The Preimplantation Embryo: Handle with Care

ABSTRACT

The past decade has seen considerable advances in our understanding of intrinsic developmental mechanisms associated with gametogenesis and embryogenesis and accompanying applications in the fields of reproductive medicine, embryonic stem cell biology, and nuclear reprogramming. However, a new focus has recently emerged concerning the homeostatic regulation of embryonic cells, how this is set, and how it may influence the longitudinal progression and optimization of the developmental program and indeed the phenotype of the offspring. Attention has been drawn to the preimplantation stage of development as a sensitive “window” when in vitro and in vivo manipulations, such as culture conditions or maternal diet, may have critical consequences. In this article, we review how changes in environmental conditions, mediated via a range of epigenetic, cellular, and metabolic mechanisms in the preimplantation embryo, may alter the pattern of cell division, gene expression, morphology, and potential. We consider how fetal and postnatal phenotype may become susceptible to the plasticity of the preimplantation embryo and the risks for adult health and physiology.

KEYWORDS

Epigenetics - gene expression - in vitro culture - maternal diet - preimplantation embryo

REFERENCES

• 1 Fleming T P, Kwong W Y, Porter R et al.. The embryo and its future.  Biol Reprod. 2004;  71 1046-1054
• 2 Sinclair K D, Singh R. Modelling the developmental origins of health and disease in the early embryo.  Theriogenology. 2007;  67 43-53
• 3 Fernandez-Gonzalez R, Ramirez M A, Bilbao A, De Fonseca F R, Gutierrez-Adan A. Suboptimal in vitro culture conditions: an epigenetic origin of long-term health effects.  Mol Reprod Dev. 2007;  74 1149-1156
• 4 Thompson J G, Mitchell M, Kind K L. Embryo culture and long-term consequences.  Reprod Fertil Dev. 2007;  19 43-52
• 5 Kwong W Y, Wild A E, Roberts P, Willis A C, Fleming T P. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension.  Development. 2000;  127 4195-4202
• 6 Kwong W Y, Miller D J, Ursell E et al.. Imprinted gene expression in the rat embryo-fetal axis is altered in response to periconceptional maternal low protein diet.  Reproduction. 2006;  132 265-277
• 7 Kwong W Y, Miller D J, Wilkins A P et al.. Maternal low protein diet restricted to the preimplantation period induces a gender-specific change on hepatic gene expression in rat fetuses.  Mol Reprod Dev. 2007;  74 48-56
• 8 Edwards L J, McMillen I C. Impact of maternal undernutrition during the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo-pituitary adrenal axis in sheep during late gestation.  Biol Reprod. 2002;  66 1562-1569
• 9 Edwards L J, McMillen I C. Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep.  Am J Physiol Regul Integr Comp Physiol. 2002;  283 R669-R679
• 10 Bloomfield F H, Oliver M H, Hawkins P et al.. Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation.  Endocrinology. 2004;  145 4278-4285
• 11 Gardner D S, Pearce S, Dandrea J et al.. Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep.  Hypertension. 2004;  43 1290-1296
• 12 Bowman P, McLaren A. Viability and growth of mouse embryos after in vitro culture and fusion.  J Embryol Exp Morphol. 1970;  23 693-704
• 13 Caro C M, Trounson A. The effect of protein on preimplantation mouse embryo development in vitro.  J In Vitro Fert Embryo Transf. 1984;  1 183-187
• 14 Arny M, Nachtigall L, Quagliarello J. The effect of preimplantation culture conditions on murine embryo implantation and fetal development.  Fertil Steril. 1987;  48 861-865
• 15 Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes.  Biol Reprod. 2001;  64 918-926
