Children conceived using Assisted Reproductive Technologies (ART) have a higher incidence of growth and birth defects, attributable in part to epigenetic perturbations. Both ART and germline defects associated with parental infertility could interfere with epigenetic reprogramming events in germ cells or early embryos. Mouse models indicate that the placenta is more susceptible to the induction of epigenetic abnormalities than the embryo, and thus the placental methylome may provide a sensitive indicator of 'at risk' conceptuses. Our goal was to use genome-wide profiling to examine the extent of epigenetic abnormalities in matched placentas from an ART/infertility group and control singleton pregnancies (n=44/group) from a human prospective longitudinal birth cohort, the 3D Study. Principal component analysis revealed a group of ART outliers. The ART outlier group was enriched for females and a subset of placentas showing loss of methylation of several imprinted genes including GNAS, SGCE, KCNQT1OT1 and BLCAP/NNAT. Within the ART group, placentas from pregnancies conceived with IVF/ICSI showed distinct epigenetic profiles as compared to those conceived with less invasive procedures (ovulation induction, intrauterine insemination). Male factor infertility and paternal age further differentiated the IVF/ICSI group, suggesting an interaction of infertility and techniques in perturbing the placental epigenome. Together, the results suggest that the human placenta is sensitive to the induction of epigenetic defects by ART and/or infertility, and we stress the importance of considering both sex and paternal factors and that some but not all ART conceptuses will be susceptible.
Human molecular genetics. 2018 Sep 19 [Epub ahead of print]
Sanaa Choufani, Andrei L Turinsky, Nir Melamed, Ellen Greenblatt, Michael Brudno, Anick BĂ©rard, William D Fraser, Rosanna Weksberg, Jacquetta Trasler, Patricia Monnier, For The D Cohort Study Group
Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada., Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada., Mount Sinai Centre for Fertility and Reproductive Health, Mount Sinai Hospital, Toronto, Ontario, Canada., Research Unit on Medications and Pregnancy, Research Centre, CHU Sainte-Justine, and Faculty of Pharmacy, University of Montreal,Montreal, Quebec, Canada., Department of Obstetrics and Gynecology, Université de Sherbrooke,and Centre de Recherche du CHUS, Sherbrooke, Quebec, Canada., Departments of Pediatrics, Human Genetics and Pharmacology & Therapeutics, and The Montreal Children's Hospital and Research Institute of the McGill University Health Centre., MUHC Reproductive Centre, Department of Obstetrics and Gynecology, Royal Victoria Hospital and Research Institut e of McGill University Health Centre, Quebec, Canada.