The Long-Term Effects of the Periconceptional Period on Embryo Epigenetic Profile and Phenotype; The Paternal Role and His Contribution, and How Males Can Affect Offspring’s Phenotype/Epigenetic Profile

  • Emma S. Lucas
  • Adam J. WatkinsEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1014)


The number of adults afflicted with heart disease, obesity and diabetes, central components of metabolic disorder, has grown rapidly in recent decades, affecting up to one quarter of the world’s population. Typically, these diseases are attributed to lifestyle factors such as poor diet, lack of exercise and smoking. However, studies have now identified strong associations between patterns of growth during foetal and neonatal life and an increase predisposition towards developing heart disease, obesity and diabetes in adult life. While the connection between a mother’s diet and the long-term health of her offspring has been studied in great detail, our understanding of whether offspring health might be affected by a father’s diet remains limited. Greater insight into the impact that paternal nutrition has on sperm quality, epigenetic status and potential offspring programming mechanisms is needed to redress this parental-programming knowledge imbalance. Disturbances in paternal reproductive epigenetic status represents one key mechanism linking paternal diet with the programing of offspring development and adult health, as many enzymatic processes involved in epigenetic regulation use metabolic intermediates to modify DNA and histones. Here, poor paternal nutrition could result in perturbed sperm and testicular epigenetic status, impacting on post-fertilisation gene transcriptional regulation and protein expression in offspring tissues, resulting in increased incidences of metabolic disorder in adult life.


Paternal nutrition DNA Histones Metabolic syndrome Reproductive fitness 



Dr Watkins is supported by an Aston Research Centre for Healthy Ageing (ARCHA) fellowship and by a Society for Reproduction and Fertility academic scholarship grant.


  1. Abel E (2004) Paternal contribution to fetal alcohol syndrome. Addict Biol 9(2):127–133. discussion 135-126. doi: 10.1080/13556210410001716980 PubMedCrossRefGoogle Scholar
  2. Abel EL, Bilitzke P (1990) Paternal alcohol exposure: paradoxical effect in mice and rats. Psychopharmacology 100(2):159–164PubMedCrossRefGoogle Scholar
  3. Agbaje IM, Rogers DA, McVicar CM, McClure N, Atkinson AB, Mallidis C, Lewis SE (2007) Insulin dependant diabetes mellitus: implications for male reproductive function. Hum Reprod 22(7):1871–1877. doi: 10.1093/humrep/dem077 PubMedCrossRefGoogle Scholar
  4. Anderson LM, Riffle L, Wilson R, Travlos GS, Lubomirski MS, Alvord WG (2006) Preconceptional fasting of fathers alters serum glucose in offspring of mice. Nutrition 22(3):327–331. doi: 10.1016/j.nut.2005.09.006 PubMedCrossRefGoogle Scholar
  5. Anway MD, Skinner MK (2008) Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reprod Biomed Online 16(1):23–25PubMedCrossRefGoogle Scholar
  6. Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308(5727):1466–1469. doi: 10.1126/science.1108190 PubMedCrossRefGoogle Scholar
  7. Anway MD, Rekow SS, Skinner MK (2008) Comparative anti-androgenic actions of vinclozolin and flutamide on transgenerational adult onset disease and spermatogenesis. Reprod Toxicol 26(2):100–106. doi: 10.1016/j.reprotox.2008.07.008 PubMedCrossRefGoogle Scholar
  8. Aoki VW, Carrell DT (2003) Human protamines and the developing spermatid: their structure, function, expression and relationship with male infertility. Asian J Androl 5(4):315–324PubMedGoogle Scholar
  9. Aston KI, Punj V, Liu L, Carrell DT (2012) Genome-wide sperm deoxyribonucleic acid methylation is altered in some men with abnormal chromatin packaging or poor in vitro fertilization embryogenesis. Fertil Steril 97(2):285–292. doi: 10.1016/j.fertnstert.2011.11.008 PubMedCrossRefGoogle Scholar