• 16 Lucifero D, Chaillet J R, Trasler J M. Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology.  Hum Reprod Update. 2004;  10 3-18
• 17 Reik W, Santos F, Dean W. Mammalian epigenomics: reprogramming the genome for development and therapy.  Theriogenology. 2003;  59 21-32
• 18 Ecker D J, Stein P, Xu Z et al.. Long-term effects of culture of preimplantation mouse embryos on behavior.  Proc Natl Acad Sci USA. 2004;  101 1595-1600
• 19 Fernandez-Gonzalez R, Moreira P, Bilbao A et al.. Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior.  Proc Natl Acad Sci USA. 2004;  101 5880-5885
• 20 Watkins A J, Platt D, Papenbrock T et al.. Mouse embryo culture induces changes in postnatal phenotype including raised systolic blood pressure.  Proc Natl Acad Sci USA. 2007;  104 5449-5454
• 21 Leese H J, Tay J I, Reischl J, Downing S J. Formation of fallopian tubal fluid: role of a neglected epithelium.  Reproduction. 2001;  121 339-346
• 22 Tay J I, Rutherford A J, Killick S R, Maguiness S D, Partridge R J, Leese H J. Human tubal fluid: production, nutrient composition and response to adrenergic agents.  Hum Reprod. 1997;  12 2451-2456
• 23 Hardy K, Spanos S. Growth factor expression and function in the human and mouse preimplantation embryo.  J Endocrinol. 2002;  172 221-236
• 24 Kane M T, Morgan P M, Coonan C. Peptide growth factors and preimplantation development.  Hum Reprod Update. 1997;  3 137-157
• 25 Kaye P L. Preimplantation growth factor physiology.  Rev Reprod. 1997;  2 121-127
• 26 Wales R G, Whittingham D G, Hardy K, Craft I L. Metabolism of glucose by human embryos.  J Reprod Fertil. 1987;  79 289-297
• 27 Conaghan J, Handyside A H, Winston R M, Leese H J. Effects of pyruvate and glucose on the development of human preimplantation embryos in vitro 11.  J Reprod Fertil. 1993;  99 87-95
• 28 Martin K L, Leese H J. Role of developmental factors in the switch from pyruvate to glucose as the major exogenous energy substrate in the preimplantation mouse embryo.  Reprod Fertil Dev. 1999;  11 425-433
• 29 Gardner D K, Lane M, Stevens J, Schoolcraft W B. Noninvasive assessment of human embryo nutrient consumption as a measure of developmental potential 2.  Fertil Steril. 2001;  76 1175-1180
• 30 Lane M, Gardner D K. Differential regulation of mouse embryo development and viability by amino acids.  J Reprod Fertil. 1997;  109 153-164
• 31 Lane M, Gardner D K. Nonessential amino acids and glutamine decrease the time of the first three cleavage divisions and increase compaction of mouse zygotes in vitro.  J Assist Reprod Genet. 1997;  14 398-403
• 32 Devreker F, Winston R M, Hardy K. Glutamine improves human preimplantation development in vitro.  Fertil Steril. 1998;  69 293-299
• 33 Steeves T E, Gardner D K. Temporal and differential effects of amino acids on bovine embryo development in culture.  Biol Reprod. 1999;  61 731-740
• 34 Gardner D K, Lane M, Spitzer A, Batt P A. Enhanced rates of cleavage and development for sheep zygotes cultured to the blastocyst stage in vitro in the absence of serum and somatic cells: amino acids, vitamins, and culturing embryos in groups stimulate development.  Biol Reprod. 1994;  50 390-400
• 35 Casslen B G. Free amino acids in human uterine fluid. Possible role of high taurine concentration.  J Reprod Med. 1987;  32 181-184
• 36 Gardner D K, Lane M, Calderon I, Leeton J. Environment of the preimplantation human embryo in vivo: metabolite analysis of oviduct and uterine fluids and metabolism of cumulus cells.  Fertil Steril. 1996;  65 349-353
• 37 Georgiou A S, Sostaric E, Wong C H et al.. Gametes alter the oviductal secretory proteome.  Mol Cell Proteomics. 2005;  4 1785-1796
• 38 Sostaric E, Georgiou A S, Wong C H, Watson P F, Holt W V, Fazeli A. Global profiling of surface plasma membrane proteome of oviductal epithelial cells.  J Proteome Res. 2006;  5 3029-3037
