whitelaw E (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23:314–318PubMedCrossRefGoogle Scholar
  132. Mueller BR, Bale TL (2008) Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 28:9055–9065PubMedPubMedCentralCrossRefGoogle Scholar
  133. Nakamura T, Liu Y-J, Nakashima H et al (2012) PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature 486:415–419PubMedGoogle Scholar
  134. Nätt D, Rubin C-J, Wright D et al (2012) Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens. BMC Genomics 13:59PubMedPubMedCentralCrossRefGoogle Scholar
  135. Naz RK, Sellamuthu R (2006) Receptors in spermatozoa: are they real? J Androl 27:627–636PubMedCrossRefGoogle Scholar
  136. Nebel BR, Amarose AP, Hacket EM (1961) Calendar of gametogenic development in the prepuberal male mouse. Science 134:832–833PubMedCrossRefGoogle Scholar
  137. Ng S-FF, Lin RCY, Laybutt DR et al (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467:963–966PubMedCrossRefGoogle Scholar
  138. Nguyen-Chi M, Morello D (2011) RNA-binding proteins, RNA granules, and gametes: is unity strength? Reproduction 142:803–817PubMedCrossRefGoogle Scholar
  139. Nilsson EE, Skinner MK (2014) Environmentally induced epigenetic transgenerational inheritance of disease susceptibility. Transl Res. doi: 10.1016/j.trsl.2014.02.003 PubMedPubMedCentralGoogle Scholar
  140. Oakes CC, La Salle S, Smiraglia DJ et al (2007) Developmental acquisition of genome-wide DNA methylation occurs prior to meiosis in male germ cells. Dev Biol 307:368–379PubMedCrossRefGoogle Scholar
  141. Ong ZY, Muhlhausler BS (2011) Maternal “junk-food” feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring. FASEB J 25:2167–2179PubMedPubMedCentralCrossRefGoogle Scholar
  142. Painter R, Osmond C, Gluckman P et al (2008) Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG 115:1243–1249PubMedCrossRefGoogle Scholar
  143. Palmer NO, Fullston T, Mitchell M et al (2011) SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity. Reprod Fertil Dev 23:929–939PubMedCrossRefGoogle Scholar
  144. Pang RTK, Liu WM, Leung CON et al (2011) miR-135a regulates preimplantation embryo development through down-regulation of E3 ubiquitin ligase seven in absentia homolog 1A (SIAH1A) expression. PLoS One 6:e27878PubMedPubMedCentralCrossRefGoogle Scholar
  145. Pathak S, D’Souza R, Ankolkar M et al (2010) Potential role of estrogen in regulation of the insulin-like growth factor2-H19 locus in the rat testis. Mol Cell Endocrinol 314:110–117PubMedCrossRefGoogle Scholar
  146. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA et al (2010) Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A 107:6328–6333PubMedPubMedCentralCrossRefGoogle Scholar
  147. Pembrey ME (2010) Male-line transgenerational responses in humans. Hum Fertil 13:268–271CrossRefGoogle Scholar
  148. Pembrey ME, Bygren LO, Kaati G et al (2006) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14:159–166PubMedCrossRefGoogle Scholar
  149. Pentinat T, Ramon-Krauel M, Cebria J et al (2010) Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition. Endocrinology 151:5617–5623PubMedCrossRefGoogle Scholar
  150. Perry JC, Sirot L, Wigby S (2013) The seminal symphony: how to compose an ejaculate. Trends Ecol Evol 28:414–422PubMedCrossRefGoogle Scholar
  151. Petropoulos S, Matthews SG, Szyf M (2014) Adult glucocorticoid exposure leads to transcriptional and DNA methylation changes in nuclear steroid receptors in the hippocampus and kidney of mouse male offspring. Biol Reprod 90:43PubMedCrossRefGoogle Scholar
  152. Pigati L, Yaddanapudi SCS, Iyengar R et al (2010) Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS One 5:e13515PubMedPubMedCentralCrossRefGoogle Scholar
  153. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression_a new animal model sensitive to antidepressant treatments. Nature 266:730–732PubMedCrossRefGoogle Scholar
  154. Radford EJ, Ito M, Shi H et al (2014) In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science. doi: 10.1126/science.1255903 PubMedPubMedCentralGoogle Scholar
  155. Rakyan VK, Chong S, Champ ME et al (2003) Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci U S A 100:2538–2543PubMedPubMedCentralCrossRefGoogle Scholar
  156. Rando TA, Chang HY (2012) Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148:46–57PubMedPubMedCentralCrossRefGoogle Scholar
  157. Rassoulzadegan M, Grandjean V, Gounon P et al (2006) RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 441:469–474PubMedCrossRefGoogle Scholar
  158. Rehan VK, Liu J, Sakurai R, Torday JS (2013) Perinatal nicotine-induced transgenerational asthma. Am J Physiol Lung Cell Mol Physiol 305:L501–L507PubMedPubMedCentralCrossRefGoogle Scholar
