Influence of Exogenous Factors on Genomic Imprinting 3. The Impact of Assisted Reproductive Technologies

A.E. Abaturov


The analytical review demonstrated the impact of assisted reproductive technologies on genomic imprinting of a child. It is shown that assisted reproductive technologies have a risk of intrauterine growth retardation and imprinting-associated Beckwith-Wiedemann, Angelman, Silver-Russell syndromes.


assisted reproductive technologies; genomic imprinting; children


Aiken C.E., Ozanne S.E. Transgenerational developmental programming // Hum. Reprod. Update. 2014 Jan-Feb; 20 (1): 63-75. doi: 10.1093/humupd/dmt043.

Angiolini E. Regulation of placental efficiency for nutrient transport by imprinted genes / E. Angiolini, A. Fowden, P. Coan et al. // Placenta. 2006 Apr; 27 Suppl A: S98-102. doi: 10.1016/j.placenta.2005.12.008.

Bliek J. Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but isolated asymmetry or an SRS-like phenotype / Bliek J., Terhal P., van den Bogaard M.J. et al. // Am. J. Hum. Genet. 2006 Apr; 78 (4): 604-14. doi: 10.1111/aogs.12799.

Bloise E. Impaired placental nutrient transport in mice generated by in vitro fertilization / E. Bloise, W. Lin, X. Liu et al. // Endocrinology. 2012 Jul; 153 (7): 3457-67. doi: 10.1210/en.2011-1921.

Boxmeer J.C. IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid / J.C. Boxmeer, N.S. Macklon, J. Lindemans et al. // Hum. Reprod. 2009 May; 24 (5): 1059-66. doi: 10.1093/humrep/dep009.

Carvalho J.O. The methylation patterns of the IGF2 and IGF2R genes in bovine spermatozoa are not affected by flow-cytometric sex sor­ting / J.O. Carvalho, V.A. Michalczechen-Lacerda, R. Sartori et al. // Mol. Reprod. Dev. 2012 Feb; 79 (2): 77-84. doi: 10.1002/mrd.21410.

Chen S. Assisted reproduction causes placental maldevelopment and dysfunction linked to reduced fetal weight in mice / S. Chen, F.Z. Sun, X. Huang et al. // Sci Rep. 2015 Jun 18; 5: 10596. doi: 10.1038/srep10596.

Chopra M. Russell-Silver syndrome due to paternal H19/IGF2 hypomethylation in a patient conceived using intracytoplasmic sperm injection / M. Chopra, D.J. Amor, L. Sutton, E. Algar, D. Mowat // Reprod. Biomed. Online. 2010 Jun; 20 (6): 843-7. doi: 10.1016/j.rbmo.2010.02.025.

Choux C. The placenta: phenotypic and epigenetic modifications induced by Assisted Reproductive Technologies throughout pregnancy / C. Choux, V. Carmignac, C. Bruno et al. // Clin. Epigenetics. 2015 Aug 21; 7 (1): 87. doi: 10.1186/s13148-015-0120-2.

Cocchi G. Silver-Russell syndrome due to paternal H19/IGF2 hypomethylation in a twin girl born after in vitro fertilization / G. Cocchi, C. Marsico, A. Cosentino et al. // Am. J. Med. Genet. A. 2013 Oct; 161A (10): 2652-5. doi: 10.1002/ajmg.a.36145.

Cox G.F. Intracytoplasmic sperm injection may increase the risk of imprinting defects / G.F. Cox, J. Bürger, V. Lip et al. // Am. J. Hum. Genet. 2002 Jul; 71 (1): 162-4. doi: 10.1086/341096.

de Waal E. In vitro culture increases the frequency of stochastic epigenetic errors at imprinted genes in placental tissues from mouse concepti produced through assisted reproductive technologies / E. de Waal, W. Mak, S. Calhoun et al. // Biol. Reprod. 2014 Feb 6; 90 (2): 22. doi: 10.1095/biolreprod.113.114785.