• 39 Houghton F D, Leese H J. Metabolism and developmental competence of the preimplantation embryo.  Eur J Obstet Gynecol Reprod Biol. 2004;  115(Suppl 1) S92-S96
• 40 Houghton F D, Hawkhead J A, Humpherson P G et al.. Non-invasive amino acid turnover predicts human embryo developmental capacity.  Hum Reprod. 2002;  17 999-1005
• 41 Brison D R, Houghton F D, Falconer D et al.. Identification of viable embryos in IVF by non-invasive measurement of amino acid turnover.  Hum Reprod. 2004;  19 2319-2324
• 42 Hawthorne G, Robson S, Ryall E A, Sen D, Roberts S H, Ward Platt M P. Prospective population based survey of outcome of pregnancy in diabetic women: results of the Northern Diabetic Pregnancy Audit 1994.  BMJ. 1997;  315 279-281
• 43 Moley K H. Hyperglycemia and apoptosis: mechanisms for congenital malformations and pregnancy loss in diabetic women.  Trends Endocrinol Metab. 2001;  12 78-82
• 44 Lea R G, McCracken J E, McIntyre S S, Smith W, Baird J D. Disturbed development of the preimplantation embryo in the insulin- dependent diabetic BB/E rat.  Diabetes. 1996;  45 1463-1470
• 45 Pampfer S. Apoptosis in rodent peri-implantation embryos: differential susceptibility of inner cell mass and trophectoderm cell lineages-a review.  Placenta. 2000;  21(Suppl A) S3-S10
• 46 Chi M M, Pingsterhaus J, Carayannopoulos M, Moley K H. Decreased glucose transporter expression triggers BAX-dependent apoptosis in the murine blastocyst.  J Biol Chem. 2000;  275 40252-40257
• 47 Moley K H, Chi M M, Mueckler M M. Maternal hyperglycemia alters glucose transport and utilization in mouse preimplantation embryos.  Am J Physiol. 1998;  275 E38-E47
• 48 Pinto A B, Carayannopoulos M O, Hoehn A, Dowd L, Moley K H. Glucose transporter 8 expression and translocation are critical for murine blastocyst survival.  Biol Reprod. 2002;  66 1729-1733
• 49 Heilig C W, Saunders T, Brosius F C et al.. Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy.  Proc Natl Acad Sci USA. 2003;  100 15613-15618
• 50 Riley J K, Moley K H. Glucose utilization and the PI3-K pathway: mechanisms for cell survival in preimplantation embryos.  Reproduction. 2006;  131 823-835
• 51 Lu D P, Chandrakanthan V, Cahana A, Ishii S, O'Neill C. Trophic signals acting via phosphatidylinositol-3 kinase are required for normal pre-implantation mouse embryo development.  J Cell Sci. 2004;  117 1567-1576
• 52 Riley J K, Carayannopoulos M O, Wyman A H, Chi M, Moley K H. Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts.  J Biol Chem. 2006;  281 6010-6019
• 53 Liu L, Hammar K, Smith P J, Inoue S, Keefe D L. Mitochondrial modulation of calcium signaling at the initiation of development.  Cell Calcium. 2001;  30 423-433
• 54 Dumollard R, Marangos P, Fitzharris G, Swann K, Duchen M, Carroll J. Sperm-triggered [Ca2 + ] oscillations and Ca2 + homeostasis in the mouse egg have an absolute requirement for mitochondrial ATP production.  Development. 2004;  131 3057-3067
• 55 Takeuchi T, Neri Q V, Katagiri Y, Rosenwaks Z, Palermo G D. Effect of treating induced mitochondrial damage on embryonic development and epigenesis.  Biol Reprod. 2005;  72 584-592
• 56 Dumollard R, Duchen M, Sardet C. Calcium signals and mitochondria at fertilisation.  Semin Cell Dev Biol. 2006;  17 314-323
• 57 Graziewicz M A, Day B J, Copeland W C. The mitochondrial DNA polymerase as a target of oxidative damage.  Nucleic Acids Res. 2002;  30 2817-2824
• 58 Nagai S, Mabuchi T, Hirata S et al.. Correlation of abnormal mitochondrial distribution in mouse oocytes with reduced developmental competence.  Tohoku J Exp Med. 2006;  210 137-144
