Bis(2-ethylhexyl)tetrabromophthalate disrupts thyroid hormone signaling and causes visual impairment in zebrafish larvae.

Bis(2-ethylhexyl)tetrabromophthalate (TBPH), a ubiquitous novel brominated flame retardant (NBFR), has been reported to disrupt thyroid hormone (TH) homeostasis and induce abnormal phototactic behavior in zebrafish larvae. However, the mechanisms by which TBPH interferes with the thyroid system remain unclear, and it is still unknown whether such endocrine disruption leads to structural impairments in retinal development. Here, we hypothesize that TBPH disrupts the hypothalamic-pituitary-thyroid (HPT) axis, impairs the TH signaling pathway, and ultimately leads to visual dysfunction during early development. Our results indicated that TBPH exposure cause structural damage in zebrafish larvae, including decreased eye size, reduced retinal layer thickness and decreased cell density in the ganglion cell layer (GCL). Meanwhile, during the light-dark cycle assay, zebrafish larvae exhibited abnormal locomotor behavior accompanied by heightened sensitivity to light. Molecular docking analyses suggested that TBPH could bind competitively to transthyretin (TTR), which may be a primary mechanism disrupting HPT axis homeostasis. In addition, TBPH exposure led to upregulation of key genes related to retinal development and opsins, suggesting a potential compensatory response to retinal injury. This study provides novel mechanistic insights into NBFR toxicity and highlights new perspectives about safe alternatives to environmental pollutants.