  159. Remy JJ (2010) Stable inheritance of an acquired behavior in Caenorhabditis elegans. Curr Biol 20:R877–R878PubMedCrossRefGoogle Scholar
  160. Rodgers AB, Morgan CP, Bronson SL et al (2013) Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 33:9003–9012PubMedPubMedCentralCrossRefGoogle Scholar
  161. Rossi P, Dolci S (2013) Paracrine mechanisms involved in the control of early stages of Mammalian spermatogenesis. Front Endocrinol (Lausanne) 4:181Google Scholar
  162. Saavedra-Rodriguez L, Feig LA (2013) Chronic social instability induces anxiety and defective social interactions across generations. Biol Psychiatry 73:44–53PubMedCrossRefGoogle Scholar
  163. Samans B, Yang Y, Krebs S et al (2014) Uniformity of nucleosome preservation pattern in Mammalian sperm and its connection to repetitive DNA elements. Dev Cell 30:23–35PubMedCrossRefGoogle Scholar
  164. Schaal B, Marlier L, Soussignan R et al (2000) Human foetuses learn odours from their pregnant mother’s diet. Chem Senses 22:729–737Google Scholar
  165. Schick M, Morina N, Klaghofer R et al (2013) Trauma, mental health, and intergenerational associations in Kosovar Families 11 years after the war. European Journal of Psychotraumatology. dio: 10.3402/ejpt.v4i0.21060
  166. Schulz LC (2010) The Dutch hunger winter and the developmental origins of health and disease. Proc Natl Acad Sci U S A 107:16757–16758PubMedPubMedCentralCrossRefGoogle Scholar
  167. Seisenberger S, Andrews S, Krueger F et al (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 48:849–862PubMedPubMedCentralCrossRefGoogle Scholar
  168. Seisenberger S, Peat JR, Hore TA et al (2013) Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers. Philos Trans R Soc Lond B Biol Sci 368:20110330PubMedPubMedCentralCrossRefGoogle Scholar
  169. Sha K (2008) A mechanistic view of genomic imprinting. Annu Rev Genomics Hum Genet 9:197–216PubMedCrossRefGoogle Scholar
  170. Sharif J, Muto M, Takebayashi S et al (2007) The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450:908–912PubMedCrossRefGoogle Scholar
  171. Sharma RP (2012) Blood chromatin as a biosensor of the epigenetic milieu: a tool for studies in living psychiatric patients. Epigenomics 4:551–559PubMedPubMedCentralCrossRefGoogle Scholar
  172. Skinner MK (2014) Endocrine disruptor induction of epigenetic transgenerational inheritance of disease. Mol Cell Endocrinol 398(1):4–12PubMedPubMedCentralCrossRefGoogle Scholar
  173. Skinner MK, Anway MD, Savenkova MI et al (2008) Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior. PLoS One 3:e3745PubMedPubMedCentralCrossRefGoogle Scholar
  174. Skinner MK, Haque CG, Nilsson E et al (2013) Environmentally induced transgenerational epigenetic reprogramming of primordial germ cells and the subsequent germ line. PLoS One 8:e66318PubMedPubMedCentralCrossRefGoogle Scholar
  175. Skinner MK, Gurerrero-Bosagna C, Haque MM et al (2014) Epigenetics and the evolution of Darwin’s finches. Genome Biol Evol. 6:1972–1989Google Scholar
  176. Smallwood SA, Tomizawa S-I, Krueger F et al (2011) Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet 43:811–814PubMedPubMedCentralCrossRefGoogle Scholar
  177. Smith ZD, Chan MM, Mikkelsen TS et al (2012) A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 484:339–344PubMedPubMedCentralCrossRefGoogle Scholar
  178. Stein AD, Lumey LH (2000) The relationship between maternal and offspring birth weights after maternal prenatal famine exposure: the Dutch Famine Birth Cohort Study. Hum Biol 72:641–654PubMedGoogle Scholar
  179. Stewart RJ, Preece RF, Sheppard HG (1975) Twelve generations of marginal protein deficiency. Br J Nutr 33:233–253PubMedCrossRefGoogle Scholar
  180. Stewart RJ, Sheppard H, Preece R, Waterlow JC (1980) The effect of rehabilitation at different stages of development of rats marginally malnourished for ten to twelve generations. Br J Nutr 43:403–412PubMedCrossRefGoogle Scholar
  181. Stilling RM, Dinan TG, Cryan JF (2014) Microbial genes, brain & behaviour – epigenetic regulation of the gut-brain axis. Genes Brain Behav 13:69–86PubMedCrossRefGoogle Scholar
  182. Stouder C, Paoloni-Giacobino A (2011) Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes. Reproduction 141:207–216PubMedCrossRefGoogle Scholar
  183. Susser M, Stein Z (1994) Timing in prenatal nutrition: a reprise of the Dutch Famine Study. Nutr Rev 52:84–94PubMedCrossRefGoogle Scholar