• 59 Nishi Y, Takeshita T, Sato K, Araki T. Change of the mitochondrial distribution in mouse ooplasm during in vitro maturation.  J Nippon Med Sch. 2003;  70 408-415
• 60 McEvoy T G, Robinson J J, Aitken R P, Findlay P A, Robertson I S. Dietary excesses 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
• 61 McEvoy T G, Robinson J J, Ashworth C J, Rooke J A, Sinclair K D. Feed and forage toxicants affecting embryo survival and fetal development.  Theriogenology. 2001;  55 113-129
• 62 Gardner D S, Jamall E, Fletcher A J, Fowden A L, Giussani D A. Adrenocortical responsiveness is blunted in twin relative to singleton ovine fetuses.  J Physiol. 2004;  557 1021-1032
• 63 Jaquiery A L, Oliver M H, Bloomfield F H, Connor K L, Challis J R, Harding J E. Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional undernutrition in sheep.  J Physiol. 2006;  572 109-118
• 64 Gallaher B W, Breier B H, Harding J E, Gluckman P D. Periconceptual undernutrition resets plasma IGFBP levels and alters the response of IGFBP-1, IGFBP-3 and IGF-1 to subsequent maternal undernutrition in fetal sheep.  Prog Growth Factor Res. 1995;  6 189-195
• 65 Gallaher B W, Breier B H, Keven C L, Harding J E, Gluckman P D. Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep.  J Endocrinol. 1998;  159 501-508
• 66 Armstrong D G, McEvoy T G, Baxter G et al.. Effect of dietary energy and protein on bovine follicular dynamics and embryo production in vitro: associations with the ovarian insulin-like growth factor system.  Biol Reprod. 2001;  64 1624-1632
• 67 Boland M P, Lonergan P, O'Callaghan D. Effect of nutrition on endocrine parameters, ovarian physiology, and oocyte and embryo development.  Theriogenology. 2001;  55 1323-1340
• 68 Mackey D R, Sreenan J M, Roche J F, Diskin M G. Effect of acute nutritional restriction on incidence of anovulation and periovulatory estradiol and gonadotropin concentrations in beef heifers.  Biol Reprod. 1999;  61 1601-1607
• 69 Bossis I, Wettemann R P, Welty S D, Vizcarra J, Spicer L J. Nutritionally induced anovulation in beef Heifers: ovarian and endocrine function during realimentation and resumption of ovulation.  Biol Reprod. 2000;  62 1436-1444
• 70 O'Callaghan D, Yaakub H, Hyttel P, Spicer L J, Boland M P. Effect of nutrition and superovulation on oocyte morphology, follicular fluid composition and systemic hormone concentrations in ewes.  J Reprod Fertil. 2000;  118 303-313
• 71 Sinclair K D, Kuran M, Gebbie F E, Webb R, McEvoy T G. Nitrogen metabolism and fertility in cattle: II. Development of oocytes recovered from heifers offered diets differing in their rate of nitrogen release in the rumen.  J Anim Sci. 2000;  78 2670-2680
• 72 Kenny D A, Humpherson P G, Leese H J et al.. Effect of elevated systemic concentrations of ammonia and urea on the metabolite and ionic composition of oviductal fluid in cattle.  Biol Reprod. 2002;  66 1797-1804
• 73 Powell K, Rooke J A, McEvoy T G et al.. Zygote donor nitrogen metabolism and in vitro embryo culture perturbs in utero development and IGF2R expression in ovine fetal tissues.  Theriogenology. 2006;  66 1901-1912
• 74 Lane M, Gardner D K. Ammonium induces aberrant blastocyst differentiation, metabolism, pH regulation, gene expression and subsequently alters fetal development in the mouse.  Biol Reprod. 2003;  69 1109-1117
• 75 Harlow G M, Quinn P. Development of preimplantation mouse embryos in vivo and in vitro.  Aust J Biol Sci. 1982;  35 187-193
• 76 Thompson J G, Gardner D K, Pugh P A, McMillan W H, Tervit H R. Lamb birth weight is affected by culture system utilized during in vitro pre-elongation development of ovine embryos.  Biol Reprod. 1995;  53 1385-1391
• 77 Sinclair K D, McEvoy T G, Maxfield E K et al.. Aberrant fetal growth and development after in vitro culture of sheep zygotes.  J Reprod Fertil. 1999;  116 177-186
