C Choux1,2, C Binquet3,4, V Carmignac1, C Bruno1,5, C Chapusot6, J Barberet1,5, M Lamotte2, P Sagot2, D Bourc'his7, P Fauque1,5. 1. Université Bourgogne Franche-Comté-Equipe Génétique des Anomalies du Développement (GAD) INSERM UMR1231, 2 Rue Angélique Ducoudray, F-21000 Dijon, France. 2. CHU Dijon Bourgogne, Service de Gynécologie-Obstétrique, 14 rue Gaffarel, F-21000 Dijon, France. 3. CHU Dijon Bourgogne, Centre d'Investigation Clinique, module Epidémiologie Clinique/essais cliniques (CIC-EC), 7 boulevard Jeanne d'Arc, F-21000 Dijon, France. 4. Université Bourgogne Franche-Comté-INSERM CIC1432, module épidémiologie clinique, 7 boulevard Jeanne d'Arc, F-21000 Dijon, France. 5. CHU Dijon Bourgogne, Laboratoire de Biologie de la Reproduction, 14 rue Gaffarel, F-21000 Dijon, France. 6. CHU Dijon Bourgogne, Service de Pathologie, F-21000 Dijon, France. 7. Institut Curie, PSL University, CNRS, INSERM, 'Epigenetic Decisions and Reproduction' Group, 26 rue d'Ulm, 75005 Paris, France.
Abstract
STUDY QUESTION: Do assisted reproductive technologies alter DNA methylation and/or transcription of transposable elements and imprinted genes in cord blood and placenta? SUMMARY ANSWER: After ART, DNA methylation and/or transcription changes of some transposable elements and imprinted genes were found in placenta samples while transcription modifications for some transposable elements were also discovered in cord blood. WHAT IS KNOWN ALREADY: Recent studies have confirmed the increased risk of placenta-related adverse pregnancy outcomes and the excess of imprinted disorders with abnormal methylation patterns after ART, which raises the issue of a potential ART-induced epigenetic risk. STUDY DESIGN, SIZE, DURATION: A total of 51 IVF/ICSI (15 conventional and 36 ICSI) singleton pregnancies were prospectively included from January 2013 to April 2015 and compared to 48 spontaneously conceived singleton pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: The DNA methylation and transcription of three imprinted loci (H19/IGF2, KCNQ1OT1 and SNURF DMRs) and four transposon families (LINE-1, ERVFRD, AluYa5 and ERVW) in cord blood and placenta obtained at birth were assessed by pyrosequencing and quantitative RT-PCR, respectively. All data were adjusted for gestational age at delivery, sex of the newborn, parity and maternal age. MAIN RESULTS AND THE ROLE OF CHANCE: DNA methylation levels of H19/IGF2, KCNQ1OT1, LINE-1Hs and ERVFRD-1 were significantly lower in IVF/ICSI placentas than in control placentas, while there was no difference for cord blood. Moreover, the expression of ERVFRD-1 and LINE-1 ORF2 in cord blood and ERVFRD-1 in placenta was lower in the IVF/ICSI group than in controls. The expression of ERVFRD-1 in placenta correlated positively with birth weight and placenta weight, but only in the control group, thus pointing to the potential deregulation of syncytin function after ART. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The control group of fertile couples having conceived within 1 year prevented us from deciphering the distinct roles of ART and infertility. WIDER IMPLICATIONS OF THE FINDINGS: These novel findings of ERVFRD (syncytin-2) expression correlating with birth weight and placenta weight suggest that more research on syncytins and pregnancy-associated diseases could lead to them being used as biomarkers or even as therapeutic targets. The epigenetic modifications in placenta for sequences involved in foetal development raise the question of their potential effects on pregnancy and future life. These results should encourage us to analyse the exact causes and consequences of epigenetic changes and strive to minimize these variations in the interests of epigenetic safety after ART. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by a grant from Besançon and Dijon University Hospitals. The authors have no conflicts of interest to declare.
STUDY QUESTION: Do assisted reproductive technologies alter DNA methylation and/or transcription of transposable elements and imprinted genes in cord blood and placenta? SUMMARY ANSWER: After ART, DNA methylation and/or transcription changes of some transposable elements and imprinted genes were found in placenta samples while transcription modifications for some transposable elements were also discovered in cord blood. WHAT IS KNOWN ALREADY: Recent studies have confirmed the increased risk of placenta-related adverse pregnancy outcomes and the excess of imprinted disorders with abnormal methylation patterns after ART, which raises the issue of a potential ART-induced epigenetic risk. STUDY DESIGN, SIZE, DURATION: A total of 51 IVF/ICSI (15 conventional and 36 ICSI) singleton pregnancies were prospectively included from January 2013 to April 2015 and compared to 48 spontaneously conceived singleton pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: The DNA methylation and transcription of three imprinted loci (H19/IGF2, KCNQ1OT1 and SNURF DMRs) and four transposon families (LINE-1, ERVFRD, AluYa5 and ERVW) in cord blood and placenta obtained at birth were assessed by pyrosequencing and quantitative RT-PCR, respectively. All data were adjusted for gestational age at delivery, sex of the newborn, parity and maternal age. MAIN RESULTS AND THE ROLE OF CHANCE: DNA methylation levels of H19/IGF2, KCNQ1OT1, LINE-1Hs and ERVFRD-1 were significantly lower in IVF/ICSI placentas than in control placentas, while there was no difference for cord blood. Moreover, the expression of ERVFRD-1 and LINE-1 ORF2 in cord blood and ERVFRD-1 in placenta was lower in the IVF/ICSI group than in controls. The expression of ERVFRD-1 in placenta correlated positively with birth weight and placenta weight, but only in the control group, thus pointing to the potential deregulation of syncytin function after ART. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The control group of fertile couples having conceived within 1 year prevented us from deciphering the distinct roles of ART and infertility. WIDER IMPLICATIONS OF THE FINDINGS: These novel findings of ERVFRD (syncytin-2) expression correlating with birth weight and placenta weight suggest that more research on syncytins and pregnancy-associated diseases could lead to them being used as biomarkers or even as therapeutic targets. The epigenetic modifications in placenta for sequences involved in foetal development raise the question of their potential effects on pregnancy and future life. These results should encourage us to analyse the exact causes and consequences of epigenetic changes and strive to minimize these variations in the interests of epigenetic safety after ART. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by a grant from Besançon and Dijon University Hospitals. The authors have no conflicts of interest to declare.
Authors: Sanaa Choufani; Andrei L Turinsky; Nir Melamed; Ellen Greenblatt; Michael Brudno; Anick Bérard; William D Fraser; Rosanna Weksberg; Jacquetta Trasler; Patricia Monnier Journal: Hum Mol Genet Date: 2019-02-01 Impact factor: 6.150
Authors: Cécile Choux; Paolo Petazzi; Marta Sanchez-Delgado; José R Hernandez Mora; Ana Monteagudo; Paul Sagot; David Monk; Patricia Fauque Journal: Epigenetics Date: 2020-06-23 Impact factor: 4.528
Authors: L Zhao; L F Sun; X L Zheng; J F Liu; R Zheng; Y Wang; R Yang; L Zhang; L Yu; H Zhang Journal: Beijing Da Xue Xue Bao Yi Xue Ban Date: 2019-02-18
Authors: D Gentilini; E Somigliana; L Pagliardini; E Rabellotti; P Garagnani; L Bernardinelli; E Papaleo; M Candiani; A M Di Blasio; P Viganò Journal: Clin Epigenetics Date: 2018-06-08 Impact factor: 6.551