Bisphenol S induces developmental neurotoxicity by disrupting Lar function in Drosophila melanogaster

Bisphenol S (BPS), a widely used substitute for Bisphenol A (BPA), has been implicated in neurodevelopmental disorders by numerous studies. While BPS has been known for neurodevelopmental disturbance, the analysis and molecular mechanisms underlying the neurotoxicity are not completely understood. This study utilizes a Drosophila model to investigate the developmental neurotoxicity of BPS and its underlying molecular mechanisms. The results demonstrate that BPS exposure significantly induces abnormal behaviors in Drosophila, including social interaction deficits, increased self-grooming, and impaired locomotor activity. Moreover, BPS disrupts axonal development, leading to abnormal α and β lobes in the mushroom body (MB) and structural damage in the neuromuscular junction (NMJ). NMJ defects are marked by reductions in area, length, perimeter, bouton number, branching, and overall morphological integrity. A genome-wide association study (GWAS) identified Lar as a key mediator of BPS-induced neurotoxicity. Molecular docking simulations and Western blot analyses further confirmed that BPS interferes with the cytoplasmic functions of Lar. Notably, neuronal overexpression of Lar's cytoplasmic domain rescued MB and NMJ defects and mitigated BPS-induced behavioral abnormalities. These findings suggest that BPS impairs Lar function, thereby disrupting MB and NMJ morphology and ultimately inducing abnormal behaviors in Drosophila.