• 78 Holm P, Walker S K, Seamark R F. Embryo viability, duration of gestation and birth weight in sheep after transfer of in vitro matured and in vitro fertilized zygotes cultured in vitro or in vivo.  J Reprod Fertil. 1996;  107 175-181
• 79 Young L E, Sinclair K D, Wilmut I. Large offspring syndrome in cattle and sheep.  Rev Reprod. 1998;  3 155-163
• 80 Wells D N, Misica P M, Tervit H R. Production of cloned calves following nuclear transfer with cultured adult mural granulosa cells.  Biol Reprod. 1999;  60 996-1005
• 81 Farin P W, Farin C E. Transfer of bovine embryos produced in vivo or in vitro: survival and fetal development.  Biol Reprod. 1995;  52 676-682
• 82 Shamsuddin M, Rodriguez-Martinez H. Fine structure of bovine blastocysts developed either in serum-free medium or in conventional co-culture with oviduct epithelial cells.  Zentralbl Veterinarmed A. 1994;  41 307-316
• 83 Rizos D, Fair T, Papadopoulos S, Boland M P, Lonergan P. Developmental, qualitative, and ultrastructural differences between ovine and bovine embryos produced in vivo or in vitro.  Mol Reprod Dev. 2002;  62 320-327
• 84 Gardner D K. Changes in requirements and utilization of nutrients during mammalian preimplantation embryo development and their significance in embryo culture.  Theriogenology. 1998;  49 83-102
• 85 Lane M, Gardner D K, Hasler M J, Hasler J F. Use of G1.2/G2.2 media for commercial bovine embryo culture: equivalent development and pregnancy rates compared to co-culture.  Theriogenology. 2003;  60 407-419
• 86 Rooke J A, McEvoy T G, Ashworth C J et al.. Ovine fetal development is more sensitive to perturbation by the presence of serum in embryo culture before rather than after compaction.  Theriogenology. 2007;  67 639-647
• 87 Sommovilla J, Bilker W B, Abel T, Schultz R M. Embryo culture does not affect the longevity of offspring in mice.  Reproduction. 2005;  130 599-601
• 88 Rinaudo P, Schultz R M. Effects of embryo culture on global pattern of gene expression in preimplantation mouse embryos.  Reproduction. 2004;  128 301-311
• 89 Rizos D, Lonergan P, Boland M P et al.. Analysis of differential messenger RNA expression between bovine blastocysts produced in different culture systems: implications for blastocyst quality.  Biol Reprod. 2002;  66 589-595
• 90 Rizos D, Gutierrez-Adan A, Perez-Garnelo S, De La F J, Boland M P, Lonergan P. Bovine embryo culture in the presence or absence of serum: implications for blastocyst development, cryotolerance, and messenger RNA expression.  Biol Reprod. 2003;  68 236-243
• 91 Lazzari G, Wrenzycki C, Herrmann D et al.. Cellular and molecular deviations in bovine in vitro-produced embryos are related to the large offspring syndrome.  Biol Reprod. 2002;  67 767-775
• 92 Harvey A J, Kind K L, Pantaleon M, Armstrong D T, Thompson J G. Oxygen-regulated gene expression in bovine blastocysts.  Biol Reprod. 2004;  71 1108-1119
• 93 Kind K L, Collett R A, Harvey A J, Thompson J G. Oxygen-regulated expression of GLUT-1, GLUT-3, and VEGF in the mouse blastocyst.  Mol Reprod Dev. 2005;  70 37-44
• 94 Lighten A D, Moore G E, Winston R M, Hardy K. Routine addition of human insulin-like growth factor-I ligand could benefit clinical in-vitro fertilization culture.  Hum Reprod. 1998;  13 3144-3150
• 95 Mihalik J, Rehak P, Koppel J. The influence of insulin on the in vitro development of mouse and bovine embryos.  Physiol Res. 2000;  49 347-354
• 96 Spanos S, Becker D L, Winston R M, Hardy K. Anti-apoptotic action of insulin-like growth factor-I during human preimplantation embryo development.  Biol Reprod. 2000;  63 1413-1420
• 97 Byrne A T, Southgate J, Brison D R, Leese H J. Regulation of apoptosis in the bovine blastocyst by insulin and the insulin-like growth factor (IGF) superfamily.  Mol Reprod Dev. 2002;  62 489-495