  10. Bakos HW, Henshaw RC, Mitchell M, Lane M (2011a) Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology. Fertil Steril 95(5):1700–1704. doi: 10.1016/j.fertnstert.2010.11.044 PubMedCrossRefGoogle Scholar
  11. Bakos HW, Mitchell M, Setchell BP, Lane M (2011b) The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model. Int J Androl 34(5 Pt 1):402–410. doi: 10.1111/j.1365-2605.2010.01092.x PubMedCrossRefGoogle Scholar
  12. Bakos HW, Thompson JG, Feil D, Lane M (2008) Sperm DNA damage is associated with assisted reproductive technology pregnancy. Int J Androl 31(5):518–526. doi: 10.1111/j.1365-2605.2007.00803.x PubMedCrossRefGoogle Scholar
  13. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS (1993) Fetal nutrition and cardiovascular disease in adult life. Lancet 341(8850):938–941PubMedCrossRefGoogle Scholar
  14. Bener A, Al-Ansari AA, Zirie M, Al-Hamaq AO (2009) Is male fertility associated with type 2 diabetes mellitus? Int Urol Nephrol 41(4):777–784. doi: 10.1007/s11255-009-9565-6 PubMedCrossRefGoogle Scholar
  15. Bertolini M, Mason JB, Beam SW, Carneiro GF, Sween ML, Kominek DJ, Moyer AL, Famula TR, Sainz RD, Anderson GB (2002) Morphology and morphometry of in vivo- and in vitro-produced bovine concepti from early pregnancy to term and association with high birth weights. Theriogenology 58(5):973–994PubMedCrossRefGoogle Scholar
  16. Bielawski DM, Zaher FM, Svinarich DM, Abel EL (2002) Paternal alcohol exposure affects sperm cytosine methyltransferase messenger RNA levels. Alcohol Clin Exp Res 26(3):347–351PubMedCrossRefGoogle Scholar
  17. Binder NK, Mitchell M, Gardner DK (2012) Parental diet-induced obesity leads to retarded early mouse embryo development and altered carbohydrate utilisation by the blastocyst. Reprod Fertil Dev 24(6):804–812. doi: 10.1071/RD11256 PubMedCrossRefGoogle Scholar
  18. Bos-Mikich A, Whittingham DG, Jones KT (1997) Meiotic and mitotic Ca2+ oscillations affect cell composition in resulting blastocysts. Dev Biol 182(1):172–179. doi: 10.1006/dbio.1996.8468 PubMedCrossRefGoogle Scholar
  19. Boucher BJ, Ewen SW, Stowers JM (1994) Betel nut (Areca catechu) consumption and the induction of glucose intolerance in adult CD1 mice and in their F1 and F2 offspring. Diabetologia 37(1):49–55PubMedCrossRefGoogle Scholar
  20. Brykczynska U, Hisano M, Erkek S, Ramos L, Oakeley EJ, Roloff TC, Beisel C, Schubeler D, Stadler MB, Peters AH (2010) Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat Struct Mol Biol 17(6):679–687. doi: 10.1038/nsmb.1821 PubMedCrossRefGoogle Scholar
  21. Calle A, Miranda A, Fernandez-Gonzalez R, Pericuesta E, Laguna R, Gutierrez-Adan A (2012) Male mice produced by in vitro culture have reduced fertility and transmit organomegaly and glucose intolerance to their male offspring. Biol Reprod 87(2):34. doi: 10.1095/biolreprod.112.100743 PubMedCrossRefGoogle Scholar
  22. Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143(7):1084–1096. doi: 10.1016/j.cell.2010.12.008 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Carrell DT, Emery BR, Hammoud S (2007) Altered protamine expression and diminished spermatogenesis: what is the link? Hum Reprod Update 13(3):313–327. doi: 10.1093/humupd/dml057 PubMedCrossRefGoogle Scholar
  24. Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA (2008) Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J Clin Endocrinol Metab 93(5):1682–1688. doi: 10.1210/jc.2007-2432 PubMedCrossRefGoogle Scholar
  25. Chavarro JE, Furtado J, Toth TL, Ford J, Keller M, Campos H, Hauser R (2011a) Trans-fatty acid levels in sperm are associated with sperm concentration among men from an infertility clinic. Fertil Steril 95(5):1794–1797. doi: 10.1016/j.fertnstert.2010.10.039 PubMedCrossRefGoogle Scholar
  26. Chen TH, Chiu YH, 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(3):688–692PubMedGoogle Scholar
