In vitro fertilization placenta overgrowth in mice is associated with downregulation of the paternal imprinting gene H19.

In vitro fertilization (IVF) is a widely used assisted reproductive technology for individuals with infertility that may cause placental maldevelopment, which is harmful to the future health of the offspring. In this study, using a mouse model, we not only revealed changes in the placenta caused by IVF at embryonic day 18.5 (E18.5), but also attempted to identify factors that correlate with IVF-induced abnormal placental development. Our results demonstrate that IVF-induced placental maldevelopment is associated with hypermethylation of the imprinting control region of the H19 imprinted maternally expressed transcript (H19). IVF, by inducing overexpression of DNA methyltransferase 3β, downregulated H19 and the derived miR675, resulting in the activation of insulin-like growth factor signaling and its downstream phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway. Therefore, we provided the first evidence of the molecular signaling pathways that link imprint genes, protein encoding genes, long noncoding RNAs, and microRNAs. This may provide new insights to inform the development of improved operational techniques for IVF and life-long health of the offspring.