• 98 Makarevich A V, Markkula M. Apoptosis and cell proliferation potential of bovine embryos stimulated with insulin-like growth factor I during in vitro maturation and culture.  Biol Reprod. 2002;  66 386-392
• 99 Augustin R, Pocar P, Wrenzycki C, Niemann H, Fischer B. Mitogenic and anti-apoptotic activity of insulin on bovine embryos produced in vitro.  Reproduction. 2003;  126 91-99
• 100 Harvey M B, Kaye P L. Insulin increases the cell number of the inner cell mass and stimulates morphological development of mouse blastocysts in vitro.  Development. 1990;  110 963-967
• 101 Harvey M B, Kaye P L. Mediation of the actions of insulin and insulin-like growth factor-1 on preimplantation mouse embryos in vitro.  Mol Reprod Dev. 1992;  33 270-275
• 102 Palma G A, Muller M, Brem G. Effect of insulin-like growth factor I (IGF-I) at high concentrations on blastocyst development of bovine embryos produced in vitro.  J Reprod Fertil. 1997;  110 347-353
• 103 Dunglison G F, Kaye P L. Insulin regulates protein metabolism in mouse blastocysts.  Mol Reprod Dev. 1993;  36 42-48
• 104 Dunglison G F, Jane S D, McCaul T F, Chad J E, Fleming T P, Kaye P L. Stimulation of endocytosis in mouse blastocysts by insulin: a quantitative morphological analysis.  J Reprod Fertil. 1995;  105 115-123
• 105 Kaye P L, Gardner H G. Preimplantation access to maternal insulin and albumin increases fetal growth rate in mice.  Hum Reprod. 1999;  14 3052-3059
• 106 Sjoblom C, Roberts C T, Wikland M, Robertson S A. Granulocyte-macrophage colony-stimulating factor alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis.  Endocrinology. 2005;  146 2142-2153
• 107 Kawamura K, Sato N, Fukuda J et al.. The role of leptin during the development of mouse preimplantation embryos.  Mol Cell Endocrinol. 2003;  202 185-189
• 108 Kawamura K, Sato N, Fukuda J et al.. Ghrelin inhibits the development of mouse preimplantation embryos in vitro.  Endocrinology. 2003;  144 2623-2633
• 109 Hardy K, Wright C, Rice S et al.. Future developments in assisted reproduction in humans.  Reproduction. 2002;  123 171-183
• 110 Ludwig A K, Sutcliffe A G, Diedrich K, Ludwig M. Post-neonatal health and development of children born after assisted reproduction: a systematic review of controlled studies.  Eur J Obstet Gynecol Reprod Biol. 2006;  127 3-25
• 111 Schieve L A, Meikle S F, Ferre C, Peterson H B, Jeng G, Wilcox L S. Low and very low birth weight in infants conceived with use of assisted reproductive technology.  N Engl J Med. 2002;  346 731-737
• 112 McMillen I C, Robinson J S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.  Physiol Rev. 2005;  85 571-633
• 113 Watkins A, Wilkins A, Osmond C et al.. The influence of mouse Ped gene expression on postnatal development.  J Physiol. 2006;  571 211-220
• 114 Wolffe A P, Matzke M A. Epigenetics: regulation through repression.  Science. 1999;  286 481-486
• 115 Kouzarides T. Chromatin modifications and their function.  Cell. 2007;  128 693-705
• 116 Morgan H D, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals.  Hum Mol Genet. 2005;  14 R47-R58
• 117 Adenot P G, Mercier Y, Renard J P, Thompson E M. Differential H4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos.  Development. 1997;  124 4615-4625
• 118 Santos F, Hendrich B, Reik W, Dean W. Dynamic reprogramming of DNA methylation in the early mouse embryo.  Dev Biol. 2002;  241 172-182
• 119 Olek A, Walter J. The pre-implantation ontogeny of the H19 methylation imprint.  Nat Genet. 1997;  17 275-276
• 120 Lane N, Dean W, Erhardt S et al.. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse.  Genesis. 2003;  35 88-93
