Maternal obesity increases the risk of congenital anomalies and later-life metabolic disease in offspring. Still, underlying mechanisms remain unclear, particularly in extraembryonic lineages at the maternal-fetal interface, which remain poorly studied. We jointly profiled gene expression and chromatin accessibility in single nuclei from mouse embryos and extraembryonic tissues in a diet-induced obesity model at embryonic day 8.5, when multiple organogenesis programs are underway. This analysis generated an atlas of 36 cell lineages, including derivatives of all three germ layers and trophoblast populations. Lineage allocation was preserved in embryos from obese dams. However, transcription was widely dysregulated. Oxidative phosphorylation genes were broadly suppressed, and genes involved in hypoxia, cytoskeleton remodeling, and cell migration were enriched among upregulated pathways. Chromatin accessibility changed in a few lineages, most notably in extraembryonic visceral endoderm and parietal trophoblast giant cells. Differently accessible chromatin was enriched in binding motifs for retinoic acid receptors. Indeed, genes involved in retinol and lipoprotein transport were suppressed, and RNA in situ hybridization confirmed reduced expression of retinol transporters Ttr, Rbp4, and Stra6, and lipoprotein transporter Apoa1 in visceral yolk sac. Thus, obesity during pregnancy causes early transcriptional dysregulation that impairs retinoic acid and lipoprotein transport at the maternal-fetal interface, suggesting a mechanism through which maternal obesity could influence long-term developmental outcomes.
Caballero et al. (Wed,) studied this question.