Bisphenol S disrupts neuronal morphogenesis in human neural cells by overactivating NMDA receptor-Ca2+ signaling.

Bisphenol S (BPS), an emerging substitute of bisphenol A, is widely used in consumer products. However, its neurodevelopmental toxicity and underlying mechanisms remain poorly understood. Using a three-stage human embryonic stem cell (hESC-H9) neural differentiation model, cells were exposed to 375 μM BPS, 375 μM BPS + 5 μM NMDAR inhibitor (MK801), 375 μM BPS + 5 μM ERK pathway inhibitor (U0126), and a 0.1% DMSO solvent control, respectively. High-content screening, qPCR, and Western blot were utilized to analyze neuromorphology, intracellular Ca2+ levels, and related genes/proteins expression. Results showed that NMDAR inhibition effectively rescued BPS-induced Ca2+ dyshomeostasis and deficits in neurite complexity. Both NMDAR and ERK inhibition exacerbated apoptosis at the precursor stage but effectively reduced it at post-maturation stages. Mechanistically, BPS hyperactivates NMDAR, leading to Ca2+ influx as the primary event, which suppresses BDNF and synaptic proteins, impairing synaptogenesis and promoting apoptosis. ERK is activated downstream but independently regulates neuronal morphology rather than serving as a linear executor of NMDAR-driven toxicity. Collectively, NMDAR is the pivotal mediator of BPS neurotoxicity, and the NMDAR-ERK axis involves both convergent and divergent mechanisms, underscoring the need for stage-specific neuroprotective strategies.