  27. Cheung YB, Low L, Osmond C, Barker D, Karlberg J (2000) Fetal growth and early postnatal growth are related to blood pressure in adults. Hypertension 36(5):795–800PubMedCrossRefGoogle Scholar
  28. Cho C, Willis WD, Goulding EH, Jung-Ha H, Choi YC, Hecht NB, Eddy EM (2001) Haploinsufficiency of protamine-1 or −2 causes infertility in mice. Nat Genet 28(1):82–86. doi: 10.1038/88313 PubMedGoogle Scholar
  29. Dabelea D, Pettitt DJ, Hanson RL, Imperatore G, Bennett PH, Knowler WC (1999) Birth weight, type 2 diabetes, and insulin resistance in pima Indian children and young adults. Diabetes Care 22(6):944–950PubMedCrossRefGoogle Scholar
  30. Das JK, Salam RA, Kumar R, Bhutta ZA (2013) Micronutrient fortification of food and its impact on woman and child health: a systematic review. Syst Rev 2:67. doi: 10.1186/2046-4053-2-67 PubMedPubMedCentralCrossRefGoogle Scholar
  31. Dumoulin JC, Land JA, Van Montfoort AP, Nelissen EC, Coonen E, Derhaag JG, Schreurs IL, Dunselman GA, Kester AD, Geraedts JP, Evers JL (2010) Effect of in vitro culture of human embryos on birthweight of newborns. Hum Reprod 25(3):605–612. doi: 10.1093/humrep/dep456 PubMedCrossRefGoogle Scholar
  32. Eckert JJ, Porter R, Watkins AJ, Burt E, Brooks S, Leese HJ, Humpherson PG, Cameron IT, Fleming TP (2012) Metabolic induction and early responses of mouse blastocyst developmental programming following maternal low protein diet affecting life-long health. PLoS One 7(12):e52791. doi: 10.1371/journal.pone.0052791 PubMedPubMedCentralCrossRefGoogle Scholar
  33. Eslamian G, Amirjannati N, Rashidkhani B, Sadeghi MR, Hekmatdoost A (2012) Intake of food groups and idiopathic asthenozoospermia: a case-control study. Hum Reprod 27(11):3328–3336. doi: 10.1093/humrep/des311 PubMedCrossRefGoogle Scholar
  34. Fleming TP, Watkins AJ, Sun C, Velazquez MA, Smyth NR, Eckert JJ (2015) Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo. Reprod Fertil Dev 27(4):684–692. doi: 10.1071/RD14455 PubMedCrossRefGoogle Scholar
  35. Forsen T, Eriksson JG, Tuomilehto J, Teramo K, Osmond C, Barker DJ (1997) Mother's weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. BMJ 315(7112):837–840PubMedPubMedCentralCrossRefGoogle Scholar
  36. Fullston T, Ohlsson Teague EM, Palmer NO, DeBlasio MJ, Mitchell M, Corbett M, Print CG, Owens JA, Lane M (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 : Off Publ Fed Am Societies Exp Biol 27(10):4226–4243. doi: 10.1096/fj.12-224048 CrossRefGoogle Scholar
  37. Fullston T, Palmer NO, Owens JA, Mitchell M, Bakos HW, Lane M (2012) Diet-induced paternal obesity in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice. Hum Reprod 27(5):1391–1400. doi: 10.1093/humrep/des030 PubMedCrossRefGoogle Scholar
  38. Gallou-Kabani C, Junien C (2005) Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes 54(7):1899–1906PubMedCrossRefGoogle Scholar
  39. Garrido N, Martinez-Conejero JA, Jauregui J, Horcajadas JA, Simon C, Remohi J, Meseguer M (2009) Microarray analysis in sperm from fertile and infertile men without basic sperm analysis abnormalities reveals a significantly different transcriptome. Fertil Steril 91(4 Suppl):1307–1310. doi: 10.1016/j.fertnstert.2008.01.078 PubMedCrossRefGoogle Scholar
  40. Gaskins AJ, Colaci DS, Mendiola J, Swan SH, Chavarro JE (2012) Dietary patterns and semen quality in young men. Hum Reprod 27(10):2899–2907. doi: 10.1093/humrep/des298 PubMedPubMedCentralCrossRefGoogle Scholar
  41. Gauthier D, Berbigier P (1982) The influence of nutritional levels and shade structure on testicular growth and hourly variations of plasma-LH and testosterone levels in young creole bulls in a tropical environment. Reprod Nutr Dev 22(5):793–801. doi: 10.1051/Rnd:19820606 PubMedCrossRefGoogle Scholar
  42. Grace KS, Sinclair KD (2009) Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking. Semin Reprod Med 27(5):409–416. doi: 10.1055/s-0029-1237429 PubMedCrossRefGoogle Scholar
