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bioRxiv · 10.64898/2026.06.20.733535

Bisphenol S causes deficits in social behaviour by disrupting serotonergic and BDNF-CREB1 signaling pathways

Hasan, A. K. M. M.·Rachamalla, M.·Nigoyi, S.·Chivers, D. P.
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Abstract

Bisphenol S (BPS), a widely used substitute for bisphenol A, is increasingly detected in aquatic environments; however, its neurodevelopmental effects remain insufficiently understood. This study investigated whether developmental exposure to an environmentally relevant concentration of BPS disrupts social behaviour and underlying neurobiological pathways in zebrafish (Danio rerio). At 21 days post-fertilization, BPS-exposed larvae exhibited a significant reduction in social preference, indicating impaired conspecific interactions. Neurochemical analysis revealed a marked increase in serotonin (5-HT) levels, whereas lipid peroxidation (MDA) remained unchanged, suggesting the absence of overt oxidative damage. Gene expression profiling demonstrated a dysregulated antioxidant response, suppression of apoptotic signaling, and pronounced upregulation of serotonergic receptors and transporters. To resolve system-level mechanisms, protein-protein interaction (PPI) network analysis identified BDNF and CREB1 as dominant regulatory hubs, with the serotonergic synapse pathway as the most significantly enriched term. Molecular docking further demonstrated direct binding of BPS to multiple serotonergic targets, including HTR1A and TPH2, supporting receptor-level interference. Expanded network and pathway analyses revealed coordinated enrichment of monoamine GPCR, oxidative stress, and inflammatory pathways. These findings demonstrate that BPS induces serotonergic dysregulation and network-level reprogramming rather than significant oxidative damage, leading to behavioural impairment. This study provides a multi-scale mechanistic framework linking molecular perturbations to neurobehavioural outcomes, identifying serotonergic signaling and BDNF-CREB1 pathways as central targets of BPS neurotoxicity.

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Hasan, A. K. M. M., Rachamalla, M., Nigoyi, S., Chivers, D. P.. 2026-06-25. Bisphenol S causes deficits in social behaviour by disrupting serotonergic and BDNF-CREB1 signaling pathways. https://doi.org/10.64898/2026.06.20.733535

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