DeBaun M.R., Niemitz E.L., Feinberg A.P. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic al.terations of LIT1 and H19 // Am. J. Hum. Genet. 2003 Jan; 72 (1): 156-60. doi: 10.1086/346031.

Denomme M.M., Mann M.R. Genomic imprints as a model for the analysis of epigenetic stability during assisted reproductive technologies // Reproduction. 2012 Oct; 144 (4): 393-409. doi: 10.1530/REP‑12-0237.

Desai M., Jellyman J.K., Ross M.G. Epigenomics, gestational programming and risk of metabolic syndrome // Int. J. Obes. (Lond). 2015 Apr; 39 (4): 633-41. doi: 10.1038/ijo.2015.13.

Diederich M. DNA methylation and mRNA expression profiles in bovine oocytes derived from prepubertal and adult donors / M. Diederich, T. Hansmann, J. Heinzmann et al. // Reproduction. 2012 Sep; 144 (3): 319-30. doi: 10.1530/REP‑12-0134.

Doornbos M.E. Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study / M.E. Doornbos, S.M. Maas, J. McDonnell, J.P. Vermeiden, R.C. Hennekam // Hum. Reprod. 2007 Sep; 22 (9): 2476-80. doi: 10.1093/humrep/dem172.

El-Maarri O. Maternal methylation imprints on human chromosome 15 are established during or after fertilization / O. El-Maarri, K. Buiting, E.G. Peery et al. // Nat. Genet. 2001 Mar; 27 (3): 341-4. doi: 10.1038/85927.

Geuns E. Methylation imprints of the imprint control region of the SNRPN-gene in human gametes and preimplantation embryos / E. Geuns, M. De Rycke, A. Van Steirteghem, I. Liebaers // Hum. Mol. Genet. 2003 Nov 15; 12 (22): 2873-9. doi: 10.1093/hmg/ddg315.

Gicquel C. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene / C. Gicquel, V. Gaston, J. Mandelbaum et al. // Am. J. Hum. Genet. 2003 May; 72 (5): 1338-41. PMID: 12772698.

Gomes M.V. Abnormal methylation at the KvDMR1 imprin­ting control region in clinically normal children conceived by assisted reproductive technologies / M.V. Gomes, J. Huber, R.A. Ferriani et al. // Mol. Hum. Reprod. 2009 Aug; 15 (8): 471-7. doi: 10.1093/molehr/gap038.

Govorko D. Male germline transmits fetal al.cohol adverse effect on hypothalamic proopiomelanocortin gene across generations / Govor­ko D., Bekdash R.A., Zhang C., Sarkar D.K. // Biol. Psychiatry. 2012 Sep 1; 72 (5): 378-88. doi: 10.1016/j.biopsych.2012.04.006.

Grafodatskaya D., Cytrynbaum C., Weksberg R. The health risks of ART // EMBO Rep. 2013 Feb; 14 (2): 129-35. doi: 10.1038/embor.2012.222.

Heinzmann J. Epigenetic profile of developmentally important genes in bovine oocytes / J. Heinzmann, T. Hansmann, D. Herrmann et al. // Mol. Reprod. Dev. 2011 Mar; 78 (3): 188-201. doi: 10.1002/mrd.21281.

Hiura H. Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies / H. Hiura, H. Okae, N. Miyauchi et al. // Hum. Reprod. 2012 Aug; 27 (8): 2541-8. doi: 10.1093/humrep/des197.

Hiura H. Imprinting methylation errors in ART / H. Hiura, H. Okae, H. Chiba et al. // Reprod. Med. Biol. 2014; 13 (4): 193-202. doi: 10.1007/s12522-014-0183-3.

Hoeijmakers L., Kempe H., Verschure P.J. Epigenetic imprin­ting during assisted reproductive technologies: The effect of temporal and cumulative fluctuations in methionine cycling on the DNA methylation state // Mol. Reprod. Dev. 2016 Feb; 83 (2): 94-107. doi: 10.1002/mrd.22605.