  43. Hales BF, Robaire B (2001) Paternal exposure to drugs and environmental chemicals: effects on progeny outcome. J Androl 22(6):927–936PubMedCrossRefGoogle Scholar
  44. Hammoud AO, Gibson M, Stanford J, White G, Carrell DT, Peterson M (2009) In vitro fertilization availability and utilization in the United States: a study of demographic, social, and economic factors. Fertil Steril 91(5):1630–1635. doi: 10.1016/j.fertnstert.2007.10.038 PubMedCrossRefGoogle Scholar
  45. Hammoud SS, Nix DA, Hammoud AO, Gibson M, Cairns BR, Carrell DT (2011) 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(9):2558–2569. doi: 10.1093/humrep/der192 PubMedPubMedCentralCrossRefGoogle Scholar
  46. Hanson MA, Gluckman PD (2014) Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev 94(4):1027–1076. doi: 10.1152/physrev.00029.2013 PubMedPubMedCentralCrossRefGoogle Scholar
  47. He F, Lidow IA, Lidow MS (2006) Consequences of paternal cocaine exposure in mice. Neurotoxicol Teratol 28(2):198–209. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  48. Heslehurst N, Rankin J, Wilkinson JR, Summerbell CD (2010) A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989-2007. Int J Obes 34(3):420–428. doi: 10.1038/ijo.2009.250 CrossRefGoogle Scholar
  49. Hinkle SN, Sharma AJ, Kim SY, Park S, Dalenius K, Brindley PL, Grummer-Strawn LM (2012) Prepregnancy obesity trends among low-income women, United States, 1999-2008. Matern Child Health J 16(7):1339–1348. doi: 10.1007/s10995-011-0898-2 PubMedCrossRefGoogle Scholar
  50. Igosheva N, Abramov AY, Poston L, Eckert JJ, Fleming TP, Duchen MR, McConnell J (2010) Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS One 5(4):e10074. doi: 10.1371/journal.pone.0010074 PubMedPubMedCentralCrossRefGoogle Scholar
  51. Inhorn MC, Patrizio P (2015) Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update 21(4):411–426. doi: 10.1093/humupd/dmv016 PubMedCrossRefGoogle Scholar
  52. Jodar M, Kalko S, Castillo J, Ballesca JL, Oliva R (2012) Differential RNAs in the sperm cells of asthenozoospermic patients. Hum Reprod 27(5):1431–1438. doi: 10.1093/humrep/des021 PubMedCrossRefGoogle Scholar
  53. Jungheim ES, Schoeller EL, Marquard KL, Louden ED, Schaffer JE, Moley KH (2010) Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology 151(8):4039–4046. doi: 10.1210/en.2010-0098 PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kaati G, Bygren LO, Edvinsson S (2002) Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur J Hum Genet 10(11):682–688. doi: 10.1038/sj.ejhg.5200859 PubMedCrossRefGoogle Scholar
  55. Kelly T, Yang W, Chen CS, Reynolds K, He J (2008) Global burden of obesity in 2005 and projections to 2030. Int J Obes 32(9):1431–1437. doi: 10.1038/ijo.2008.102 CrossRefGoogle Scholar
  56. Knott JG, Kurokawa M, Fissore RA, Schultz RM, Williams CJ (2005) Transgenic RNA interference reveals role for mouse sperm phospholipase Czeta in triggering Ca2+ oscillations during fertilization. Biol Reprod 72(4):992–996. doi: 10.1095/biolreprod.104.036244 PubMedCrossRefGoogle Scholar
  57. Kort HI, Massey JB, Elsner CW, Mitchell-Leef D, Shapiro DB, Witt MA, Roudebush WE (2006a) Impact of body mass index values on sperm quantity and quality. J Androl 27(3):450–452. doi: 10.2164/jandrol.05124 PubMedCrossRefGoogle Scholar
  58. Krawetz SA, Kruger A, Lalancette C, Tagett R, Anton E, Draghici S, Diamond MP (2011) A survey of small RNAs in human sperm. Hum Reprod 26(12):3401–3412. doi: 10.1093/humrep/der329 PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kulie T, Slattengren A, Redmer J, Counts H, Eglash A, Schrager S (2011) Obesity and women's health: an evidence-based review. J Am Board Fam Med 24(1):75–85. doi: 10.3122/jabfm.2011.01.100076 PubMedCrossRefGoogle Scholar
  60. Lambrot R, Xu C, Saint-Phar S, Chountalos G, Cohen T, Paquet M, Suderman M, Hallett M, Kimmins S (2013) Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun 4:2889. doi: 10.1038/ncomms3889 PubMedPubMedCentralCrossRefGoogle Scholar
