Abstract
SARS-CoV-2 infection has raised significant concerns regarding its impact on assisted reproductive technology. We found that oocyte retrieval during acute SARS-CoV-2 infection significantly reduced the rates of good-quality blastocyst formation, but the underlying molecular mechanisms remain poorly understood. To address this, we investigated the effects of maternal acute SARS-CoV-2 infection on preimplantation embryo development and the early offspring hematopoietic system. Using single-cell RNA sequencing (scRNA-seq), we identified developmental delays in morphologically normal blastocysts from infected mothers, characterized by prolonged expression of zygotic genome activation-related genes, downregulation of mTORC1 signaling, and altered energy metabolism, including suppressed oxidative phosphorylation (OXPHOS) and enhanced glycolysis. We further revealed that maternal acute infection induced abnormal methylation/demethylation patterns in preimplantation embryos. To assess the potential long-term impact on offspring, we conducted integrated multi-tissue analyses, including bulk RNA-seq and genome-wide DNA methylation profiling of placental tissues, along with scRNA-seq of umbilical cord blood (UCB) cells from neonates delivered by SARS-CoV-2-infected mothers. Neonates exhibited elevated levels of inflammatory cytokines and an increased abundance of monocytes, indicating an activated myelopoiesis response. In addition, hematopoietic stem and progenitor cells (HSPCs) from UCB showed reduced OXPHOS activity and a skewed differentiation bias toward the myeloid lineage, potentially impacting long-term immune function. Collectively, these findings reveal that maternal acute SARS-CoV-2 infection impairs preimplantation embryo development and leaves a lasting imprint on offspring hematopoietic health through dysregulated energy metabolism, epigenetic modifications, and altered immune responses.