Dexamethasone as an emerging environmental pollutant: Disruption of cholesterol-dependent synaptogenesis in the hippocampus and subsequent neurobehavioral impacts in offspring

When fetuses are exposed to abnormally high levels of glucocorticoids in utero, irreversible damage to neuronal synaptogenesis occurs, leading to long-term cognitive and emotional behavioral abnormalities after birth. In this study, we investigated how maternal exposure to a novel environmental pollutant-synthetic glucocorticoid dexamethasone-affects offspring cognitive and emotional behaviors enduringly. We noted that offspring subjected to maternal dexamethasone exposure (MDE) displayed cognitive and emotional neurobehavioral deficits beginning in infancy, and these impairments persisted into adulthood. The principal mechanism involves MDE-induced damage to hippocampal neuronal synapse formation in the offspring, primarily due to a cholesterol deficiency which destabilizes neuronal membranes, thereby affecting normal synapse formation and ultimately leading to cognitive and emotional deficiencies. Specifically, we demonstrated abnormal activation of glucocorticoid receptors in hippocampal astroglial cells of MDE offspring, which triggers changes in the miR-450a-3p/HAT1/ABCG1 signaling axis, causing impaired cholesterol efflux in astroglial cells and insufficient cholesterol supply to neurons, further impairing synaptogenesis. This research not only underscores the significant impact of prenatal environmental pollutants on long-term health outcomes in offspring but also broadens our understanding of how prenatal exposure to glucocorticoids affects brain development in the progeny, providing new insights for interventions in neurodevelopmental and psychiatric disorders of fetal origin.