Adaptive Responses of Early Embryos to Their Microenvironment and Consequences for Post-Implantation Development

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 573)


Early embryos are adaptive to the environment they encounter during development and this facilitates embryo resilience to environmental insults. However, it is clear from findings in nonhuman species that adaptive plasticity during early development can have adverse consequences manifesting over the long-term in formation of the post-natal and adult phenotype, and that this occurs via partially characterized programming phenomena. Environmental effectors resulting in adaptive changes to embryos discovered to date include amino acid nutrition, oxygen concentration (both hypoxic and hyperoxic) and growth factor exposure. Other environmental factors known to influence programming of early development have yet to be fully evaluated for their long-term consequences, an area which still requires much work. The mechanisms involved in translation of environmental adaptations to long-term programming are only now being elucidated. Epigenetic mechanisms, especially DNA methylation of imprinted genes, have been associated with adaptive responses to altered environments. Other proposed mechanisms involve temporal gene expression patterns perturbed at critical events during development, such as implantation and early placental morphogenesis. The contribution of programming in early embryos to phenotypic variation and, more importantly, potential health status of resulting offspring has particular relevance to health and diet at the time of conception and to children born following assisted reproductive technologies, especially where embryonic manipulations in artificial environments are involved.


Assisted Reproductive Technology Early Embryo Imprint Gene Preimplantation Embryo Bovine Embryo 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Land JA, Evers JLH. Risks and complications in assisted reproductiontechniques: Report of an ESHRE consensus meeting. Hum Reprod 2003; 18:455–457.PubMedCrossRefGoogle Scholar
  2. 2.
    Halliday J, Oke K, Breheny S et al. Beckwith-wiedemann syndrome and IVF: A case-control study. Am J Hum Genet 2004; 75:526–528.PubMedCrossRefGoogle Scholar
  3. 3.
    Maher ER, Afnan M, Barratt CL et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet 2003; 40:55–61.CrossRefGoogle Scholar
  4. 4.
    Walker SK, Hartwich KM, Seamark RF. The production of unusually large offspring following embryo manipulation: Concepts and challanges. Theriogenology 1996; 45:111–120.CrossRefGoogle Scholar
  5. 5.
    Kruip TAM, den Daas JHG. In vitro produced and cloned embryos: Effects on pregnancy, parturition and offspring. Theriogenology 1997; 47:43–52.CrossRefGoogle Scholar
  6. 6.
    Bowman P, McLaren A. Viability and growth of mouse embryos after in vitro culture and fusion. J Embryol Exp Morphol 1970; 23:693–704.PubMedGoogle Scholar
  7. 7.
    Thompson JG, Sherman AN, Allen NW et al. Total protein content and protein synthesis within preelongation stage bovine embryos. Mol Reprod Dev 1998; 50:139–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Hamatani T, Carter MG, Sharov AA et al. Dynamics of global gene expression changes during mouse preimplantation development. Dev Cell 2004; 6:117–131.PubMedCrossRefGoogle Scholar
  9. 9.
    Schultz RM. The molecular foundations of the maternal to zygotic transition in the preimplantation embryo. Hum Reprod Update 2002; 8:323–331.PubMedCrossRefGoogle Scholar
  10. 10.
    Forlani S, Bonnerot C, Capgras S et al. Relief of a repressed gene expression state in the mouse 1-cell embryo requires DNA replication. Development 1998; 125:3153–3166.PubMedGoogle Scholar
  11. 11.
    Wang QT, Piotrowska K, Ciemerych MA et al. A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev Cell 2004; 6:133–144.PubMedCrossRefGoogle Scholar
  12. 12.
    Howlett SK, Reik W. Methylation levels of maternal and paternal genomes during preimplantation development. Development 1991; 113:119–127.PubMedGoogle Scholar
  13. 13.
    Young LE, Beaujean N. DNA methylation in the preimplantation embryo: The differing stories of the mouse and sheep. Anim Reprod Sci 2004; 82–83:61–78.PubMedCrossRefGoogle Scholar
  14. 14.
    Sonn S, Khang I, Kim K et al. Suppression of Nek2A in mouse early embryos confirms its requirement for chromosome segregation. J Cell Sci 2004; 117:5557–5566.PubMedCrossRefGoogle Scholar
  15. 15.
