Astrocyte activation mediates UV filter PBSA-induced impairment of neurogenesis via the rxrga/tsp-1 axis during a sensitive developmental window in early life stage zebrafish

2-phenylbenzimidazole-5-sulfonic acid (PBSA), a widely used organic UV filter, is frequently detected in aquatic environments, yet its developmental neurotoxicity (DNT) remains poorly understood. Here, we exposed zebrafish embryos to 0.1-1000 μg/L PBSA and identified 10 μg/L as the effective concentration and 6-48 hours post-fertilization (hpf) as the sensitive developmental window for PBSA-induced DNT. Exposure to 10 μg/L PBSA during the critical window led to a significant increase in reactive oxygen species (ROS) levels and inflammatory response, accompanied by astrocyte activation in specific brain region (elevated GFAP, S100B, and glutamine synthetase), while neurogenesis was inhibited independent of apoptosis. Moreover, PBSA exposure upregulated retinoid X receptor gamma (rxrga) expression and downregulated thrombospondin-1 (tsp-1) expression, with rxrga positively correlated with astrocyte activation markers and negatively correlated with tsp-1 levels. Knockdown of rxrga using morpholino rescued PBSA-induced tsp-1 suppression, neurogenesis impairments, and behavioral abnormalities at 120 hpf, while leaving astrocyte activation unaffected, suggesting that astrocyte activation may operate upstream of rxrga. Collectively, these findings demonstrate that PBSA exposure during a sensitive developmental window induces DNT through oxidative stress, inflammation, and astrocyte activation, with the rxrga/tsp-1 axis mediating neurogenesis inhibition. This study provides mechanistic insights into PBSA-induced neurotoxicity and emphasizes the importance of incorporating DNT assessment in UV filter safety evaluation.