Semin Reprod Med 2009; 27(5): 409-416
DOI: 10.1055/s-0029-1237429
© Thieme Medical Publishers

Assisted Reproductive Technology, Epigenetics, and Long-Term Health: A Developmental Time Bomb Still Ticking

Kristen S. Grace1 , Kevin D. Sinclair2
  • 1Laboratory of Cellular and Developmental Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  • 2Center for Reproduction and Early Life, School of Biosciences, University of Nottingham, Sutton Bonington, Leicestershire, United Kingdom
Further Information

Publication History

Publication Date:
26 August 2009 (online)

ABSTRACT

Live birthrates following assisted reproduction account for 1 to 3% of pregnancies in developed countries, and these figures seem set to rise. Concerns regarding the safe use of assisted reproductive technology (ART) for the treatment of infertility have been voiced for several years, yet, to date, the vast majority of children conceived using these techniques are apparently normal. Controversy surrounding reports of epigenetic alterations to genomic imprinting following human ART in recent years has fueled the ongoing debate. In contrast, both the incidence and severity of such anomalies are more apparent following ART in comparative animal species. The reasons for this are not known. By and large, the confounding effects of infertility and advanced maternal age do not apply to animal studies, which report better pregnancy rates following embryo transfer. Perhaps the incidence of imprinting disorders is increased when procedures such as ovarian stimulation, in vitro maturation, or both are used in conjunction with extended periods of embryo culture; this frequently occurs in animal but rarely in human ART. The focus of attention on imprinting, however, may have served to distract the scientific community from more subtle epigenetic modifications to nonimprinted loci in gametes and the preimplantation embryo, with health-related consequences that do not manifest until adulthood. Accumulating evidence from animal studies indicates that such effects, not yet apparent in human subjects, exist; and this may ultimately transpire to be the true developmental legacy of human ART. This article discusses these issues in the context of epigenetic and developmental abnormalities following ART in animals.