  61. Ledig M, Misslin R, Vogel E, Holownia A, Copin JC, Tholey G (1998) Paternal alcohol exposure: developmental and behavioral effects on the offspring of rats. Neuropharmacology 37(1):57–66PubMedCrossRefGoogle Scholar
  62. Lee HS (2015) Impact of maternal diet on the Epigenome during in utero life and the developmental programming of diseases in childhood and adulthood. Forum Nutr 7(11):9492–9507. doi: 10.3390/nu7115467 Google Scholar
  63. Lin WY, Chiu TY, Lee LT, Lin CC, Huang CY, Huang KC (2008) Betel nut chewing is associated with increased risk of cardiovascular disease and all-cause mortality in Taiwanese men. Am J Clin Nutr 87(5):1204–1211PubMedGoogle Scholar
  64. Little RE, Sing CF (1987) Father's drinking and infant birth weight: report of an association. Teratology 36(1):59–65. doi: 10.1002/tera.1420360109 PubMedCrossRefGoogle Scholar
  65. Ly L, Chan D, Trasler JM (2015) Developmental windows of susceptibility for epigenetic inheritance through the male germline. Semin Cell Dev Biol 43:96–105. doi: 10.1016/j.semcdb.2015.07.006 PubMedCrossRefGoogle Scholar
  66. Martin GB, Blache D, Miller DW, Vercoe PE (2010a) Interactions between nutrition and reproduction in the management of the mature male ruminant. Animal 4(7):1214–1226. doi: 10.1017/S1751731109991674 PubMedCrossRefGoogle Scholar
  67. McPherson NO, Bakos HW, Owens JA, Setchell BP, Lane M (2013) Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth. PLoS One 8(8):e71459. doi: 10.1371/journal.pone.0071459 PubMedPubMedCentralCrossRefGoogle Scholar
  68. McPherson NO, Fullston T, Bakos HW, Setchell BP, Lane M (2014) Obese father's metabolic state, adiposity, and reproductive capacity indicate son's reproductive health. Fertil Steril 101(3):865–873. doi: 10.1016/j.fertnstert.2013.12.007 PubMedCrossRefGoogle Scholar
  69. McPherson NO, Fullston T, Kang WX, Sandeman LY, Corbett MA, Owens JA, Lane M (2016) Paternal under-nutrition programs metabolic syndrome in offspring which can be reversed by antioxidant/vitamin food fortification in fathers. Sci Rep 6:27010. doi: 10.1038/srep27010 PubMedPubMedCentralCrossRefGoogle Scholar
  70. Meek LR, Myren K, Sturm J, Burau D (2007) Acute paternal alcohol use affects offspring development and adult behavior. Physiol Behav 91(1):154–160. doi: 10.1016/j.physbeh.2007.02.004 PubMedCrossRefGoogle Scholar
  71. Mitchell M, Bakos HW, Lane M (2011) Paternal diet-induced obesity impairs embryo development and implantation in the mouse. Fertil Steril 95(4):1349–1353. doi: 10.1016/j.fertnstert.2010.09.038 PubMedCrossRefGoogle Scholar
  72. Mitchell M, Schulz SL, Armstrong DT, Lane M (2009) Metabolic and mitochondrial dysfunction in early mouse embryos following maternal dietary protein intervention. Biol Reprod 80(4):622–630. doi: 10.1095/biolreprod.108.072595 PubMedPubMedCentralCrossRefGoogle Scholar
  73. Montjean D, De La Grange P, Gentien D, Rapinat A, Belloc S, Cohen-Bacrie P, Menezo Y, Benkhalifa M (2012) Sperm transcriptome profiling in oligozoospermia. J Assist Reprod Genet 29(1):3–10. doi: 10.1007/s10815-011-9644-3 PubMedCrossRefGoogle Scholar
  74. Nelissen EC, Van Montfoort AP, Smits LJ, Menheere PP, Evers JL, Coonen E, Derhaag JG, Peeters LL, Coumans AB, Dumoulin JC (2013) IVF culture medium affects human intrauterine growth as early as the second trimester of pregnancy. Hum Reprod 28(8):2067–2074. doi: 10.1093/humrep/det131 PubMedCrossRefGoogle Scholar
  75. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467(7318):963–966. doi: 10.1038/nature09491 PubMedCrossRefGoogle Scholar
  76. Ombelet W, Cooke I, Dyer S, Serour G, Devroey P (2008) Infertility and the provision of infertility medical services in developing countries. Hum Reprod Update 14(6):605–621. doi: 10.1093/humupd/dmn042 PubMedPubMedCentralCrossRefGoogle Scholar
