Hostname: page-component-586b7cd67f-l7hp2 Total loading time: 0 Render date: 2024-11-28T02:25:10.603Z Has data issue: false hasContentIssue false
  • English
  • Français

Association of in vitro fertilization with global and IGF2/H19 methylation variation in newborn twins

Part of: Epigenetics as the Mediator of the Gene/Environment Interactions in DOHAD

Published online by Cambridge University Press:  10 April 2015

Y. J. Loke ,
J. C. Galati ,
R. Saffery  and
J. M. Craig Open the ORCID record for J. M. Craig [Opens in a new window]
Y. J. Loke*
Affiliation:
Early Life Epigenetics Group, Murdoch Childrens Research Institute (MCRI), Royal Children’s Hospital, Parkville, VIC, Australia
J. C. Galati
Affiliation:
Clinical Epidemiology and Biostatistics Unit, MCRI, Royal Children’s Hospital, Parkville, VIC, Australia
R. Saffery
Affiliation:
Cancer, Disease and Developmental Epigenetics Group, MCRI, Royal Children’s Hospital, Parkville, VIC, Australia Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
J. M. Craig
Affiliation:
Early Life Epigenetics Group, Murdoch Childrens Research Institute (MCRI), Royal Children’s Hospital, Parkville, VIC, Australia Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
*
*Address for correspondence: Y. J. Loke, Early Life Epigenetics, Murdoch Childrens Research Institute (MCRI), Royal Children’s Hospital, Flemington Rd, Parkville, VIC 3052, Australia. (Email [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

In vitro fertilization (IVF) and its subset intracytoplasmic sperm injection (ICSI), are widely used medical treatments for conception. There has been controversy over whether IVF is associated with adverse short- and long-term health outcomes of offspring. As with other prenatal factors, epigenetic change is thought to be a molecular mediator of any in utero programming effects. Most studies focused on DNA methylation at gene-specific and genomic level, with only a few on associations between DNA methylation and IVF. Using buccal epithelium from 208 twin pairs from the Peri/Postnatal Epigenetic Twin Study (PETS), we investigated associations between IVF and DNA methylation on a global level, using the proxies of Alu and LINE-1 interspersed repeats in addition to two locus-specific regulatory regions within IGF2/H19, controlling for 13 potentially confounding factors. Using multiple correction testing, we found strong evidence that IVF-conceived twins have lower DNA methylation in Alu, and weak evidence of lower methylation in one of the two IGF2/H19 regulatory regions and LINE-1, compared with naturally conceived twins. Weak evidence of a relationship between ICSI and DNA methylation within IGF2/H19 regulatory region was found, suggesting that one or more of the processes associated with IVF/ICSI may contribute to these methylation differences. Lower within- and between-pair DNA methylation variation was also found in IVF-conceived twins for LINE-1, Alu and one IGF2/H19 regulatory region. Although larger sample sizes are needed, our results provide additional insight to the possible influence of IVF and ICSI on DNA methylation. To our knowledge, this is the largest study to date investigating the association of IVF and DNA methylation.