Kagami M. Silver-Russell syndrome in a girl born after in vitro fertilization: partial hypermethylation at the differentially methylated region of PEG1/MEST / M. Kagami, T. Nagai, M. Fukami, K. Yamazawa, T. Ogata // J. Assist. Reprod. Genet. 2007 Apr; 24 (4): 131-6. doi: 10.1007/s10815-006-9096-3.

Katari S. DNA methylation and gene expression differences in children conceived in vitro or in vivo / S. Katari, N. Turan, M. Bibikova et al. // Hum. Mol. Genet. 2009 Oct 15; 18 (20): 3769-78. doi: 10.1093/hmg/ddp319.

Khoueiry R. Abnormal methylation of KCNQ1OT1 and differential methylation of H19 imprinting control regions in human ICSI embryos / R. Khoueiry, S. Ibala-Romdhane, Méry L. et al. — ​Khtib et al. // Zygote. 2013 May; 21 (2): 129-38. doi: 10.1017/S0967199411000694.

Khoueiry R. Dynamic CpG methylation of the KCNQ1OT1 gene during maturation of human oocytes / Khoueiry R., Ibala-Rhomdane S., Méry L. et al. // J. Med. Genet. 2008 Sep; 45 (9): 583-8. doi: 10.1136/jmg.2008.057943.

Kopeika J., Thornhill A., Khalaf Y. The effect of cryopreservation on the genome of gametes and embryos: principles of cryobiology and critical appraisal of the evidence // Hum. Reprod. Update. 2015 Mar-Apr; 21 (2): 209-27. doi: 10.1093/humupd/dmu063.

Li B. Assisted Reproduction Causes Reduced Fetal Growth Associated with Downregulation of Paternally Expressed Imprinted Genes That Enhance Fetal Growth / B. Li, S. Chen, N. Tang et al. // Biol. Reprod. 2016 Jan 13. pii: biolreprod.115.136051.

Lim D. Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies / D. Lim, S.C. Bowdin, L. Tee et al. // Hum. Reprod. 2009 Mar; 24 (3): 741-7. doi: 10.1093/humrep/den406.

Liu S. Effect of gonadotropins on dynamic events and global deoxyribonucleic acid methylation during in vitro maturation of oocytes: an animal model / S. Liu, H.L. Feng, D. Marchesi, Z.J. Chen, A. Hershlag // Fertil. Steril. 2011 Mar 15; 95 (4): 1503-6.e1-3. doi: 10.1016/j.fertnstert.2010.09.049.

Lou H. Assisted reproductive technologies impair the expression and methylation of insulin-induced gene 1 and sterol regulatory element-binding factor 1 in the fetus and placenta / H. Lou, F. Le, Y. Zheng et al. // Fertil. Steril. 2014 Apr; 101 (4): 974-980.e2. doi: 10.1016/j.fertnstert.2013.12.034.

Ludwig M. Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples / M. Ludwig, A. Katalinic, S. Gross et al. // J. Med. Genet. 2005 Apr; 42 (4): 289-91. doi: 10.1136/jmg.2004.026930.

Martinez D. In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving al.tered lxra DNA methylation / D. Martinez, T. Pentinat, S. Ribo et al. // Cell. Metab. 2014 Jun 3; 19 (6): 941-51. doi: 10.1016/j.cmet.2014.03.026.

Melamed N. Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies / N. Melamed, S. Choufani, L.E. Wilkins-Haug, G. Koren, R. Weksberg // Epigenetics. 2015; 10 (6): 474-83. doi: 10.4161/15592294.2014.988041.

Menezo Y. DNA methylation and gene expression in IVF / Y. Menezo, K. Elder, M. Benkhalifa, B. Dale // Reprod. Biomed. Online. 2010 Jun; 20 (6): 709-10. doi: 10.1016/j.rbmo.2010.02.016.

Mundim T.C. Changes in gene expression profiles of bovine embryos produced in vitro, by natural ovulation, or hormonal superstimulation / T.C. Mundim, A.F. Ramos, R. Sartori et al. // Genet. Mol. Res. 2009 Nov 24; 8 (4): 1398-407. doi: 10.4238/vol8-4gmr646.