REFERENCES

  • 1 Lawrence L T, Moley K H. Epigenetics and assisted reproductive technologies: human imprinting syndromes.  Semin Reprod Med. 2008;  26 143-152
  • 2 Amor D J, Halliday J. A review of known imprinting syndromes and their association with assisted reproduction technologies.  Hum Reprod. 2008;  23(12) 2826-2834
  • 3 Manipalviratn S, DeCherney A, Segars J. Imprinting disorders and assisted reproductive technology.  Fertil Steril. 2009;  91(2) 305-315
  • 4 Young L E, Sinclair K D, Wilmut I. Large offspring syndrome in cattle and sheep.  Rev Reprod. 1998;  3 155-163
  • 5 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(suppl 5) 68-86
  • 6 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
  • 7 Sinclair K D, Broadbent P J, Dolman D F. In vitro produced embryos as a means of achieving pregnancy and improving productivity in beef cows.  Anim Sci. 1995;  60 55-64
  • 8 Walker S K, Hartwich K M, Seamark R F. The production of unusually large offspring following embryo manipulation: concepts and challenges.  Theriogenology. 1996;  45 111-120
  • 9 Kruip Th A M, den Daas J HG. In vitro produced and cloned embryos: effects on pregnancy, parturition and offspring.  Theriogenology. 1997;  47 43-52
  • 10 Peterson A J, McMillan W H. Allantoic aplasia—a consequence of in vitro production of bovine embryos and the main cause of late gestation embryo loss. In: Proceedings of the 29th Annual Conference of the Australian Society for Reproductive Biology 1998 abstract 4 Perth, Australia;
  • 11 van Wagtendonk-de Leeuw A M, Aerts B J, den Daas J H. Abnormal offspring following in vitro production of bovine preimplantation embryos: a field study.  Theriogenology. 1998;  49(5) 883-894
  • 12 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
  • 13 Moise K J. Polyhydramnios.  Clin Obstet Gynecol. 1997;  40 266-279
  • 14 McCowan L M, Becroft D M. Beckwith-Wiedemann syndrome, placental abnormalities, and gestational proteinuric hypertension.  Obstet Gynecol. 1994;  83(5 Pt 2) 813-817
  • 15 Farin H M, Abbasi F, Reaven G M. Comparison of body mass index versus waist circumference with the metabolic changes that increase the risk of cardiovascular disease in insulin-resistant individuals.  Am J Cardiol. 2006;  98(8) 1553-1556
  • 16 Barker D J. Fetal origins of coronary heart disease.  BMJ. 1995;  311(6998) 171-174
  • 17 McMillen I C, Robinson J S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.  Physiol Rev. 2005;  85 571-633
  • 18 Langley-Evans S C. Developmental programming of health and disease.  Proc Nutr Soc. 2006;  65(1) 97-105
  • 19 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.  Biol Reprod. 2008;  78(2) 299-306
  • 20 Caperton L, Murphey P, Yamazaki Y et al.. Assisted reproductive technologies do not alter mutation frequency or spectrum.  Proc Natl Acad Sci U S A. 2007;  104(12) 5085-5090
  • 21 Wilmut I, Sales D I. Effect of an asynchronous environment on embryonic development in sheep.  J Reprod Fertil. 1981;  61 179-184
  • 22 Sinclair K D, Dunne L D, Maxfield E K et al.. Fetal growth and development following temporary exposure of day 3 ovine embryos to an advanced uterine environment.  Reprod Fertil Dev. 1998;  10 263-269
  • 23 Maxfield E K, Sinclair K D, Dunne L D et al.. Temporary exposure of ovine embryos to an advanced uterine environment does not affect fetal weight but alters fetal muscle development.  Biol Reprod. 1998;  59 321-325
  • 24 Maltin C A, Delday M I, Sinclair K D, Steven J, Sneddon A A. Impact of manipulations of myogenesis in utero on the performance of adult skeletal muscle.  Reproduction. 2001;  22(3) 359-374
  • 25 Rupp R A, Singhal N, Veenstra G J. When the embryonic genome flexes its muscles.  Eur J Biochem. 2002;  269(9) 2294-2299
  • 26 Crosier A E, Farin C E, Rodriguez K F, Blondin P, Alexander J E, Farin P W. Development of skeletal muscle and expression of candidate genes in bovine fetuses from embryos produced in vivo or in vitro.  Biol Reprod. 2002;  67(2) 401-408
  • 27 Robertson S A. Seminal fluid signaling in the female reproductive tract: lessons from rodents and pigs.  J Anim Sci. 2007;  85(13, Suppl) E36-E44