Keywords

DNA methylationearly life environmentin vitro fertilization (IVF)twins
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 6 , Supplement 2 , April 2015 , pp. 115 - 124
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Bird, A. Perceptions of epigenetics. Nature. 2007; 447, 396–398.Google Scholar
2. Smith, ZD, Chan, MM, Mikkelsen, TS, et al. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012; 484, 339–344.CrossRefGoogle ScholarPubMed
3. Guo, H, Zhu, P, Yan, L, et al. The DNA methylation landscape of human early embryos. Nature. 2014; 511, 606–610.Google Scholar
4. Chason, RJ, Csokmay, J, Segars, JH, et al. Environmental and epigenetic effects upon preimplantation embryo metabolism and development. Trends Endocrinol Metab. 2011; 22, 412–420.Google Scholar
5. Katari, S, Turan, N, Bibikova, M, et al. DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum Mol Genet. 2009; 18, 3769–3778.Google Scholar
6. Tierling, S, Souren, NY, Gries, J, et al. Assisted reproductive technologies do not enhance the variability of DNA methylation imprints in human. J Med Genet. 2010; 47, 371–376.CrossRefGoogle Scholar
7. Zheng, HY, Tang, Y, Niu, J, et al. Aberrant DNA methylation of imprinted loci in human spontaneous abortions after assisted reproduction techniques and natural conception. Hum Reprod. 2013; 28, 265–273.Google Scholar
8. Turan, N, Katari, S, Gerson, LF, et al. Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology. PLoS Genet. 2010; 6, e1001033.CrossRefGoogle ScholarPubMed
9. Nelissen, EC, Dumoulin, JC, Daunay, A, et al. Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions. Hum Reprod. 2013; 28, 1117–1126.Google Scholar
10. Kobayashi, H, Hiura, H, John, RM, et al. DNA methylation errors at imprinted loci after assisted conception originate in the parental sperm. Eur J Hum Genet. 2009; 17, 1582–1591.Google Scholar
11. Breton, CV, Byun, HM, Wenten, M, et al. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Resp Crit Care. 2009; 180, 462–467.Google Scholar
12. Terry, MB, Ferris, JS, Pilsner, R, et al. Genomic DNA methylation among women in a multiethnic New York City birth cohort. Cancer Epidem Biomar. 2008; 17, 2306–2310.Google Scholar
13. Wilhelm-Benartzi, CS, Houseman, EA, Maccani, MA, et al. In utero exposures, infant growth, and DNA methylation of repetitive elements and developmentally related genes in human placenta. Environ Health Persp. 2012; 120, 296–302.Google Scholar
14. Loke, YJ, Galati, JC, Morley, R, et al. Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins. Epigenetics. 2013; 8, 1069–1079.CrossRefGoogle ScholarPubMed
15. Hoyo, C, Murtha, AP, Schildkraut, JM, et al. Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics. 2011; 6, 928–936.Google Scholar
16. Steegers-Theunissen, RP, Obermann-Borst, SA, Kremer, D, et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One. 2009; 4, e7845.CrossRefGoogle Scholar
17. Haycock, PC, Ramsay, M. Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol Reprod. 2009; 81, 618–627.Google Scholar
18. Chen, J, Li, Q, Rialdi, A, et al. Influences of maternal stress during pregnancy on the Epi/genome: comparison of placenta and umbilical cord blood. J Depress Anxiety. 2014; 3, 1–6.Google Scholar
19. Tobi, EW, Slagboom, PE, van Dongen, J, et al. Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19. PLoS One. 2012; 7, e37933.Google Scholar
20. Tobi, EW, Lumey, LH, Talens, RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009; 18, 4046–4053.Google Scholar
21. Heijmans, BT, Tobi, EW, Stein, AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA. 2008; 105, 17046–17049.CrossRefGoogle ScholarPubMed
22. Kulkarni, A, Dangat, K, Kale, A, et al. Effects of altered maternal folic Acid, vitamin b(12) and docosahexaenoic acid on placental global DNA methylation patterns in wistar rats. PLoS One. 2011; 6, e17706.Google Scholar
23. Takimoto, H, Hayashi, F, Kusama, K, et al. Elevated maternal serum folate in the third trimester and reduced fetal growth: a longitudinal study. J Nutr Sci Vitaminol. 2011; 57, 130–137.Google Scholar
24. Cordaux, R, Batzer, MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet. 2009; 10, 691–703.Google Scholar
25. Murrell, A, Heeson, S, Reik, W. Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops. Nat Genet. 2004; 36, 889–893.Google Scholar
26. Goshen, R, Rachmilewitz, J, Schneider, T, et al. The expression of the H-19 and IGF-2 genes during human embryogenesis and placental development. Mol Reprod Dev. 1993; 34, 374–379.Google Scholar
27. O’Dell, SD, Day, INM. Molecules in focus insulin-like growth factor II (IGF-II). Int J Biochem Cell B. 1998; 30, 767–771.Google Scholar
28. Szabo, PE, Tang, SH, Silva, FJ, et al. Role of CTCF binding sites in the Igf2/H19 imprinting control region. Mol Cell Biol. 2004; 24, 4791–4800.CrossRefGoogle ScholarPubMed
