Gestational and Lactational Exposure to BPS Triggers Microglial Ferroptosis via the SLC7A11/GPX4 Antioxidant Axis and Induces Memory Impairment in Offspring Mice

This study aimed to examine the role of maternal BPS gestational and lactational exposure to BPS in neurotoxicity in offspring <i>mice</i> and to uncover the regulatory mechanisms driven by microglial ferroptosis. In this study, C57BL/6J <i>mice</i> were treated with BPS during pregnancy and lactation. The results revealed that BPS induced memory impairment and anxiety in offspring <i>mice</i>, accompanied by abnormal expression levels of brain neurotrophic factor and synaptic plasticity factor (PSD95, SYP). Additionally, exposure to BPS activated microglia by upregulating the expression of IBA1 and concurrently promoting the release of inflammatory factors in the hippocampus and cortex. BPS exposure also contributed to iron overload, aberrant mitochondrial morphology, oxidative stress, and abnormal expression of ferroptosis-associated genes (GPX4, SCL7A11, TFR1, ACSL4) in the brains of offspring <i>mice</i>. Importantly, immunofluorescence analysis demonstrated concomitant microglial activation and ferroptosis in the brain tissue of offspring <i>mice</i> following BPS exposure. Moreover, experiments in BV2 microglial cells showed that the ferroptosis inhibitor Fer-1 reversed BPS-induced microglial ferroptosis and the release of inflammatory cytokines. These findings collectively elucidate the regulatory role mechanism of microglial ferroptosis in BPS-induced neurotoxicity in offspring <i>mice</i>, and we propose potential therapeutic targets for attenuating BPS-mediated neurotoxic effects.