  • 28 Roberts C T, White C A, Wiemer N G, Ramsay A, Robertson S A. Altered placental development in interleukin-10 null mutant mice.  Placenta. 2003;  24(Suppl A) S94-S99
  • 29 Robinson W P, McFadden D E, Stephenson M D. The origin of abnormalities in recurrent aneuploidy/polyploidy.  Am J Hum Genet. 2001;  69(6) 1245-1254
  • 30 de Moraes A A, Hannsen P J. Granulocyte-macrophage colony-stimulating factor promotes development of in vitro produced bovine embryos.  Biol Reprod. 1997;  57(5) 1060-1065
  • 31 Sjöblom C, Wikland M, Robertson S A. Granulocyte-macrophage colony-stimulating factor promotes human blastocyst development in vitro.  Hum Reprod. 1999;  14(12) 3069-3076
  • 32 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
  • 33 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(2) 175-181
  • 34 McEvoy T G, Sinclair K D, Broadbent P J, Goodhand K L, Robinson J J. Post-natal growth and development of Simmental calves derived from in vivo or in vitro embryos.  Reprod Fertil Dev. 1998;  10 459-464
  • 35 Ecker D J, Stein P, Xu Z et al.. Long-term effects of culture of preimplantation mouse embryos on behavior.  Proc Natl Acad Sci U S A. 2004;  101(6) 1595-1600
  • 36 Sommovilla J, Bilker W B, Abel T, Schultz R M. Embryo culture does not affect the longevity of offspring in mice.  Reproduction. 2005;  130(5) 599-601
  • 37 Fernández-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 U S A. 2004;  101(16) 5880-5885
  • 38 Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development.  Nature. 2007;  447(7143) 425-432
  • 39 Ooi S L, Henikoff S. Germline histone dynamics and epigenetics.  Curr Opin Cell Biol. 2007;  19(3) 257-265
  • 40 Lees-Murdock D J, Walsh C P. DNA methylation reprogramming in the germ line.  Epigenetics. 2008;  3(1) 5-13
  • 41 Lucifero D, Mann M R, Bartolomei M S, Trasler J M. Gene-specific timing and epigenetic memory in oocyte imprinting.  Hum Mol Genet. 2004;  13 839-849
  • 42 Russo V, Martelli A, Berardinelli P et al.. Modifications in chromatin morphology and organization during sheep oogenesis.  Microsc Res Tech. 2007;  70 733-744
  • 43 Kageyama S, Liu H, Kaneko N, Ooga M, Nagata M, Aoki F. Alterations in epigenetic modifications during oocyte growth in mice.  Reproduction. 2007;  133(1) 85-94
  • 44 Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Demethylation of the zygotic paternal genome.  Nature. 2000;  403(6769) 501-502
  • 45 Beaujean N, Hartshorne G, Cavilla J et al.. Non-conservation of mammalian preimplantation methylation dynamics.  Curr Biol. 2004;  14(7) R266-R267
  • 46 Beaujean N, Taylor J, Gardner J, Wilmut I, Meehan R, Young L. Effect of limited DNA methylation reprogramming in the normal sheep embryo on somatic cell nuclear transfer.  Biol Reprod. 2004;  71(1) 185-193
  • 47 Young L E, Beaujean N. DNA methylation in the preimplantation embryo: the differing stories of the mouse and sheep.  Anim Reprod Sci. 2004;  82–83 61-78
  • 48 Sinclair K D. Assisted reproductive technologies and pregnancy outcomes: mechanistic insights from animal studies.  Semin Reprod Med. 2008;  26 153-161
  • 49 Pan H, Ma P, Zhu W, Schultz R M. Age-associated increase in aneuploidy and changes in gene expression in mouse eggs.  Dev Biol. 2008;  316(2) 397-407
  • 50 Akiyama T, Nagata M, Aoki F. Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice.  Proc Natl Acad Sci U S A. 2006;  103(19) 7339-7344
  • 51 Hamatani T, Falco G, Carter M G et al.. Age-associated alteration of gene expression patterns in mouse oocytes.  Hum Mol Genet. 2004;  13(19) 2263-2278
  • 52 Bellver J, Ayllón Y, Ferrando M et al.. Female obesity impairs in vitro fertilization outcome without affecting embryo quality.  Available at: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T6K-4VG35RF-B&_user=5755111&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000000150&_version=1&_urlVersion=0&_userid=5755111&md5=bc2d5fc2c7fcaede69f3cba74e826ba9 Accessed January 24, 2009; 
  • 53 Thatcher S S, Jackson E M. Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin.  Fertil Steril. 2006;  85(4) 1002-1009
  • 54 Minge C E, Bennett B D, Norman R J, Robker R L. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality.  Endocrinology. 2008;  149 2646-2656