29. 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.Google Scholar
30. Li, L, Wang, L, Le, F, et al. Evaluation of DNA methylation status at differentially methylated regions in IVF-conceived newborn twins. Fertil Steril. 2011; 95, 1975–1979.Google Scholar
31. Saffery, R, Morley, R, Carlin, JB, et al. Cohort profile: the peri/post-natal epigenetic twins study. Int J Epidemiol. 2012; 41, 55–61.Google Scholar
32. Loke, YJ, Novakovic, B, Ollikainen, M, et al. The Peri/Postnatal Epigenetic Twins Study (PETS). Twin Res Hum Genet. 2013; 16, 13–20.Google Scholar
33. Ollikainen, M, Smith, KR, Joo, EJ, et al. DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. Hum Mol Genet. 2010; 19, 4176–4188.CrossRefGoogle ScholarPubMed
34. Flotho, C, Claus, R, Batz, C, et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009; 23, 1019–1028.Google Scholar
35. Bland, JM, Altman, DG. Multiple significance tests: the Bonferroni method. BMJ. 1995; 310, 170.CrossRefGoogle ScholarPubMed
36. Whitelaw, N, Bhattacharya, S, Hoad, G, et al. Epigenetic status in the offspring of spontaneous and assisted conception. Hum Reprod. 2014; 29, 1452–1458.Google Scholar
37. Luo, Y, Lu, X, Xie, H. Dynamic methylation during normal development, aging, and tumorigenesis. Biomed Res Int. 2014; 2014, 784706.Google Scholar
38. Kitkumthorn, N, Keelawat, S, Rattanatanyong, P, et al. LINE-1 and Alu methylation patterns in lymph node metastases of head and neck cancers. Asian Pac J Cancer Prev. 2012; 13, 4469–4475.Google Scholar
39. Li, J, Huang, Q, Zeng, F, et al. The prognostic value of global DNA hypomethylation in cancer: a meta-analysis. PLoS One. 2014; 9, e106290.Google Scholar
40. Baccarelli, A, Wright, RO, Bollati, V, et al. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med. 2009; 179, 572–578.CrossRefGoogle ScholarPubMed
41. Perng, W, Mora-Plazas, M, Marin, C, et al. A prospective study of LINE-1DNA methylation and development of adiposity in school-age children. PLoS One. 2013; 8, e62587.Google Scholar
42. Baccarelli, A, Wright, R, Bollati, V, et al. Ischemic heart disease and stroke in relation to blood DNA methylation. Epidemiology. 2010; 21, 819–828.Google Scholar
43. Baccarelli, A, Tarantini, L, Wright, RO, et al. Repetitive element DNA methylation and circulating endothelial and inflammation markers in the VA normative aging study. Epigenetics. 2010; 5, 222–228.Google Scholar
44. Pearce, MS, McConnell, JC, Potter, C, et al. Global LINE-1 DNA methylation is associated with blood glycaemic and lipid profiles. Int J Epidemiol. 2012; 41, 210–217.CrossRefGoogle ScholarPubMed
45. Cash, HL, McGarvey, ST, Houseman, EA, et al. Cardiovascular disease risk factors and DNA methylation at the LINE-1 repeat region in peripheral blood from Samoan Islanders. Epigenetics. 2011; 6, 1257–1264.Google Scholar
46. Zhao, J, Goldberg, J, Bremner, JD, et al. Global DNA methylation is associated with insulin resistance: a monozygotic twin study. Diabetes. 2012; 61, 542–546.CrossRefGoogle ScholarPubMed
47. Hart, R, Norman, RJ. The longer-term health outcomes for children born as a result of IVF treatment: Part I – General health outcomes. Hum Reprod Update. 2013; 19, 232–243.Google Scholar
48. Kawano, H, Saeki, H, Kitao, H, et al. Chromosomal instability associated with global DNA hypomethylation is associated with the initiation and progression of esophageal squamous cell carcinoma. Ann Surg Oncol. 2014; 21 (suppl 4), 696–702.Google Scholar
49. Esteller, M. Epigenetics in cancer. N Engl J Med. 2008; 358, 1148–1159.CrossRefGoogle ScholarPubMed
50. Suter, CM, Martin, DI, Ward, RL. Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int J Colorectal Dis. 2004; 19, 95–101.Google Scholar
51. Gao, XD, Qu, JH, Chang, XJ, et al. Hypomethylation of long interspersed nuclear element-1 promoter is associated with poor outcomes for curative resected hepatocellular carcinoma. Liver Int. 2014; 34, 136–146.CrossRefGoogle ScholarPubMed
52. Bell, AC, Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature. 2000; 405, 482–485.Google Scholar
53. Thorvaldsen, JL, Duran, KL, Bartolomei, MS. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes Dev. 1998; 12, 3693–3702.Google Scholar
54. Bloise, E, Lin, W, Liu, X, et al. Impaired placental nutrient transport in mice generated by in vitro fertilization. Endocrinology. 2012; 153, 3457–3467.Google Scholar
55. Delle Piane, L, Lin, W, Liu, X, et al. Effect of the method of conception and embryo transfer procedure on mid-gestation placenta and fetal development in an IVF mouse model. Hum Reprod. 2010; 25, 2039–2046.Google Scholar
Supplementary material: File

Loke supplementary material

Tables S1-S6

Download Loke supplementary material(File)
File 121.3 KB