    Tanaka Y, Patestos NP, Maekawa T et al. B-myb is required for inner cell mass formation at an early stage of development. J Biol Chem 1999; 274:28067–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Rinkenberger JL, Cross JC, Werb Z. Molecular genetics of implantation in the mouse. Dev Genet 1997; 21:6–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Bavister BD. Culture of preimplantation embryos: Facts and artifacts. Hum Reprod Update 1995; 1(2):91–148.PubMedCrossRefGoogle Scholar
  18. 18.
    Leese HJ. Quiet please, do not disturb: A hypothesis of embryo metabolism and viability. Bio Essays 2002; 24:845–849.Google Scholar
  19. 19.
    Thompson JG, Kind KL, Roberts CT et al. Epigenetic risks related to assisted reproductive technologies: Short-and long-term consequences for the health of children conceived through assisted reproduction technology: More reason for caution? Hum Reprod 2002; 17:2783–2786.PubMedCrossRefGoogle Scholar
  20. 20.
    Gardner DK, Sakkas D. Assessment of embryo viability: The ability to select a single embryo for transfer-a review. Placenta 2003; 24:S5–S12.PubMedCrossRefGoogle Scholar
  21. 21.
    Lane M, Gardner DK. Selection of viable mouse blastocysts prior to transfer using a metabolic criterion. Hum Reprod 1996; 11(9):1975–1978.PubMedGoogle Scholar
  22. 22.
    Houghton FD, Hawkhead JA, Humpherson PG et al. Noninvasive amino acid turnover predicts human embryo developmental capacity. Hum Reprod 2002; 17(4):999–1005.PubMedCrossRefGoogle Scholar
  23. 23.
    Zeng F, Baldwin DA, Schultz RM. Transcript profiling during preimplantation mouse development. Dev Biol 2004; 272:483–496.PubMedCrossRefGoogle Scholar
  24. 24.
    Dawson KM, Collins JL, Baltz JM. Osmolarity-dependent glycine accumulation indicates a role for glycine as an organic osmolyte in early preimplantation mouse embryos. Biol Reprod 1998; 59:225–232.PubMedCrossRefGoogle Scholar
  25. 25.
    Baltz JM. Intracellular pH regulation in the early embryo. Bioessays 1993; 15(8):523–539.PubMedCrossRefGoogle Scholar
  26. 26.
    Lane M, Baltz JM, Bavister BD. Na+/H+ antiporter activity in hamster embryos activated during fertilization. Dev Biol 1998; 208:244–252.CrossRefGoogle Scholar
  27. 27.
    Steeves CL, Lane M, Bavister BD et al. Differences in intracelluar pH regulation by Na+/H+ antiporter among two-cell mouse embryos derived from females of different strains. Biol Reprod 2001; 65:14–22.PubMedCrossRefGoogle Scholar
  28. 28.
    Squirrell JM, Lane M, Bavister BD. Altering intracellular pH disrupts development and cellular organization in preimplantion hamster embryos. Biol Reprod 2001; 64:1845–1854.PubMedCrossRefGoogle Scholar
  29. 29.
    Ho Y, Dohert AS, Schultz RM. Mouse preimplantation embryo development in vitro: Effect of sodium concentration in culture media on RNA synthesis and accumulation and gene expression. Mol Reprod Dev 1994; 38:131–141.PubMedCrossRefGoogle Scholar
  30. 30.
    Payne SR, Munday R, Thompson JG. Addition of superoxide dismutase and catalase does not necessarily overcome developmental retardation of one-cell mouse embryos during in-vitro culture. Reprod Fertil Dev 1992; 4:167–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Dumoulin JC, Meijers CJ, Bras M et al. Effect of oxygen concentration on human in vitro fertilization and embryo culture. Hum Reprod 1999; 14:465–469.PubMedCrossRefGoogle Scholar
  32. 32.
    Thompson JG, Simpson AC, Pugh PA et al. Effect of oxygen concentration on in-vitro development of preimplantation sheep and cattle embryos. J Reprod Fertil 1990; 89:573–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Harvey AJ, Kind KL, Thompson JG. REDOX regulation of early embryo development. Reproduction 2002; 123:479–486.PubMedCrossRefGoogle Scholar
  34. 34.
    Bean CJ, Hassold TJ, Judis L et al. Fertilization in vitro increases nondisjunction during early cleavage divisions in a mouse model system. Hum Reprod 2002; 17:2362–2367.PubMedCrossRefGoogle Scholar
  35. 35.
    Karagenc L, Sertkaya Z Ciray N et al. Impact of oxygen concentration on embryonic development of mouse zygotes. Reprod BioMed Online 2004; 9:409–417.PubMedCrossRefGoogle Scholar
  36. 36.
