Transformation of BPS to TBBPS in Brominated Wastewater Increases Toxicity: Evidence from Zebrafish Development

Herein, we compared the developmental and neurotoxic effects of Bisphenol S (BPS) and Tetrabromobisphenol S (TBBPS) on zebrafish embryos at their environmentally relevant concentrations. Both compounds induced dose-dependent malformations like delayed hatching, shortened somites, spinal curvature, and brain deformities. TBBPS was significantly more toxic (LC₅₀ = 5.73   mg/L) than BPS (LC₅₀ = 65.2   mg/L), with the 24-48   hours post-fertilization window being most sensitive. TBBPS caused more spinal/circulatory defects, while BPS induced more eye/pericardial issues. Target prediction identified 228 genes for BPS and 165 for TBBPS, both enriched in FoxO, P53, and hormone signaling. BPS primarily affected MAPK and neurotrophin pathways, whereas TBBPS targeted PI3K-Akt and receptor-mediated carcinogenesis pathways. Both triggered brain/spinal oxidative stress, reduced neurogenesis, increased apoptosis, and impaired neurotransmission, evidenced by decreased serotonin (5-HT) and suppressed acetylcholinesterase (AChE) activity, leading to abnormal behavior. Hub gene analysis revealed distinct mechanisms: BPS disrupted neuronal proliferation via genes like Cdk2 , Cdk6 , Tyms; TBBPS interfered with the cell cycle via Plk4, Ccnb2. RT-qPCR confirmed these differences. TBBPS exhibits stronger developmental and neurotoxicity than BPS, indicating bromination significantly increases toxicity, providing a basis for environmental risk assessment of bisphenol analogs.