Prenatal arsenic exposure disrupts placental angiogenesis by altering Pdgfb promoter epigenetic modification.

Abnormal placentation causes adverse pregnancy and birth outcomes. This study aimed to explore the influence of prenatal arsenic (As) exposure on placental angiogenesis and its mechanism. Dams were orally administered with NaAsO throughout pregnancy. HTR8/SVneo cells were used to establish an in vitro model. RNA-sequencing was performed to identify key regulators. The methylation and hydroxymethylation levels of key regulators were detected. Metabolomics was used to find the potential mechanism. The results showed that As exposure reduces the diameter and number of placental vascular in mice, and weakens endothelial-like tube formation ability in HTR8/SVneo cells. RNA-sequencing identified platelet-derived growth factor b (Pdgfb) as a critical regulator. Mechanistically, As exposure downregulates PDGFB expression, which was attributed to alteration of Pdgfb methylation and hydroxymethylation by inhibiting TET activity. Metabolomics indicated that As exposure downregulates TCA-cycle metabolite α-ketoglutarate (α-KG), probably reason for TET activity inhibition. Mice and cells supplementation with α-KG ameliorates As-induced alteration of Pdgfb methylation and hydroxymethylation, and improves As-induced the weakening of angiogenic ability, and prevents As-induced fetal growth restriction in mice. In case-control study, maternal serum α-KG content and placental PDGFB content were negatively correlated with the urinary As concentration, while placental PDGFB content was positively correlated with birth weight. Collectively, prenatal As exposure impairs placental angiogenesis through altering Pdgfb epigenetic programming.