    Fischer B, Bavister BD. Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. J Reprod Fertil 1993; 99:673–679.PubMedCrossRefGoogle Scholar
  37. 37.
    Jauniaux E, Watson AJ, Burton G. Evaluation of respiratory gases and acid-base gradients in human fetal fluids and uteroplacental tissue between 7 and 16 weeks’ gestation. Am J Obstet Gynecol 2001; 184:998–1003.PubMedCrossRefGoogle Scholar
  38. 38.
    Kind KL, Collett RA, Harvey AJ et al. Oxygen-regulated expression of GLUT-1, GLUT-3, and VEGF in the mouse blastocyst. Mol Reprod Dev 2005; 70:37–44.PubMedCrossRefGoogle Scholar
  39. 39.
    Harvey AJ, Kind KL, Pantaleon M et al. Oxygen-regulated gene expression in bovine blastocysts. Biol Reprod 2004; 71:1108–1119.PubMedCrossRefGoogle Scholar
  40. 40.
    Thompson JG, McNaughton C, Gasparrini B et al. Effect of inhibitors and uncouplers of oxidative phosphorylation during compaction and blastulation of bovine embryos cultured in vitro. J Reprod Fertil 2000; 118:47–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Van Winkle IJ. Amino acid transport regulation and early embryo development. Biol Reprod 2001; 64:1–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Lane M, Gardner DK. Differential regulation of mouse embryo development and viability by amino acids. J Reprod Fertil 1997; 109:153–164.PubMedCrossRefGoogle Scholar
  43. 43.
    Lane M, Gardner DK. Amino acids and vitamins prevent cultureinduced metabolic perturbations and associated loss of viability of mouse blastocysts. Hum Reprod 1998; 13:991–997.PubMedCrossRefGoogle Scholar
  44. 44.
    Lane M, Gardner DK. Increase in postimplantation development of cultured mouse embryos by amino acids and induction of fetal retardation and exencephaly by ammonium ions. J Reprod Fertil 1994; 102:305–312.PubMedCrossRefGoogle Scholar
  45. 45.
    Lane M, Gardner DK. Ammonium induces aberrant blastocyst differentiation, metabolism, pH regulation, gene expression and subsequently alters fetal developmentin the mouse. Biol Reprod 2003; 69:1109–1117.PubMedCrossRefGoogle Scholar
  46. 46.
    McEvoy TG, Robinson JJ, Aitken RP et al. Dietary excess of urea influence the viability and metabolism of preimplantation sheep embryos and may affect fetal growth among survivors. Anim Reprod Sci 1997; 47:71–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Sinclair KD, McEvoy TG, Carolan C et al. Conceptus growth and development following in vitro culture of ovine embryos in media supplemented with bovine sera. Theriogenology 1998; 49:218.CrossRefGoogle Scholar
  48. 48.
    Leese HJ. Metabolism of the preimplantation mammalian embryo. Oxford Rev Reprod Biology 1991; 13 (CHAP 2):35–72.Google Scholar
  49. 49.
    Thompson JG. Comparison between in vivo-derived and in vitro-produced preelongation embryos from domestic ruminants. Reprod Fertil Dev 1997; 9:341–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Moley KH. Hyperglycemia and apoptosis: Mechanisms for congenital malformations and pregnancy loss in diabetic women. TRENDS in Endocrinology and Metabolism 2001; 12:78–82.PubMedCrossRefGoogle Scholar
  51. 51.
    Beebe LFS. The effect of maternal diabetes on the preimplantation mouse embryo. Ph.D. Thesis University of Queensland 1993.Google Scholar
  52. 52.
    Hinck L, Thissen JP, De Hertogh R. Identification of caspase-6 in rat blastocysts and its implication in the induction of apoptosis by high glucose. Biol Reprod 2003; 68:1808–1812.PubMedCrossRefGoogle Scholar
  53. 53.
    Keim AL, Chi MM-Y, Moley KH. Hyperglycemia-induced apoptotic cell death in the mouse blastocyst is dependent on experession of p53. Mol Reprod Dev 2001; 60:214–224.PubMedCrossRefGoogle Scholar
  54. 54.
    Scott L, Whittingham DG. Influence of genetic background and media components on the development of mouse embryos in vitro. Mol Reprod Dev 1996; 43:336–346.PubMedCrossRefGoogle Scholar
  55. 55.
    Ferguson EM, Leese HJ. Triglyceride content of bovine oocytes and early embryos. J Reprod Fertil 1999; 116:373–378.PubMedCrossRefGoogle Scholar
  56. 56.