• 121 Rougier N, Bourc'his D, Gomes D M et al.. Chromosome methylation patterns during mammalian preimplantation development.  Genes Dev. 1998;  12 2108-2113
• 122 Watanabe D, Suetake I, Tada T, Tajima S. Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis.  Mech Dev. 2002;  118 187-190
• 123 Ralston A, Rossant J. Genetic regulation of stem cell origins in the mouse embryo.  Clin Genet. 2005;  68 286
• 124 Torres-Padilla M E, Parfitt D E, Kouzarides T, Zernicka-Goetz M. Histone arginine methylation regulates pluripotency in the early mouse embryo.  Nature. 2007;  445 214-218
• 125 Sinclair K D, Young L E, Wilmut I, McEvoy T G. In-utero overgrowth in ruminants following embryo culture: lessons from mice and a warning to men.  Hum Reprod. 2000;  15 68-86
• 126 Young L E, Fernandes K, McEvoy T G et al.. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture.  Nat Genet. 2001;  27 153-154
• 127 Wang Z Q, Fung M R, Barlow D P, Wagner E F. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene.  Nature. 1994;  372 464-467
• 128 Lau M MH, Stewart C EH, Liu Z Y, Bhatt H, Rotwein P, Stewart C L. Loss of the imprinted Igf2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality.  Genes Dev. 1994;  8 2953-2963
• 129 Li E, Bestor T H, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.  Cell. 1992;  69 915-926
• 130 Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes.  Biol Reprod. 2001;  64 918-926
• 131 Doherty A S, Mann M RW, Tremblay K D, Bartolomei M S, Schultz R M. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo.  Biol Reprod. 2000;  62 1526-1535
• 132 Mann M RW, Lee S S, Doherty A S et al.. Selective loss of imprinting in the placenta following preimplantation development in culture.  Development. 2004;  131 3727-3735
• 133 Li T, Vu T H, Ulaner G A et al.. IVF results in de novo DNA methylation and histone methylation at an Igf2-H19 imprinting epigenetic switch.  Mol Hum Reprod. 2005;  11 631-640
• 134 Zander D L, Thompson J G, Lane M. Perturbations in mouse embryo development and viability caused by ammonium are more severe after exposure at the cleavage stages.  Biol Reprod. 2006;  74 288-294
• 135 Horsthemke B, Ludwig M. Assisted reproduction: the epigenetic perspective.  Hum Reprod Update. 2005;  11 473-482
• 136 Cox G F, Burger J, Lip V et al.. Intracytoplasmic sperm injection may increase the risk of imprinting defects.  Am J Hum Genet. 2002;  71 162-164
• 137 Orstavik K H, Eiklid K, van der Hagen C B et al.. Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic sperm injection.  Am J Hum Genet. 2003;  72 218-219
• 138 Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology.  Lancet. 2003;  361 1975-1977
• 139 DeBaun M R, Niemitz E L, Feinberg A P. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19.  Am J Hum Genet. 2003;  72 156-160
• 140 Gicquel C, Gaston V, Mandelbaum J, Siffroi J P, Flahault A, Le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCNQ1OT gene.  Am J Hum Genet. 2003;  72 1338-1341
• 141 Maher E R, Afnan M, Barratt C L. Epigenetic risks related to assisted reproductive technologies: Epigenetics, imprinting, ART and icebergs?.  Hum Reprod. 2003;  18 2508-2511
• 142 Halliday J, Oke K, Breheny S, Algar E, Amor D J. Beckwith-Wiedemann syndrome and IVF: a case-control study.  Am J Hum Genet. 2004;  75 526-528
• 143 Lillycrop K A, Phillips E S, Jackson A A, Hanson M A, Burdge G C. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring.  J Nutr. 2005;  135 1382-1386
• 144 Lillycrop K A, Slater-Jefferies J L, Hanson M A, Godfrey K M, Jackson A A, Burdge G C. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications.  Br J Nutr. 2007;  97 1064-1073
• 145 Watkins A J, Ursell E, Panton R et al.. Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease.  Bio Reprod. 2008;  78 299-306