Bisphenol mixture impairs offspring social memory via an H4K8 Lactylation-Fyn-Microglial synaptic pruning axis

Bisphenol A (BPA) and its structural analogs, i.e., bisphenol S (BPS) and bisphenol F (BPF), are commonly incorporated into consumer products, resulting in simultaneous human exposure to multiple bisphenols. Prospective cohort studies have linked prenatal exposure to individual bisphenols to disrupted neurodevelopment and cognitive dysfunction; however, the mechanisms by which bisphenol mixtures affect neural health remain underexplored. Here, we show that maternal exposure to an environmentally relevant bisphenol mixture during pregnancy and lactation elicits aberrant microglial activation in male offspring, mediated by estrogen receptor β-dependent metabolic reprogramming. This exposure enhances microglial glycolytic activity and histone H4K8 lactylation, thereby directly boosting Fyn transcription. Elevated Fyn expression accelerates microglia-mediated synaptic pruning, leading to decreased hippocampal synaptic density and subsequent deficits in social memory. Notably, genetic and pharmacological suppression of microglial activity, including microglial ablation and selective Fyn inhibition during the exposure period, substantially alleviates these synaptic deficits and behavioral impairments. Similar microglia-dependent synaptic abnormalities are further validated in cell-based and human brain organoid co-culture models. Together, these results reveal a previously unrecognized metabolic-epigenetic pathway by which chemical mixtures disrupt neurodevelopment, emphasizing the critical importance of examining the neurodevelopmental consequences of exposure to real-world chemical mixture during early development.