  184. Todrank J, Heth G, Restrepo D (2011) Effects of in utero odorant exposure on neuroanatomical development of the olfactory bulb and odour preferences. Proc R Soc Lond B Biol Sci 278:1949–1955CrossRefGoogle Scholar
  185. Uzumcu M, Suzuki H, Skinner MK (2004) Effect of the anti-androgenic endocrine disruptor vinclozolin on embryonic testis cord formation and postnatal testis development and function. Reprod Toxicol 18:765–774PubMedCrossRefGoogle Scholar
  186. Vaage AB, Thomsen PH, Rousseau C et al (2011) Paternal predictors of the mental health of children of Vietnamese refugees. Child Adolesc Psychiatr Ment Health 5:2CrossRefGoogle Scholar
  187. Van Den Berg GJ, Pinger PR (2014) A validation study of transgenerational effects of childhood conditions on the third generation offspring’s economic and health outcomes potentially driven by epigenetic imprinting. IZA Discussion Paper, No. 7999Google Scholar
  188. Vassoler FM, White SL, Schmidt HD et al (2013) Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16:42–47PubMedCrossRefGoogle Scholar
  189. Vavouri T, Lehner B (2011) Chromatin organization in sperm may be the major functional consequence of base composition variation in the human genome. PLoS Genet 7:e1002036PubMedPubMedCentralCrossRefGoogle Scholar
  190. Veenendaal MVE, Painter RC, de Rooij SR et al (2013) Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine. BJOG 120:548–553PubMedCrossRefGoogle Scholar
  191. Vickers KC, Palmisano BT, Shoucri BM et al (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13:423–433PubMedPubMedCentralCrossRefGoogle Scholar
  192. Vitale R, Fawcett DW, Dym M (1973) The normal development of the blood-testis barrier and the effects of clomiphene and estrogen treatment. Anat Rec 176:331–344PubMedCrossRefGoogle Scholar
  193. Vitku J, Starka L, Bicikova M et al (2014) Endocrine disruptors and other inhibitors of 11β-hydroxysteroid dehydrogenase 1 and 2: tissue-specific consequences of enzyme inhibition. J Steroid Biochem Mol Biol. doi: 10.1016/j.jsbmb.2014.07.007 PubMedGoogle Scholar
  194. Vojtech L, Woo S, Hughes S et al (2014) Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic Acids Res 42:7290–7304PubMedPubMedCentralCrossRefGoogle Scholar
  195. Wagner KD, Wagner N, Ghanbarian H et al (2008) RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. Dev Cell 14:962–969PubMedCrossRefGoogle Scholar
  196. Walker AK, Hawkins G, Sominsky L, Hodgson DM (2012) Transgenerational transmission of anxiety induced by neonatal exposure to lipopolysaccharide: implications for male and female germ lines. Psychoneuroendocrinology 37:1320–1335PubMedCrossRefGoogle Scholar
  197. Waterland RA, Kellermayer R, Laritsky E et al (2010) Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet 6:e1001252PubMedPubMedCentralCrossRefGoogle Scholar
  198. Weaver IC, Cervoni N, Champagne FA et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854PubMedCrossRefGoogle Scholar
  199. Wei Y-PPY, Yang C-RR, Zhao Z-AA et al (2014) Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc Natl Acad Sci U S A 111:1873–1878PubMedPubMedCentralCrossRefGoogle Scholar
  200. Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32:1073–1086PubMedCrossRefGoogle Scholar
  201. Weiss IC, Franklin TB, Vizi SS, Mansuy IM (2011) Inheritable effect of unpredictable maternal separation on behavioral responses in mice. Front Behav Neurosci 5:3PubMedPubMedCentralCrossRefGoogle Scholar
  202. Wolstenholme JT, Edwards M, Shetty SR et al (2012) Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. Endocrinology 153:3828–3838PubMedPubMedCentralCrossRefGoogle Scholar
  203. Wolstenholme JT, Goldsby JA, Rissman EF (2013) Transgenerational effects of prenatal bisphenol A on social recognition. Horm Behav 64:833–839PubMedPubMedCentralCrossRefGoogle Scholar
  204. Yamagata K, Yamazaki T, Miki H et al (2007) Centromeric DNA hypomethylation as an epigenetic signature discriminates between germ and somatic cell lineages. Dev Biol 312:419–426PubMedCrossRefGoogle Scholar
  205. Zernecke A, Bidzhekov K, Noels H et al (2009) Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2:ra81PubMedCrossRefGoogle Scholar
  206. Zeybel M, Hardy T, Wong YK et al (2012) Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med 18:1369–1377PubMedPubMedCentralCrossRefGoogle Scholar
  207. Zhou Q, Nie R, Prins GS et al (2002) Localization of androgen and estrogen receptors in adult male mouse reproductive tract. J Androl 23:870–881PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Brain Research Institute, Neuroscience Center ZürichUniversity of Zürich and Swiss Federal Institute of TechnologyZürichSwitzerland

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