Perinatal BPS exposure induces offspring neurotoxicity via ferroptosis mediated by the SLC7A11/GPX4 pathway.

Bisphenol S (BPS), a common substitute for bisphenol A, has raised considerable concern due to its potential neurotoxicity. However, the understanding of generational effect of BPS on neurotoxic effect is still unclear. Herein, parental pregnant mice and HT22 cells were exposed to varying BPS concentrations to investigate its neurotoxicity on offspring mice and explore the role of ferroptosis in this process. These results revealed a spatial memory and synaptic impairment in offspring mice after early BPS exposure, characterized by hippocampal pathological damage and decreased expression of PSD95, SYP, and BDNF. as evidenced by increased lipid peroxidation, iron accumulation, disrupted mitochondrial ultrastructure, and altered expression of ferroptosis-related proteins (SLC7A11, GPX4, FTH1, and ACSL4). Furthermore, Fer-1 pre-treatment mitigated lipid peroxidation and iron overload while restoring the expression of SLC7A11, GPX4, PSD95, and SYP in HT22 cells. Collectively, our results demonstrate that perinatal BPS exposure causes neurotoxicity in offspring, which is mediated by ferroptosis through the SLC7A11/GPX4 pathway. This report lays the foundation investigating the correlation between BPS neurotoxicity and ferroptosis, and offers novel insights for assessing the multigenerational toxicity of BPS.