Ultra-low oxygen tension during in vitro fertilization improves embryonic and adult outcomes in mice

Embryo culture, a required step during in vitro fertilization (IVF), exposes developing embryos to altered environmental conditions not normally experienced in vivo , including altered oxygen (O ₂ ) tension. Importantly, O ₂ influences gene expression, metabolism, and the activity of enzymes that sculpt the epigenetic landscape. The lowest O ₂ tension currently used in clinics during embryo culture is 5%, despite evidence that sections of the mammalian female reproductive tract have O ₂ levels as low at 2%. Lower O ₂ may therefore better mimic the in vivo environment and thus lead to improved pre- and postnatal outcomes in IVF-conceived offspring. Using our validated IVF mouse model, we show embryo culture at 2% O ₂ compared to culture under 5% O ₂ significantly improves embryo cell number, the chromatin landscape in preimplantation embryos, fetal and placental development during gestation, and metabolic function in adulthood. We further uncover mechanisms by which culture under ultra-low O ₂ mediates these improvements. Overall, these results suggest embryo culture with 2% O ₂ ameliorates adverse outcomes after IVF and provide evidence that IVF could be further improved by adjusting culture conditions to model the in vivo environment.