Valproic acid elevates HIF-1α-mediated CGB expression and suppresses glucose uptake in BeWo cells

Placental dysfunction can disrupt pregnancy. However, few studies have assessed the effects of chemical-induced toxicity on placental function. Here, we examined the effects of valproic acid (VPA) as a model chemical on production of hormones and on glucose uptake in human choriocarcinoma cell line BeWo. Cells were treated with forskolin to differentiate into syncytiotrophoblasts, which were then treated with VPA for 72 hr. Real-time RT-PCR analysis showed that VPA significantly increased the mRNA expression of chorionic gonadotropin β (CGB), a hormone that is produced by the placenta in the first trimester of pregnancy, relative to that in the forskolin-only group. It also suppressed the increase in intracellular glucose uptake and GLUT1 level observed in the forskolin-only group. RNA-seq analysis and pathway database analysis revealed that VPA consistently decreased the level of HIF-1α protein and expression of its downstream target genes HK2 and ADM in the hypoxia pathway. Cobalt chloride, a HIF-1α inducer, inhibited CGB upregulation in VPA-treated cells and rescued VPA-induced suppression of glucose uptake and GLUT1 level. Thus, HIF-1α-mediated elevation of CGB expression and suppression of glucose uptake by VPA is a novel mechanism of placental dysfunction.