Global DNA methylation levels are altered by modifiable clinical manipulations in assisted reproductive technologies

Abstract

BackgroundWe analyzed placental DNA methylation levels at repeated sequences (LINE1 elements) and all CCGG sites (the LUMA assay) to study the effect of modifiable clinical or laboratory procedures involved in in vitro fertilization. We included four potential modifiable factors: oxygen tension during embryo culture, fresh embryo transfer vs frozen embryo transfer, intracytoplasmic sperm injection (ICSI) vs conventional insemination or day 3 embryo transfer vs day 5 embryo transfer.ResultsGlobal methylation levels differed between placentas from natural conceptions compared to placentas conceived by IVF. Placentas from embryos cultured at 20% oxygen showed significant differences in LINE1 methylation compared to in vivo conceptions, while those from embryos cultured at 5% oxygen, did not have significant differences. In addition, placentas from fresh embryo transfer had significantly different LINE1 methylation compared to placentas from in vivo conceptions, while embryos resulting from frozen embryos were not significantly different from controls. On sex-stratified analysis, only males had significant methylation differences at LINE1 elements stratified for the modifiable factors. As expected, LINE1 methylation was significantly different between males and females in the control population. However, we did not observe sex-specific differences in the IVF group. We validated this sex-specific observation in an additional cohort and in opposite sex IVF twins.ConclusionWe show that two clinically modifiable factors (embryo culture in 5 vs 20% oxygen tension and fresh vs frozen embryo transfer) are associated with global placental methylation differences. Interestingly, males appear more vulnerable to such treatment-related global changes in DNA methylation than do females.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0318-6) contains supplementary material, which is available to authorized users.

Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization

“…A particular strength of this study is that the embryos in both IVF groups were transferred into physiologic hormonal environments, thus minimizing the confounding effects of superovulation on the endometrium. Several other studies have reported similar patterns in other genes related to growth, with frozen embryos yielding epigenetic patterns and gene expression more similar to natural conception (Estill et al, ; Ghosh, Coutifaris, Sapienza, & Mainigi, ). This suggests a potential mechanism of vitrification resulting in reversal of the epigenetic effects of superovulation on the oocyte, with consequentially larger babies.…”

RW‐2018—Research Workshop: The Effect of Nutrition on Epigenetic Status, Growth, and Health

“…Periconceptional developmental programming (ie, embryonic developmental decisions) can also be influenced by a broad spectrum of conditions other than maternal nutrition. These include maternal age, xenobiotic exposures, and conditions of exposure during in vitro fertilization and assisted reproductive technologies (ARTs) . These have all been associated with increased long‐term risk of cardiometabolic dysfunction in human as well as in animal models.…”

“…These include maternal age, 19 xenobiotic exposures, 1,2 and conditions of exposure during in vitro fertilization and assisted reproductive technologies (ARTs). 22,23 These have all been associated with increased long-term risk of cardiometabolic dysfunction in human as well as in animal models. To minimize the risk of heritable noncommunicable, nongenetic, or DOHaD diseases, there must be greater resources directed toward preconception care and preparation for pregnancy to protect the health of the next generation as well as those that follow.…”

Reformatting the reproductive tract to accommodate the needs of human ARTs

“…Taking one step further, Scott Morin then tackles the question of oxygen tension in the context of spatial and temporal changes that the conceptus might be expected to face within confines of the reproductive tract [10]. Interestingly, a recent publication identifies oxygen tension as having an important influence on global DNA methylation patterns when embryos cultured at 5 or 20% were compared [11].…”