Pre-implantation embryo metabolism identified by PEMA reveals endogenous lactate insufficiency contributes to pre-implantation development arrest

Metabolism is a major regulator of pre-implantation embryonic development, but pre-implantation development arrest (PIDA) due to abnormal metabolisms remains ambiguous. By estimating a weight for each metabolic reaction using the translatome data, we developed a computational tool to perform pre-implantation embryos metabolic analysis (PEMA), and uncovered that the embryos exist in high activities of lactate dehydrogenase and lactate synthesis when major zygotic genome activation (ZGA) occurs in humans and mice. The insufficiency of endogenous lactate was predicted by PEMA in human 8-cell PIDA and corrected human tripronuclear (ch3PN) embryos, which was coordinated with failed H3K18lac and major ZGA. In transcriptomes, the human PIDA embryos resembled endogenous lactate-deprived mouse embryos. Lac-CoA addition could promote H3K18lac, major ZGA, and ch3PN pre-implantation development. Collectively, our study decodes the metabolic abnormalities in human PIDA embryos. The experimental validation suggests that PEMA offers an opportunity to study metabolic heterogeneity in early embryos.