Placental small extracellular vesicles as modulators of bisphenol A-induced oxidative stress and mitochondrial activation in human astrocytoma cells (U-373 MG)

: Astrocytes play a crucial role in maintaining central nervous system homeostasis, supporting neuronal function and regulating oxidative stress. The placenta, through the secretion of small extracellular vesicles (sEVs), facilitates communication between the maternal and fetal environments, potentially mitigating external stressors. Bisphenol A (BPA), an endocrine disruptor, has been implicated in oxidative stress and mitochondrial dysfunction, particularly in the developing brain. However, the mechanisms by which placental sEVs influence astrocyte responses to BPA remain unclear. This study investigates the effects of BPA on astrocyte oxidative stress and mitochondrial activity and explores how placental sEVs modulate these responses. Human glioblastoma astrocytoma (U-373 MG) cells were exposed to environmentally relevant concentrations of BPA (10 nM), with or without placental sEVs isolated from human term placental explants. Reactive oxygen species (ROS) levels, mitochondrial activation, and antioxidant enzyme expression (SOD1, GCLC, and GSTA) were assessed. Direct BPA exposure increased astrocyte ROS levels and mitochondrial activation, indicative of oxidative stress. Placental sEVs were rapidly internalized by astrocytes and counteracted BPA-induced ROS accumulation, restoring mitochondrial homeostasis. Notably, sEVs from BPA-exposed placental explants were more efficiently incorporated into astrocytes, suggesting an adaptive response. sEVs treatment also upregulated antioxidant enzyme expression and reduced inflammatory cytokine markers (CCL2 and IL-1β), indicating a potential protective mechanism. These findings suggest that placental sEVs play a critical role in modulating astrocyte responses to oxidative stress and mitochondrial dysfunction. The ability of sEVs to restore redox homeostasis highlights their potential physiological function in fetal neuroprotection against environmental stressors.NEW & NOTEWORTHY The study demonstrates that BPA induces oxidative stress and mitochondrial dysfunction in human astrocytes. It introduces a novel role of sEVs in counteracting these effects by reducing ROS, restoring mitochondrial activity, and upregulating antioxidant enzymes. Notably, sEVs from BPA-exposed placental explants were more efficiently incorporated into astrocytes, suggesting an adaptive protective mechanism. These findings highlight a potential fetal neuroprotective role of placental sEVs against environmental stressors.