DNA methylation differences between in vitro- and in vivo-conceived children are associated with ART procedures rather than infertility

Clinical Epigenetics

Carmen Sapienza¹  Christos Coutifaris³  May Truongcao²  Rachel Weinerman³  Nahid Turan²  Monica Mainigi³  Jayashri Ghosh²  Sisi Song² 

[1] Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia 19140, PA, USA;Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N Broad Street, Philadelphia 19140, PA, USA;Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, 3701 Market Street, 8th Floor, Philadelphia 19119, PA, USA

关键词: Placenta;    Infertility;    Donor oocytes;    Assisted reproduction;    DNA methylation;   

Others  :  1210213
DOI  :  10.1186/s13148-015-0071-7

 received in 2014-12-02, accepted in 2015-03-10,  发布年份 2015

【 摘 要 】

Background

We, and others, have demonstrated previously that there are differences in DNA methylation and transcript levels of a number of genes in cord blood and placenta between children conceived using assisted reproductive technologies (ART) and children conceived in vivo. The source of these differences (the effect of ART versus the underlying infertility) has never been determined in humans. In this study, we have attempted to resolve this issue by comparing placental DNA methylation levels at 37 CpG sites in 16 previously identified candidate genes in independent populations of children conceived in vivo (‘fertile control’ group) with ART children conceived from two groups: either autologous oocytes with infertility in one or both parents (‘infertile ART’ group) or donor oocytes (obtained from young fertile donors) without male infertility (‘donor oocyte ART’ group).

Results

Of the 37 CpG sites analyzed, significant differences between the three groups were found in 11 CpGs (29.73 %), using ANOVA. Tukey’s post hoc test on the significant results indicated that seven (63.63 %) of these differences were significant between the donor oocyte ART and fertile control groups. In addition, 20 of the 37 CpGs analyzed had been identified as differentially methylated between ART and fertile control groups in an independent population in a prior study. Of these 20 CpG sites, 9 also showed significant differences in the present population. An additional 9 CpGs were found to be significantly different between the two groups. Of these 18 candidate CpGs, 12 CpGs (in seven candidate genes) also showed significant differences in placental DNA methylation levels between the donor oocyte ART and fertile control groups.

Conclusions

These data suggest strongly that the DNA methylation differences observed between ART and in vivo conceptions are associated with some aspect of ART protocols, not simply the underlying infertility.