  • 55 Shao W J, Tao L Y, Gao C, Xie J Y, Zhao R Q. Alterations in methylation and expression levels of imprinted genes H19 and Igf2 in the fetuses of diabetic mice.  Comp Med. 2008;  58(4) 341-346
  • 56 Watkins A J, Wilkins A, Cunningham C et al.. Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring.  J Physiol. 2008;  586(8) 2231-2244
  • 57 Sinclair K D, Allegrucci C, Singh R et al.. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status.  Proc Natl Acad Sci U S A. 2007;  104 19351-19356
  • 58 Haggarty P, McCallum H, McBain H et al.. Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study.  Lancet. 2006;  367 1513-1519
  • 59 Steele W, Allegrucci C, Singh R et al.. Human embryonic stem cell methyl cycle enzyme expression: modelling epigenetic programming in assisted reproduction?.  Reprod Biomed Online. 2005;  10 755-766
  • 60 Van der Auwera I, Pijnenborg R, Koninckx P R. The influence of in-vitro culture versus stimulated and untreated oviductal environment on mouse embryo development and implantation.  Hum Reprod. 1999;  14 2570-2574
  • 61 Van der Auwera I, D'Hooghe T. Superovulation of female mice delays embryonic and fetal development.  Hum Reprod. 2001;  16 1237-1243
  • 62 Ertzeid G, Storeng R. The impact of ovarian stimulation on implantation and fetal development in mice.  Hum Reprod. 2001;  16 221-225
  • 63 Sato A, Otsu E, Negishi H, Utsunnomiya T, Arima T. Aberrant DNA methylation of imprinted loci in superovulated oocytes.  Hum Reprod. 2007;  22 26-35
  • 64 Shi W, Haaf T. Aberrant methylation patterns at the two cell stage as an indicator of early developmental failure.  Mol Reprod Dev. 2002;  63 329-334
  • 65 Fortier A L, Lopes F L, Darricarrere N, Martel J, Trasler J M. Superovulation alters the expression of imprinted genes in the midgestation mouse placenta.  Hum Mol Genet. 2008;  17 1653-1665
  • 66 Quinn and Horstman FC . Is the mouse a good model for the human with respect to the development of the preimplantation embryo in vitro?.  Hum Reprod. 1998;  13(suppl 4) 173-183
  • 67 Khosla S, Dean W, Reik W, Feil R. Culture of preimplantation embryos and its long-term effects on gene expression and phenotype.  Hum Reprod Update. 2001;  7(4) 419-427
  • 68 Fernández-Gonzalez R, Ramirez M A, Bilbao A, De Fonseca F R, Gutiérrez-Adán A. Suboptimal in vitro culture conditions: an epigenetic origin of long-term health effects.  Mol Reprod Dev. 2007;  74(9) 1149-1156
  • 69 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(3) 639-647
  • 70 Suzuki Jr J, Therrien J, Filion F, Lefebvre R, Goff A K, Smith L C. In vitro culture and somatic cell nuclear transfer affect imprinting of SNRPN gene in pre- and post-implantation stages of development in cattle.  BMC Dev Biol. 2009;  9 9
  • 71 Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology.  Lancet. 2003;  361(9373) 1975-1977
  • 72 Mann M R, Lee S S, Doherty A S et al.. Selective loss of imprinting in the placenta following preimplantation development in culture.  Development. 2004;  131(15) 3727-3735
  • 73 Fauque P, Jouannet P, Lesaffre C et al.. Assisted reproductive technology affects developmental kinetics, H19 imprinting control region methylation and H19 gene expression in individual mouse embryos.  BMC Dev Biol. 2007;  7 116
  • 74 Liang X W, Zhu J Q, Miao Y L et al.. Loss of methylation imprint of Snrpn in postovulatory aging mouse oocyte.  Biochem Biophys Res Commun. 2008;  371(1) 16-21
  • 75 Sutcliffe A G, Peters C J, Bowdin S et al.. Assisted reproductive therapies and imprinting disorders—a preliminary British survey.  Hum Reprod. 2006;  21(4) 1009-1011
  • 76 Ceelen M, van Weissenbruch M M, Vermeiden J P, van Leeuwen F E, Delemarre-van de Waal H A. Cardiometabolic differences in children born after in vitro fertilization: follow-up study.  J Clin Endocrinol Metab. 2008;  93(5) 1682-1688
  • 77 Hvidtjørn D, Schieve L, Schendel D, Jacobsson B, Sværke C, Thorsen P. Cerebral palsy, autism spectrum disorders, and developmental delay in children born after assisted conception: a systematic review and meta-analysis.  Arch Pediatr Adolesc Med. 2009;  163(1) 72-83

Kevin D SinclairPh.D. 

School of Biosciences, University of Nottingham, Sutton Bonington Campus

Leicestershire LE12 5RD, United Kingdom

Email: kevin.Sinclair@nottingham.ac.uk