  77. Ostermeier GC, Dix DJ, Miller D, Khatri P, Krawetz SA (2002) Spermatozoal RNA profiles of normal fertile men. Lancet 360(9335):772–777. doi: 10.1016/S0140-6736(02)09899-9 PubMedCrossRefGoogle Scholar
  78. Ouko LA, Shantikumar K, Knezovich J, Haycock P, Schnugh DJ, Ramsay M (2009) Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes: implications for fetal alcohol spectrum disorders. Alcohol Clin Exp Res 33(9):1615–1627. doi: 10.1111/j.1530-0277.2009.00993.x PubMedCrossRefGoogle Scholar
  79. Ozil JP, Huneau D (2001) Activation of rabbit oocytes: the impact of the Ca2+ signal regime on development. Development 128(6):917–928PubMedGoogle Scholar
  80. Palmer NO, Bakos HW, Owens JA, Setchell BP, Lane M (2012) Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function. Am J Phys Endocrinol Metab 302(7):E768–E780. doi: 10.1152/ajpendo.00401.2011 CrossRefGoogle Scholar
  81. Pandey SC, Ugale R, Zhang H, Tang L, Prakash A (2008) Brain chromatin remodeling: a novel mechanism of alcoholism. J Neurosci : Off J Soc Neurosci 28(14):3729–3737. doi: 10.1523/JNEUROSCI.5731-07.2008 CrossRefGoogle Scholar
  82. Parker GV, Thwaites CJ (1972) Effects of Undernutrition on libido and semen quality in adult merino rams. Aust J Agric Res 23(1):109–115. doi: 10.1071/Ar9720109 CrossRefGoogle Scholar
  83. Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, Golding J (2006a) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet : EJHG 14(2):159–166. doi: 10.1038/sj.ejhg.5201538 PubMedCrossRefGoogle Scholar
  84. Pentinat T, Ramon-Krauel M, Cebria J, Diaz R, Jimenez-Chillaron JC (2010) Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition. Endocrinology 151(12):5617–5623. doi: 10.1210/en.2010-0684 PubMedCrossRefGoogle Scholar
  85. Perez-Crespo M, Moreira P, Pintado B, Gutierrez-Adan A (2008) Factors from damaged sperm affect its DNA integrity and its ability to promote embryo implantation in mice. J Androl 29(1):47–54. doi: 10.2164/jandrol.107.003194 PubMedCrossRefGoogle Scholar
  86. Platts AE, Dix DJ, Chemes HE, Thompson KE, Goodrich R, Rockett JC, Rawe VY, Quintana S, Diamond MP, Strader LF, Krawetz SA (2007) Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs. Hum Mol Genet 16(7):763–773. doi: 10.1093/hmg/ddm012 PubMedCrossRefGoogle Scholar
  87. Radlowski EC, Johnson RW (2013) Perinatal iron deficiency and neurocognitive development. Front Hum Neurosci 7:585. doi: 10.3389/fnhum.2013.00585 PubMedPubMedCentralCrossRefGoogle Scholar
  88. Rato L, Alves MG, Dias TR, Lopes G, Cavaco JE, Socorro S, Oliveira PF (2013) High-energy diets may induce a pre-diabetic state altering testicular glycolytic metabolic profile and male reproductive parameters. Andrology 1(3):495–504. doi: 10.1111/j.2047-2927.2013.00071.x PubMedCrossRefGoogle Scholar
  89. Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351(9097):173–177PubMedCrossRefGoogle Scholar
  90. Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP (1999) Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70(5):811–816PubMedGoogle Scholar
  91. Rexhaj E, Paoloni-Giacobino A, Rimoldi SF, Fuster DG, Anderegg M, Somm E, Bouillet E, Allemann Y, Sartori C, Scherrer U (2013) Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span. J Clin Invest 123(12):5052–5060. doi: 10.1172/JCI68943 PubMedPubMedCentralCrossRefGoogle Scholar
  92. Reynolds CM, Gray C, Li M, Segovia SA, Vickers MH (2015) Early life nutrition and energy balance disorders in offspring in later life. Forum Nutr 7(9):8090–8111. doi: 10.3390/nu7095384 Google Scholar
  93. Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, Willett WC, Hennekens CH (1997) Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 315(7105):396–400PubMedPubMedCentralCrossRefGoogle Scholar
  94. Robinson JJ, Ashworth CJ, Rooke JA, Mitchell LM, McEvoy TG (2006) Nutrition and fertility in ruminant livestock. Anim Feed Sci Technol 126(3–4):259–276. doi: 10.1016/j.anifeedsci.2005.08.006 CrossRefGoogle Scholar