【 授权许可】

   
2015 Song et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Katari S, Turan N, Bibikova M, Erinle O, Chalian R, Foster M, et al.: DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum Mol Genet 2009, 18:3769-78.
• [2]Kobayashi H, Hiura H, John RM, Sato A, Otsu E, Kobayashi N, et al.: DNA methylation errors at imprinted loci after assisted conception originate in the parental sperm. Eur J Hum Genet 2009, 17(12):1582-91.
• [3]Gomes MV, Huber J, Ferriani RA, Amaral Neto AM, Ramos ES: Abnormal methylation at the KvDMR1 imprinting control region in clinically normal children conceived by assisted reproductive technologies. Mol Hum Reprod 2009, 15:471-7.
• [4]Turan N, Katari S, Gerson LF, Chalian R, Foster MW, Gaughan JP, et al.: Inter- and intraindividual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology. PLoS Genet 2010, 6:e1001033.
• [5]Katagiri Y, Aoki C, Tamaki-Ishihara Y, Fukuda Y, Kitamura M, Matsue Y, et al.: Effects of assisted reproduction technology on placental imprinted gene expression. Obstet Gynecol Int 2010, 2010:pii: 437528.
• [6]Santos F, Hyslop L, Stojkovic P, Leary C, Murdoch A, Reik W, et al.: Evaluation of epigenetic marks in human embryos derived from IVF and ICSI. Hum Reprod 2010, 25(9):2387-95.
• [7]Shi X, Ni Y, Zheng H, Chen S, Zhong M, Wu F, et al.: Abnormal methylation patterns at the IGF2/H19 imprinting control region in phenotypically normal babies conceived by assisted reproductive technologies. Eur J Obstet Gynecol Reprod Biol 2011, 158(1):52-5.
• [8]Nelissen EC, Dumoulin JC, Daunay A, Evers JL, Tost J, Van Montfoort AP: 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(4):1117-26.
• [9]Zheng HY, Tang Y, Niu J, Li P, Ye DS, Chen X, et al.: Aberrant DNA methylation of imprinted loci in human spontaneous abortions after assisted reproduction techniques and natural conception. Hum Reprod 2013, 28(1):265-73.
• [10]Lou H, Le F, Zheng Y, Li L, Wang L, Wang N, et al.: 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. Fertil Steril 2014, 101(4):974-80.
• [11]Tierling S, Souren NY, Gries J, Loporto C, Groth M, Lutsik P, et al.: Assisted reproductive technologies do not enhance the variability of DNA methylation imprints in human. J Med Genet 2010, 47:371-6.
• [12]Zechner U, Pliushch G, Schneider E, El Hajj N, Tresch A, Shufaro Y, et al.: Quantitative methylation analysis of developmentally important genes in human pregnancy losses after ART and spontaneous conception. Mol Hum Reprod 2010, 16(9):704-13.
• [13]Li L, Wang L, Le F, Liu X, Yu P, Sheng J, et al.: Evaluation of DNA methylation status ay differentially methylated regions in IVF-conceived newborn twins. Fertil Steril 2011, 95(6):1975-9.
• [14]Wong EC, Hatakeyama C, Robinson WP, Ma S: DNA methylation at H19/IGF2 ICR1 in the placenta of pregnancies conceived by in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril 2011, 95:2524-6.
• [15]Feng C, Tian S, Zhang Y, He J, Zhu XM, Zhang D, et al.: General imprinting status is stable in assisted reproduction conceived offspring. Fertil Steril 2011, 96:1417-23.
• [16]Zheng HY, Shi XY, Wang LL, Wu YQ, Chen SL, Zhang L: Study of DNA methylation patterns of imprinted genes in children born after assisted reproductive technologies reveals no imprinting errors: a pilot study. Exp Ther Med 2011, 2(4):751-5.
• [17]Oliver VF, Miles HL, Cutfield WS, Hofman PL, Ludgate JL, Morison IM: Defects in imprinting and genome-wide DNA methylation are not common in the in the in vitro fertilization population. Fertil Steril 2012, 97(1):147-53.
• [18]Puumala SE, Nelson HH, Ross JA, Nguyen RH, Damario MA, Spector LG: Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study. BMC Pediatr 2012, 12:33. BioMed Central Full Text
• [19]Rancourt RC, Harris HR, Michels KB: Methylation levels at imprinting control regions are not altered with ovulation induction or in vitro fertilization in a birth cohort. Hum Reprod 2012, 27:2208-16.