Nelissen E.C. Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions / E.C. Nelissen, J.C. Dumoulin, A. Daunay et al. // Hum. Reprod. 2013 Apr; 28 (4): 1117-26. doi: 10.1093/humrep/des459.

Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway // Nut­rients. 2013 Sep 9; 5 (9): 3481-95. doi: 10.3390/nu5093481.

Okun N., Sierra S. Pregnancy outcomes after assisted human reproduction // J. Obstet Gynaecol. Can. 2014 Jan; 36 (1): 64-83. PMID: 24444289.

Ørstavik K.H. Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection / K.H. Ørstavik, K. Eiklid, C.B. van der Hagen et al. // Am. J. Hum. Genet. 2003 Jan; 72 (1): 218-9. PMID: 12549484.

Owen C.M., Segars J.H. Jr. Imprinting disorders and assisted reproductive technology // Semin. Reprod. Med. 2009 Sep; 27 (5): 417-28. doi: 10.1055/s‑0029-1237430.

Padmanabhan N., Watson E.D. Lessons from the one-carbon metabolism: passing it to the next generation // Reprod. Biomed. Online. 2013 Dec; 27 (6): 637-43. doi: 10.1016/j.rbmo.2013.09.008.

Pinborg A. Epigenetics and assisted reproductive technologies / A. Pinborg, A. Loft, L.B. Romundstad, U.B. Wennerholm // Acta Obstet. Gynecol. Scand. 2016 Jan; 95 (1): 10-5. doi: 10.1111/aogs.12799.

Radford E.J. An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming / E.J. Radford, E. Isganaitis, J. Jimenez-Chillaron et al. // PLoS Genet. 2012; 8 (4): e1002605. doi: 10.1371/journal.pgen.1002605.

Rancourt R.C., Harris H.R., Michels K.B. Methylation levels at imprinting control regions are not al.tered with ovulation induction or in vitro fertilization in a birth cohort // Hum. Reprod. 2012 Jul; 27 (7): 2208-16. doi: 10.1093/humrep/des151.

Rehan V.K. Perinatal nicotine-induced transgenerational asthma / V.K. Rehan, J. Liu, R. Sakurai, J.S. Torday // Am. J. Physiol. Lung Cell Mol. Physiol. 2013 Oct 1; 305 (7): L501-7. doi: 10.1152/ajplung.00078.2013.

Rossignol S. The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region / S. Rossignol, V. Steunou, C. Chalas et al. // J. Med. Genet. 2006 Dec; 43 (12): 902-7. doi: 10.1136/jmg.2006.042135.

Sato A. Aberrant DNA methylation of imprinted loci in superovulated oocytes / A. Sato, E. Otsu, H. Negishi, T. Utsunomiya, T. Arima // Hum. Reprod. 2007 Jan; 22 (1): 26-35. doi: 10.1093/humrep/del316.

Seisenberger S. Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers // S. Seisenberger, J.R. Peat, T.A. Hore et al. // Philos Trans R Soc Lond B Biol. Sci. 2013 Jan 5; 368 (1609): 20110330. doi: 10.1098/rstb.2011.0330.

Skinner M.K. Endocrine disruptor induction of epigenetic transgenerational inheritance of disease. Mol Cell Endocrinol. 2014 Dec; 398 (1-2): 4-12. doi: 10.1016/j.mce.2014.07.019.

Skinner M.K. Environmentally induced transgenerational epigenetic reprogramming of primordial germ cells and the subsequent germ line / M.K. Skinner, C. Guerrero-Bosagna, M. Haque et al. // PLoS One. 2013 Jul 15; 8 (7): e66318. doi: 10.1371/journal.pone.0066318.

Skinner M.K., Manikkam M., Guerrero-Bosagna C. Epigenetic transgenerational actions of environmental factors in disease etiology // Trends Endocrinol. Metab. 2010 Apr; 21 (4): 214-22. doi: 10.1016/j.tem.2009.12.007.