    Thompson JG, Gardner DK, Pugh PA et al. Lamb birth weight is affected by culture system utilized during in vitro pre-elongation development of ovine embryos. Biol Reprod 1995; 53:1385–91.PubMedCrossRefGoogle Scholar
  57. 57.
    Krisher RL, Lane M, Bavister BD. Developmental competence and metabolism of bovine embryos cultured in semi-defiend and defined culture media. Biol Reprod 1999; 60:1345–1352.PubMedCrossRefGoogle Scholar
  58. 58.
    Pollard JW, Leibo SP. Chilling sensitivity of mammalian embryos. Theriogenology 1994; 41:101–106.CrossRefGoogle Scholar
  59. 59.
    Khosla S, Dean W, Reik W et al. Epigenetic and experimental modifications in early mammalian development: Part II Culture of preimplantation embryos and its long-term effects on gene expression and phenotype. Hum Reprod Update 2001; 7:419–427.PubMedCrossRefGoogle Scholar
  60. 60.
    Sinclair KD, McEvoy TG, Maxfield EK et al. Aberrant fetal growth and development after in vitro culture of sheep zygotes. J Reprod Fertil 1999; 116:177–86.PubMedCrossRefGoogle Scholar
  61. 61.
    Wrenzycki C, Herrmann D, Carnwath JW et al. Alterations in the relative abundance of gene transcripts in pre-implantation bovine embryos cultured in medium supplemented with either serum or PVA. Mol Reprod Dev 1999; 53:8–18.PubMedCrossRefGoogle Scholar
  62. 62.
    Pampfer S, Arceci RJ, Pollard JW. Role of colony stimulating factor-1 (CSF-1) and other lympho-hematopoietic growth factors in mouse preimplantation development. Bioessays 1991; 13:535–540.PubMedCrossRefGoogle Scholar
  63. 63.
    Kaye PL, Harvey MB. The role of growth factors in preimplantation development. Prog Growth Factor Res 1995; 6:1–24.PubMedCrossRefGoogle Scholar
  64. 64.
    Kane MT, Morgan PM, Coonan C. Peptide growth factors and preimplantation development. Hum Reprod Update 1997; 3:137–57.PubMedCrossRefGoogle Scholar
  65. 65.
    Diaz-Cueto L, Gerton GL. The influence of growth factors on the development of preimplantation mammalian embryos. Arch Med Res 2001; 32:619–26.PubMedCrossRefGoogle Scholar
  66. 66.
    Hardy K, Spanos S. Growth factor expression and function in the human and mouse preimplantation embryo. J Endocrinol 2002; 172:221–36.PubMedCrossRefGoogle Scholar
  67. 67.
    Robertson SA, Seamark RF, Guilbert LJ et al. The role of cytokines in gestation. Crit Rev Immunol 1994; 14:239–92.PubMedGoogle Scholar
  68. 68.
    Sharkey AM, Dellow K, Blayney M et al. Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biol Reprod 1995; 53:974–981.PubMedCrossRefGoogle Scholar
  69. 69.
    Paria BC, Dey SK. Preimplantation embryo development in vitro: Cooperative interactions among embryos and role of growth factors. Proc Natl Acad Sci USA 1990; 87:4756–4760.PubMedCrossRefGoogle Scholar
  70. 70.
    De Hertogh R, Vanderheyden I, Pampfer S et al. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro. Diabetes 1991; 40:641–7.PubMedGoogle Scholar
  71. 71.
    Zhang X, Armstrong DT. Presence of amino acids and insulin in a chemically defined medium improves development of 8-cell rat embryos in vitro and subsequent implantation in vivo. Biol Reprod 1990; 42:662–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Kaye PL, Gardner HG. Preimplantation access to maternal insulin and albumin increases fetal growth rate in mice. Hum Reprod 1999; 14:3052–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Ryan JP, O’Neill C, Ammit AJ et al. Metabolic and developmental responses of preimplantation embryos to platelet activating factor (PAF). Reprod Fertil Dev 1992; 4:387–98.PubMedCrossRefGoogle Scholar
  74. 74.
    Wuu YD, Pampfer S, Becquet P et al. Tumor necrosis factor alpha decreases the viability of mouse blastocysts in vitro and in vivo. Biol Reprod 1999; 60:479–83.PubMedCrossRefGoogle Scholar
  75. 75.
    Robertson SA, Sjoblom C, Jasper MJ et al Granulocyte-macrophage colony-stimulating factor promotes glucose transport and blastomere viability in murine preimplantation embryos. Biol Reprod 2001; 64:1206–15.PubMedCrossRefGoogle Scholar
  76. 76.