• [20]Camprubí C, Iglesias-Platas I, Martin T, Salvador-Alarcon C, Rodriguez MA, Barredo DR, et al.: Stability of genomic imprinting and gestational-age dynamic methylation in complicated pregnancies conceived following assisted reproductive technologies. Biol Reprod 2013, 89(3):50.
• [21]Bloise E, Lin W, Liu X, Simbulan R, Kolahi KS, Petraglia F, et al.: Impaired placental nutrient transport in mice generated by in vitro fertilization. Endocrinology 2012, 153(7):3457-67.
• [22]Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM: Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 2000, 62:1526-35.
• [23]Young LE, Fernandes K, McEvoy TG, Butterwith SC, Gutierrez CG, Carolan C, et al.: Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat Genet 2001, 27:153-4.
• [24]Mann MR, Lee SS, Doherty AS, Verona RL, Nolen LD, Schultz RM, et al.: Selective loss of imprinting in the placenta following preimplantation development in culture. Development 2004, 131:3727-35.
• [25]Farin PW, Piedrahita JA, Farin CE: Errors in development of fetuses and placentas from in vitro-produced bovine embryos. Theriogenology 2006, 65(1):178-91.
• [26]Rivera RM, Stein P, Weaver JR, Mager J, Schultz RM, Bartolomei MS: Manipulations of mouse embryos prior to implantation result in aberrant expression of imprinted genes on day 95 of development. Hum Mol Genet 2008, 17:1-14.
• [27]Fortier AL, Lopes FL, Darricarrère N, Martel J, Trasler JM: Superovulation alters the expression of imprinted genes in the midgestation mouse placenta. Hum Mol Genet 2008, 17(11):1653-65.
• [28]Li L, Wang L, Xu X, Lou H, Le F, Li L, et al.: Genome-wide DNA methylation patterns in IVF-conceived mice and their progeny: a putative model for ART-conceived humans. Reprod Toxicol 2011, 32:98-105.
• [29]Wright K, Brown L, Brown G, Casson P, Brown S: Microarray assessment of methylation in individual mouse blastocyst stage embryos shows that in vitro culture may have widespread genomic effects. Hum Reprod 2011, 26:2576-85.
• [30]Turan N, Ghalwash MF, Katari S, Coutifaris C, Obradovic Z, Sapienza C: DNA methylation differences at growth related genes correlate with birth weight: a molecular signature linked to developmental origins of adult disease? BMC Med Genomics 2012, 5:10. BioMed Central Full Text
• [31]Schieve LA, Rasmussen SA, Buck GM, Schendel DE, Reynolds MA, Wright VC: Are children born after assisted reproductive technology at increased risk for adverse health outcomes? Obstet Gynecol 2004, 103(6):1154-63.
• [32]Helmerhorst FM, Perquin DA, Donker D, Keirse MJ: Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. Br Med J 2004, 328:261.
• [33]Jackson RA, Gibson KA, Wu YW, Croughan MS: Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004, 103:551-63.
• [34]Sunderam S, Chang J, Flowers L, Kulkarni A, Sentelle G, Jeng G, et al.: Assisted reproductive technology surveillance - United States, 2006. Morb Mortal Wkly Rep 2009, 58:1-25.
• [35]McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A: Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur J Obstet Gynecol Reprod Biol 2009, 146:138-48.
• [36]Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS: Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002, 346(10):731-7.
• [37]Kallen B, Finnstrom O, Nygren KG, Olausson PO: In vitro fertilization (IVF) in Sweden: risk for congenital malformations after different IVF methods. Birth Defects Res A Clin Mol Teratol 2005, 73:162-9.
• [38]Rimm AA, Katayama AC, Diaz M, Katayama KP: A meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children. J Assist Reprod Genet 2004, 21(12):437-43.
• [39]Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ: Assisted reproductive technologies and the risk of birth defects - a systematic review. Hum Reprod 2005, 20(2):328-38.
• [40]Wen J, Jiang J, Ding C, Dai J, Liu Y, Xia Y, et al.: Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis. Fertil Steril 2012, 97(6):1331-7.
• [41]Ceelen M, van Weissenbruch MM, Prein J, Smit JJ, Vermeiden JP, Spreeuwenberg M, et al.: Delemarre-van de Waal HA. Growth during infancy and early childhood in relation to blood pressure and body fat measures at age 8–18 years of IVF children and spontaneously conceived controls born to subfertile parents. Hum Reprod 2009, 24(11):2788-95.
