Hypoxia in extravillous trophoblasts links maternal obesity and offspring neurobehavior
Fatima Gunter-Rahman,
Shayna Mallett,
Frédérique White,
Pierre-Étienne Jacques,
Ravikiran M. Raju,
Marie-France Hivert,
Eunjung Alice Lee
Affiliations
Fatima Gunter-Rahman
Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Shayna Mallett
Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Frédérique White
Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
Pierre-Étienne Jacques
Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Institut de Recherche sur le Cancer de l’Université de Sherbrooke, Sherbrooke, QC, Canada
Ravikiran M. Raju
Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA
Marie-France Hivert
Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA, USA; Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Eunjung Alice Lee
Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Summary: While maternal obesity (MO) is associated with neurobehavioral impairment (NBI) in offspring, the underlying mechanisms remain unknown. The placenta is thought to play a role in fetal programming. To elucidate the association between MO and offspring NBI, we performed single-nucleus RNA-seq on maternal- and fetal-facing sides of human term placentas from MO and lean groups. MO placentas showed the upregulation of hypoxia response genes in multiple cell types, and maternal-facing hypoxia gene expression correlated with offspring NBI in an independent birth cohort, Gen3G. Extravillous trophoblasts (EVTs) showed the highest expression of NBI-correlated genes, and EVT NBI-gene expression correlated with hypoxia signatures in two cohorts. Exposing cultured EVTs to hypoxia increased NBI gene expression, and 44% of the association between maternal BMI and NBI-gene expression in EVTs was mediated by hypoxia. Our findings suggest that hypoxia in EVTs is a key process in the neurodevelopmental programming of fetal exposure to MO.