Song S. DNA methylation differences between in vitro- and in vivo-conceived children are associated with ART procedures rather than infertility / S. Song, J. Ghosh, M. Mainigi et al. // Clin. Epigenetics. 2015 Apr 8; 7 (1): 41. doi: 10.1186/s13148-015-0071-7.

Steegers-Theunissen R.P. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism / R.P. Steegers-Theunissen, J. Twigt, V. Pestinger, K.D. Sinclair // Hum. Reprod. Update. 2013 Nov-Dec; 19 (6): 640-55. doi: 10.1093/humupd/dmt041.

Sutcliffe A.G. Assisted reproductive therapies and imprinting disorders — ​a preliminary British survey / Sutcliffe A.G., Peters C.J., Bowdin S. et al. // Hum. Reprod. 2006 Apr; 21 (4): 1009-11. doi: 10.1093/humrep/dei405.

Tee L. Epimutation profiling in Beckwith-Wiedemann syndrome: relationship with assisted reproductive technology / L. Tee, D.H. Lim, R.P. Dias et al. // Clin. Epigenetics. 2013 Dec 10; 5 (1): 23. doi: 10.1186/1868-7083-5-23.

Tierling S. Assisted reproductive technologies do not enhance the variability of DNA methylation imprints in human / S. Tierling, N.Y. Souren, J. Gries et al. // J. Med. Genet. 2010 Jun; 47 (6): 371-6. doi: 10.1136/jmg.2009.073189.

Turan N. Inter- and intra-individual variation in al.lele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology / N. Turan, S. Katari, L.F. Gerson et al. // PLoS Genet. 2010 Jul 22; 6 (7): e1001033. doi: 10.1371/journal.pgen.1001033.

Uyar A., Seli E. The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders // Curr. Opin. Obstet. Gynecol. 2014 Jun; 26 (3): 210-21. doi: 10.1097/GCO.0000000000000071.

Veenendaal M.V. Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine / M.V. Veenendaal, R.C. Painter, S.R. de Rooij et al. // BJOG. 2013 Apr; 120 (5): 548-53. doi: 10.1111/1471-0528.12136.

White C.R. High Frequency of Imprinted Methylation Errors in Human Preimplantation Embryos / C.R. White, M.M. Denomme, F.R. Tekpetey et al. // Sci Rep. 2015 Dec 2; 5: 17311. doi: 10.1038/srep17311.

Wolstenholme J.T. Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression/ J.T. Wolstenholme, M. Edwards, S.R. Shetty et al. // Endocrinology. 2012 Aug; 153 (8): 3828-38. doi: 10.1210/en.2012-1195.

Xu X.R. Epigenetic inheritance of paternally expressed imprinted genes in the testes of ICSI mice / X.R. Xu, R.G. Fu, L.Y. Wang et al. // Curr. Pharm. Des. 2014; 20 (11): 1764-71. doi: 10.2174/13816128113199990520.

Young L.E. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture / L.E. Young, K. Fernandes, T.G. McEvoy et al. // Nat. Genet. 2001 Feb; 27 (2): 153-4. doi: 10.1038/84769.

Zechner U. Quantitative methylation analysis of developmentally important genes in human pregnancy losses after ART and spontaneous conception / Zechner U., Pliushch G., Schneider E. et al. // Mol. Hum. Reprod. 2010 Sep; 16 (9): 704-13. doi: 10.1093/molehr/gap107.

Zhang B. Both the folate cycle and betaine-homocysteine methyltransferase contribute methyl groups for DNA methylation in mouse blastocysts / Zhang B., Denomme M.M., White C.R. et al. // FASEB J. 2015 Mar; 29 (3): 1069-79. doi: 10.1096/fj.14-261131.

Copyright (c) 2017 CHILD`S HEALTH

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.


© Publishing House Zaslavsky, 1997-2019


   Seo анализ сайта