https://orcid.org/0000-0001-5383-8286
Key Points
Maternal obesity accelerates fetal erythroid differentiation but impairs terminal maturation.
Maternal obesity affects fetal hemoglobin synthesis and switching process.
Abstract
Maternal obesity (MO) has been associated with an increased risk of anemia in infants and children; however, the underlying mechanisms remain poorly understood. To address this, we conducted single-cell RNA sequencing (scRNA-seq) on embryonic tissues involved in erythropoiesis—including the embryo proper, fetal liver, placenta and yolk sac—across multiple developmental stages (E9.5, E11.5, E13.5 and E17.5) in mouse models of MO. To further assess epigenetic regulation, we performed single-cell ATAC sequencing (scATAC-seq) on E13.5 embryos. These findings were validated using publicly available scRNA-seq data from human umbilical cord blood (UBC) collected from neonates born to lean and obese mothers, along with measurements of oxygenation parameters. Additionally, erythrocyte composition at different developmental stages (E13.5, E17.5 and P0) was evaluated through blood smear analysis. Our data revealed that MO induced fetal hypoxia, which enhanced embryonic erythropoiesis via activation of the HIF1A–erythropoietin (EPO) signaling axis. While MO promoted erythroid output and accelerated early differentiation, it concurrently impaired terminal erythrocyte maturation. Furthermore, MO delayed β-globin switching, with minimal effects on α-globin switching in fetal liver and human UBC-derived erythrocytes. Notably, MO markedly reduced hemoglobin gene expression in both the mouse placenta and human UBC. Collectively, these data demonstrated that MO disrupted fetal erythropoiesis and impaired erythrocyte maturation, potentially increasing the risk of anemia and related developmental consequences in offspring.
Author notes
Data sharing
The scRNA-seq and scATAC-seq datasets used in this study comprise both publicly available and newly generated data. Public datasets include embryonic scRNA-seq data at E9.5, E11.5, E13.5 and embryonic scATAC-seq data at E13.5 (GEO accession numbers: GSE173994 and GSE278631), as well as adult mouse peripheral blood scRNA-seq (GSE120505) and human fetal umbilical cord blood scRNA-seq (NCBI BioProject: PRJNA847067). Newly generated datasets include scRNA-seq of E13.5, E17.5 embryonic liver and scRNA-seq of E13.5 placenta with yolk sac. These datasets have been deposited in the GEO database prior to publication, and accession numbers will be provided upon availability.
