Low-dose exposure of Bisphenol A and placenta small extracellular vesicles: effects on oxidative stress in vitro and in vivo

Bisphenol A (BPA) is an organic synthetic compound commonly used as a monomer in the production of phenolic resins and polycarbonate plastic products including food packaging, healthcare equipment, and items for babies and children. It can migrate from these products into their contents and enter our bodies. As an endocrine-disrupting compound (EDC), BPA interferes with the function of endocrine, reproductive, immune, cardiovascular, and nervous system functions, making exposure potentially harmful to human and animal health. Studies have shown that maternal exposure to EDCs at environmentally relevant concentrations affects early embryo development and uterine receptivity through their estrogenic activity. BPA has been detected in the brain, indicating its ability to cross the blood-brain barrier (BBB), therefore increasing the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), as well as central nervous system (CNS) neurodegenerative diseases like Alzheimer’s and Parkinson’s. BPA can also disrupt normal endocrine functions, which are crucial for healthy pregnancy. The placenta facilitates bidirectional communication between mother and fetus, providing oxygen and nutrients to the developing baby, and removing waste from the fetus’ bloodstream. It also plays an active role through in the synthesis and release of “informational” factors into the maternal and fetal circulation. Of particular interest is the potential action of small extracellular vesicles (sEV) produced by the placenta in modulating BPA damaging effects. This study focuses on the placenta-brain axis, which is central to pathological conditions associated with significant placental insufficiency—a risk factor for nervous system-related diseases. The nervous system contains neurons and various excitable and non-excitable cells called neuroglia. Astrocytes, named for their star-like shape, are the most abundant glial cells. Through their communication with blood vessels, neurons and other glial cells, astrocytes play a crucial role in maintaining nervous system homeostasis. We hypothesized that the placental sEV modulate astrocytes’ physiological response of following their BPA-induced activation toward a pro-oxidative phenotype. Our in vitro studies demonstrated that direct exposure to BPA triggers an oxidative response in these cells, compromising their viability. By mimicking in vivo conditions—where both direct and placenta-mediated effects of BPA on astrocytes occur—we revealed the placenta’s pivotal role in maintaining astrocyte redox status. Using a mouse model, we examined whether astrocytes were also targets of BPA exposure in vivo and whether placenta sEV could mitigate the damage of this chemical, providing insights into the complex relationship between the placenta, its secretome, and brain development.