Mouse placentae generated by in vitro fertilization exhibit altered gene expression, activated hypoxia responses, and reduced fitness†

In this study, we utilized single-nucleus RNA sequencing to quantify alterations in the gene expression programs of mouse placentaeconceived through in vitro fertilization (IVF). We identified genetic programs exhibiting both global and cell type-specific differences between IVF and natural in vivo fertilization groups. Gene set enrichment analysis revealed pathways associated with parietal trophoblast giant cell differentiation and implicated in the regulation of lactation (placental lactogens), along with hypoxia-inducible factor-dependent gene expression. Importantly, IVF-derived conceptuses showed increased abortion rates when their surrogate mothers were exposed to hypoxia (10.5% O2) during pregnancy (from E7.5 to 12.5). Collectively, our findings shed light on the cellular and molecular underpinnings driving differences in pregnancy outcomes associated with these conception methods and indicate that IVF can sensitize embryos to additional stressful events, as proposed by the developmental origin of health and disease hypothesis.