Epigenetic Effects of Assisted Reproductive Technology in Human Offspring

The births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the potential for elevated risks of ART-related disorders persists in adult life, and the underlying epigenetic mechanisms are largely uncharacterized. Here, we recruited 100 nuclear families and profiled the DNA methylomes, genome-wide histone modifications, and transcriptomes to clarify the inherent extra risks attributable to specific ART procedures. We discovered that IVF-ET seemed to introduce less disturbance into the infant epigenome than IVF-FET or ICSI-ET did. Furthermore, we noted approximately half of the DNA methylomic changes in ART-conceived offspring could be explained by parental background biases. Through removal of the parental effect, we confirmed that ART per se would introduce minor DNA methylation changes locally. More importantly, we found that ART-induced epigenomic alterations were highly enriched in the processes which might contribute to increased incidence of preeclampsia during pregnancy and metabolic syndrome in offspring. Overall, our study provides an epigenetic basis for the potential long-term health risks in ART-conceived offspring that reinforces the need to review all methods of human ART.