Examining the placenta’s role in neurodevelopment in the context of maternal obesity

Abstract

The placenta is a key organ determining fetal development and likely contributes to programming of long-term offspring health, in particular neurodevelopment. Various maternal exposures, such as psychosocial stress, diabetes, infection, and high body mass index (BMI) are associated with higher risks of impaired neurodevelopment in the offspring. One third of women in the United States are affected by maternal obesity (MO) during pregnancy, making it one of the most common exposures. We profiled the term placental transcriptome in humans using single-nucleus RNA-seq, comparing expression profiles in MO versus lean conditions, in each of the two faces of the placenta separately. On both sides of the placenta across several cell types, MO was associated with upregulation of hypoxia response genes. On only the maternal-facing side, hypoxia gene expression was associated with offspring neurodevelopment outcomes measured at multiple time-points, in the Genetics of Glucose regulation in Gestation and Growth (Gen3G) cohort, an independent pre-birth cohort with bulk RNA-seq from placental tissue. We leveraged Gen3G to determine genes that correlated with impaired neurodevelopment and found these genes to be most highly expressed in extravillous trophoblasts (EVTs). EVTs further showed the strongest correlation between neurodevelopment impairment gene scores (NDIGSs) and the hypoxia gene score. We validated these findings in EVTs in an independent single-cell RNA-seq cohort from second trimester placenta, and found that cultured EVTs have increased NDIGSs in response to exposure to hypoxia. These data suggest that hypoxia in EVTs may be a key process in the neurodevelopmental programming of fetal exposure to MO. Our work opens up new directions of research, such as exploring applications of antioxidants to potentially mitigate some of the offspring consequences associated with MO.