  95. Robker RL, Akison LK, Bennett BD, Thrupp PN, Chura LR, Russell DL, Lane M, Norman RJ (2009) Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women. J Clin Endocrinol Metab 94(5):1533–1540. doi: 10.1210/jc.2008-2648 PubMedCrossRefGoogle Scholar
  96. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Bleker OP (2000) Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am J Clin Nutr 72(5):1101–1106PubMedGoogle Scholar
  97. Roseboom TJ, van der Meulen JH, van Montfrans GA, Ravelli AC, Osmond C, Barker DJ, Bleker OP (2001) Maternal nutrition during gestation and blood pressure in later life. J Hypertens 19(1):29–34PubMedCrossRefGoogle Scholar
  98. Scherrer U, Rimoldi SF, Rexhaj E, Stuber T, Duplain H, Garcin S, de Marchi SF, Nicod P, Germond M, Allemann Y, Sartori C (2012) Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation 125(15):1890–1896. doi: 10.1161/CIRCULATIONAHA.111.071183 PubMedCrossRefGoogle Scholar
  99. Seli E, Gardner DK, Schoolcraft WB, Moffatt O, Sakkas D (2004) Extent of nuclear DNA damage in ejaculated spermatozoa impacts on blastocyst development after in vitro fertilization. Fertil Steril 82(2):378–383. doi: 10.1016/j.fertnstert.2003.12.039 PubMedCrossRefGoogle Scholar
  100. Sendler E, Johnson GD, Mao S, Goodrich RJ, Diamond MP, Hauser R, Krawetz SA (2013) Stability, delivery and functions of human sperm RNAs at fertilization. Nucleic Acids Res 41(7):4104–4117. doi: 10.1093/nar/gkt132 PubMedPubMedCentralCrossRefGoogle Scholar
  101. Sharkey DJ, Macpherson AM, Tremellen KP, Robertson SA (2007) Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells. Mol Hum Reprod 13(7):491–501. doi: 10.1093/molehr/gam028 PubMedCrossRefGoogle Scholar
  102. Shi L, Wu J (2009) Epigenetic regulation in mammalian preimplantation embryo development. Reprod Biol Endocrinol : RB&E 7:59. doi: 10.1186/1477-7827-7-59 CrossRefGoogle Scholar
  103. Sinclair KD, Watkins AJ (2013) Parental diet, pregnancy outcomes and offspring health: metabolic determinants in developing oocytes and embryos. Reprod Fertil Dev 26(1):99–114. doi: 10.1071/RD13290 PubMedCrossRefGoogle Scholar
  104. Sjoblom C, Roberts CT, Wikland M, Robertson SA (2005) Granulocyte-macrophage colony-stimulating factor alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis. Endocrinology 146(5):2142–2153. doi: 10.1210/en.2004-1260 PubMedCrossRefGoogle Scholar
  105. Soubry A, Schildkraut JM, Murtha A, Wang F, Huang Z, Bernal A, Kurtzberg J, Jirtle RL, Murphy SK, Hoyo C (2013) Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a newborn epigenetics study (NEST) cohort. BMC Med 11:29. doi: 10.1186/1741-7015-11-29 PubMedPubMedCentralCrossRefGoogle Scholar
  106. Steilmann C, Paradowska A, Bartkuhn M, Vieweg M, Schuppe HC, Bergmann M, Kliesch S, Weidner W, Steger K (2011) Presence of histone H3 acetylated at lysine 9 in male germ cells and its distribution pattern in the genome of human spermatozoa. Reprod Fertil Dev 23(8):997–1011. doi: 10.1071/RD10197 PubMedCrossRefGoogle Scholar
  107. Stewart TM, Liu DY, Garrett C, Brown EH, Baker HW (2009) Recruitment bias in studies of semen and other factors affecting pregnancy rates in fertile men. Hum Reprod 24(10):2401–2408. doi: 10.1093/humrep/dep215 PubMedCrossRefGoogle Scholar
  108. Stouder C, Deutsch S, Paoloni-Giacobino A (2009) Superovulation in mice alters the methylation pattern of imprinted genes in the sperm of the offspring. Reprod Toxicol 28(4):536–541. doi: 10.1016/j.reprotox.2009.06.009 PubMedCrossRefGoogle Scholar
  109. Stouder C, Paoloni-Giacobino A (2010) Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. Reproduction 139(2):373–379. doi: 10.1530/REP-09-0340 PubMedCrossRefGoogle Scholar
  110. Swann K, Saunders CM, Rogers NT, Lai FA (2006) PLCzeta(zeta): a sperm protein that triggers Ca2+ oscillations and egg activation in mammals. Semin Cell Dev Biol 17(2):264–273. doi: 10.1016/j.semcdb.2006.03.009 PubMedCrossRefGoogle Scholar
