PD-1/PD-L1 mediated glycolysis-driven M1 polarization of Hofbauer cells impairs placental and fetal development following maternal mixed bisphenols exposure.

Real-world gestational bisphenols (BPs) exposure typically occurs as complex mixtures and is associated with placental dysfunction as well as impaired fetal growth. However, the underlying mechanisms remain poorly defined. This study investigated how environmentally relevant mixed BPs disrupt placental immune homeostasis and fetal development. Maternal mixed BPs exposure induced placental pro-inflammatory milieu and impaired placental development, leading to fetal growth restriction (FGR) by promoting M1 polarization of Hofbauer cells (HBCs), particularly at mid-gestation. Functionally, M1 macrophage compromised trophoblast migration and invasion in co-culture system. Mechanistically, mixed BPs exposure disrupted the PD-1/PD-L1 immune checkpoint through downregulating the expression of PD-L1 in trophoblasts and PD-1 in HBCs, which may contribute to activation of the PI3K/AKT/mTOR/HIF-1α axis and glycolytic reprogramming that favored M1 HBCs polarization. Additionally, restoration of PD-1/PD-L1 signaling using PD-L1-Fc attenuated HBCs glycolytic reprogramming and reduced M1 polarization, with partially ameliorated placental inflammation and FGR induced by mixed BPs. Collectively, our results support PD-1/PD-L1-associated metabolic reprogramming of HBCs as an important contributing mechanism linking maternal mixed BPs exposure to adverse pregnancy outcomes. These findings provide new insights into the immune-metabolic basis of environmental stress-induced pregnancy complications and offer a mechanistic foundation for developing prevention strategies against gestational exposure to pollutant mixtures.