    Sjoblom C, Roberts CT, Wikland M et al. GM-CSF alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis. Endocrinology 2005; 146:2142–53.PubMedCrossRefGoogle Scholar
  77. 77.
    Fleming TP, Ghassemifar MR, Sheth B. Junctional complexes in the early mammalian embryo. Semin Reprod Med 2000; 18:185–93.PubMedCrossRefGoogle Scholar
  78. 78.
    Kwong WY, Wild AE, Roberts P et al Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 2000; 127:4195–202.PubMedGoogle Scholar
  79. 79.
    Tam PP. Postimplantation development of mitomycin C-treated mouse blastocysts. Teratology 1988; 37:205–12.PubMedCrossRefGoogle Scholar
  80. 80.
    Pampfer S. Peri-implantation embryopathy induced by maternal diabetes. J Reprod Fertil Suppl 2000; 55:129–39.PubMedGoogle Scholar
  81. 81.
    Maher ER, Afnan M, Barratt CL. Epigenetic risks related to assisted reproductive technologies: Epigenetics, imprinting, ART and icebergs? Hum Reprod 2003; 18(12):2508–2511.PubMedCrossRefGoogle Scholar
  82. 82.
    Khosla S, Dean W, Brown D et al. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol Reprod 2001; 64:918–26.PubMedCrossRefGoogle Scholar
  83. 83.
    Young LE, Fairburn HR. Improving the safety of embryo technologies: Possible role of genomic imprinting. Theriogenology 2000; 53:627–48.PubMedCrossRefGoogle Scholar
  84. 84.
    Young LE, Fernandes K, McEvoy TG et al. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat Genet 2001; 27:153–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Caspary T, Cleary MA, Baker CC et al. Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol Cell Biol 1998; 18:3466–74.PubMedGoogle Scholar
  86. 86.
    McLaughlin KJ, Szabo P, Haegel H et al. Mouse embryos with paternal duplication of an imprinted chromosome 7 region die at midgestation and lack placental spongiotrophoblast. Development 1996; 122:265–70.PubMedGoogle Scholar
  87. 87.
    Tanaka M, Gertsenstein M, Rossant J et al. Mash2 acts cell autonomously in mouse spongiotrophoblast development. Dev Biol 1997; 190:55–65.PubMedCrossRefGoogle Scholar
  88. 88.
    Viuff D, Richards L, Offenberg H et al. A high proportion of bovine blastocysts produced in vitro are mixoploid. Biol Reprod 1999; 60:1273–1278.PubMedCrossRefGoogle Scholar
  89. 89.
    Yadav BR, King WA, Betteridge KJ. Relationship between the completion of first cleavage and the chromosomal complement, sex, and developmental rates of bovine embryos generated in vitro. Mol Reprod Dev 1993; 36:434–439.PubMedCrossRefGoogle Scholar
  90. 90.
    De Rycke M, Liebaers I, Van Steirteghem A. Epigenetic risks related to assisted reproductive technologies: Risk analysis and epigenetic inheritance. Hum Reprod 2000; 17:2487–94.CrossRefGoogle Scholar
  91. 91.
    Koudstaal J, Braat DD, Bruinse HW et al. Obstetric outcome of singleton pregnancies after IVF: A matched control study in four Dutch university hospitals. Hum Reprod 2000; 15(8):1819–1825.PubMedCrossRefGoogle Scholar
  92. 92.
    Wang JX, Clark AM, Kirby CA et al. The obstetric outcome of singleton pregnancies following in-vitro fertilization/gamete intra-fallopian transfer. Hum Reprod 1994; 9:141–146.PubMedGoogle Scholar
  93. 93.
    Wilmut I, Sales DI. Effect of an asynchronous environment on embryonic development in sheep. J Reprod Fertil 1981; (61):179–184.PubMedCrossRefGoogle Scholar
  94. 94.
    Kleemann DO, Walker SK, Seamark RF. Enhanced fetal growth in sheep administered progesterone during the first three days of pregnancy. J Reprod Fertil 1994; 102:411–417.PubMedCrossRefGoogle Scholar

Copyright information

© and Springer Science+Business Media 2006

Authors and Affiliations

  • Jeremy Thompson
    • 1
  • Michelle Lane
    • 1
  • Sarah Robertson
    • 1
  1. 1.Research Centre for Reproductive Health, Department of Obstetrics and GynaecologyThe University of AdelaideAdelaideAustralia

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