• [42]Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, de Waal HA D-v: Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J Clin Endocrinol Metab 2008, 93(5):1682-8.
• [43]Wikstrand MH, Niklasson A, Strömland K, Hellström A: Abnormal vessel morphology in boys born after intracytoplasmic sperm injection. Acta Paediatr 2008, 97(11):1512-7.
• [44]Scott KA, Yamazaki Y, Yamamoto M, Lin Y, Melhorn SJ, Krause EG, et al.: Glucose parameters are altered in mouse offspring produced by assisted reproductive technologies and somatic cell nuclear transfer. Biol Reprod 2010, 83(2):220-7.
• [45]Scherrer U, Rimoldi SF, Rexhaj E, Stuber T, Duplain H, Garcin S, et al.: Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation 2012, 125(15):1890-6.
• [46]DeBaun MR, Niemitz EL, Feinberg AP: Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alteration of LIT1 and H19. Am J Hum Genet 2003, 72:156-60.
• [47]Maher ER, Brueton LA, Bowdin SC, Luharia A, Cooper W, Cole TR, et al.: Beckwith-Wiedemann syndrome and assisted reproductive technology (ART). J Med Genet 2003, 40:62-4.
• [48]Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, 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, 72:1338-41.
• [49]Halliday J, Oke K, Breheny S, Algar E, Amor DJ: Beckwith-Wiedemann syndrome and IVF: a case-control study. Am J Hum Genet 2004, 75:526-8.
• [50]Weksberg R, Shuman C, Smith AC: Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 2005, 137:12-23.
• [51]Sutcliffe AG, Peters CJ, Bowdin S, Temple K, Reardon W, Wilson L, et al.: Assisted reproductive therapies and imprinting disorders - a preliminary British survey. Hum Reprod 2006, 21:1009-11.
• [52]Doornbos ME, Maas SM, McDonnell J, Vermeiden JPW, Hennekam RCM: Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study. Hum Reprod 2007, 22:2476-80.
• [53]Urrego R, Rodriguez-Osorio N, Niemann H: Epigenetic disorders and altered gene expression after use of assisted reproductive technologies in domestic cattle. Epigenetics 2014, 9(6):803-15.
• [54]van Montfoort APA, Hanssen LLP, de Sutter P, Viville S, Geraedts JPM, de Boer P: Assisted reproduction treatment and epigenetic inheritance. Hum Reprod 2012, 18(2):171-97.
• [55]Rieusset A, Schaller F, Unmehopa U, Matarazzo V, Watrin F, Linke M, et al.: Stochastic loss of silencing of the imprinted Ndn/NDN allele, in a mouse and humans with Prader-Willi syndrome, has functional consequences. PLoS Genet 2013, 9(9):e1003752.
• [56]Ribarska T, Goering W, Droop J, Bastian KM, Ingenwerth M, Schulz WA: Deregulation of an imprinted gene network in prostate cancer. Epigenetics 2014, 9(5):704-17.
• [57]Chen M, Ni J, Chang HC, Lin CY, Muyan M, Yeh S: CCDC62/ERAP75 functions as a coactivator to enhance estrogen receptor beta-mediated transactivation and target gene expression in prostate cancer cells. Carcinogenesis 2009, 30(5):841-50.
• [58]Tarabeux J, Kebir O, Gauthier J, Hamdan FF, Xiong L, Piton A, et al.: Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl Psychiatry 2011, 1:e55.
• [59]Chandley MJ, Szebeni A, Szebeni K, Crawford JD, Stockmeier CA, Turecki G, et al.: Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression. Int J Neuropsychopharmacol 2014, 17(10):1569-78.
• [60]Nystad M, Sitras V, Larsen M, Acharya G: Placental expression of aminopeptidase-Q (laeverin) and its role in pathophysiology of pre-eclampsia. Am J Obstet Gynecol 2014, 211(6):686.
• [61]Looijenga LH, Gillis AJ, Verkerk AJ, Van Putten WL, Oosterhuis JW: Heterogeneous X inactivation in trophoblastic cells of human full-term female placentas. Am J Hum Genet 1999, 64:1445-52.
• [62]Silviera ML, Smith BP, Powell J, Sapienza C: Epigenetic differences in normal colon mucosa of cancer patients suggests altered dietary metabolic pathways. Cancer Prev Res 2012, 5(3):374-84.
• [63]Cesaroni M, Powell J, Sapienza C: Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer. Cancer Prev Res (Phila) 2014, 7(7):717-26.