  111. Tunc O, Bakos HW, Tremellen K (2011) Impact of body mass index on seminal oxidative stress. Andrologia 43(2):121–128. doi: 10.1111/j.1439-0272.2009.01032.x PubMedCrossRefGoogle Scholar
  112. van der Heijden GW, Derijck AA, Ramos L, Giele M, van der Vlag J, de Boer P (2006) Transmission of modified nucleosomes from the mouse male germline to the zygote and subsequent remodeling of paternal chromatin. Dev Biol 298(2):458–469. doi: 10.1016/j.ydbio.2006.06.051 PubMedCrossRefGoogle Scholar
  113. van der Heijden GW, Ramos L, Baart EB, van den Berg IM, Derijck AA, van der Vlag J, Martini E, de Boer P (2008) Sperm-derived histones contribute to zygotic chromatin in humans. BMC Dev Biol 8:34. doi: 10.1186/1471-213X-8-34 PubMedPubMedCentralCrossRefGoogle Scholar
  114. Vandemark NL, Mauger RE, Fritz GR (1964) Effect of energy intake on reproductive performance of dairy bulls .2. Semen production + replenishment. J Dairy Sci 47(8):898CrossRefGoogle Scholar
  115. Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M (2011) Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378(9793):815–825. doi: 10.1016/S0140-6736(11)60814-3 PubMedCrossRefGoogle Scholar
  116. Watkins AJ, Lucas ES, Wilkins A, Cagampang FR, Fleming TP (2011) Maternal periconceptional and gestational low protein diet affects mouse offspring growth, cardiovascular and adipose phenotype at 1 year of age. PLoS One 6(12):e28745. doi: 10.1371/journal.pone.0028745 PubMedPubMedCentralCrossRefGoogle Scholar
  117. Watkins AJ, Platt D, Papenbrock T, Wilkins A, Eckert JJ, Kwong WY, Osmond C, Hanson M, Fleming TP (2007) Mouse embryo culture induces changes in postnatal phenotype including raised systolic blood pressure. Proc Natl Acad Sci U S A 104(13):5449–5454. doi: 10.1073/pnas.0610317104 PubMedPubMedCentralCrossRefGoogle Scholar
  118. Watkins AJ, Sinclair KD (2014) Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice. Am J Phys Heart Circ Phys 306(10):H1444–H1452. doi: 10.1152/ajpheart.00981.2013 Google Scholar
  119. Watkins AJ, Ursell E, Panton R, Papenbrock T, Hollis L, Cunningham C, Wilkins A, Perry VH, Sheth B, Kwong WY, Eckert JJ, Wild AE, Hanson MA, Osmond C, Fleming TP (2008) Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease. Biol Reprod 78(2):299–306. doi: 10.1095/biolreprod.107.064220 PubMedCrossRefGoogle Scholar
  120. Wrenzycki C, Herrmann D, Lucas-Hahn A, Lemme E, Korsawe K, Niemann H (2004) Gene expression patterns in in vitro-produced and somatic nuclear transfer-derived preimplantation bovine embryos: relationship to the large offspring syndrome? Anim Reprod Sci 82-83:593–603. doi: 10.1016/j.anireprosci.2004.05.009 PubMedCrossRefGoogle Scholar
  121. Wu LL, Norman RJ, Robker RL (2011) The impact of obesity on oocytes: evidence for lipotoxicity mechanisms. Reprod Fertil Dev 24(1):29–34. doi: 10.1071/RD11904 PubMedCrossRefGoogle Scholar
  122. Yap DB, Walker DC, Prentice LM, McKinney S, Turashvili G, Mooslehner-Allen K, de Algara TR, Fee J, de Tassigny X, Colledge WH, Aparicio S (2011) Mll5 is required for normal spermatogenesis. PLoS One 6(11):e27127. doi: 10.1371/journal.pone.0027127 PubMedPubMedCentralCrossRefGoogle Scholar
  123. Yeung EH, Druschel C (2013) Cardiometabolic health of children conceived by assisted reproductive technologies. Fertil Steril 99(2):318–326. doi: 10.1016/j.fertnstert.2012.12.015 PubMedPubMedCentralCrossRefGoogle Scholar
  124. Zhao J, Zhai L, Liu Z, Wu S, Xu L (2014) Leptin level and oxidative stress contribute to obesity-induced low testosterone in murine testicular tissue. Oxidative Med Cell Longev 2014:190945. doi: 10.1155/2014/190945 Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Reproductive Health, Clinical Science Research Laboratories, Warwick Medical SchoolUniversity of WarwickCoventryUK
  2. 2.Aston Research Centre for Healthy Ageing, School of Life and Health SciencesAston UniversityBirminghamUK

Personalised recommendations