Concentration-Specific Neurotoxic Pathways of Tetrabromobisphenol A and Tetrabromobisphenol A Bis(2-Hydroxyethyl Ether) in Zebrafish Larvae

Tetrabromobisphenol A (TBBPA) and its derivative, TBBPA bis-(2-hydroxyethyl ether) (TBBPA-BHEE), are widely used brominated flame retardants commonly detected in environmental media and biota. While regulatory bodies deem these chemicals unlikely to pose significant risks, emerging evidence highlights their potential neurotoxic effects. In this study, we evaluated the neurodevelopmental toxicity of TBBPA and TBBPA-BHEE in zebrafish embryos exposed to nonlethal (94-470 μg/L for TBBPA, 610-2030 μg/L for TBBPA-BHEE) and environmentally relevant concentrations (0.094-0.47 μg/L for TBBPA, 0.061-0.203 μg/L for TBBPA-BHEE) for up to 120 h postfertilization (hpf). Our findings show that at nonlethal concentrations, both TBBPA and TBBPA-BHEE impaired craniofacial development, induced apoptosis, reduced γ-aminobutyric acid (GABA) levels, and disrupted motor behavior, with significant alterations in the expression of genes involved in GABAergic signaling and synaptic plasticity. Transcriptomic and miRNA profiling revealed that downregulation of GABA receptor genes and miRNAs (e.g., let-7i, miR-192,) contributed to neurodevelopmental defects through disruption of CREB signaling and synaptogenesis. In contrast, exposure to environmentally relevant concentrations induced similar phenotypes (craniofacial malformations and apoptosis) without major changes in neurotransmitter levels, suggesting that low-dose neurotoxicity might be mediated by alternative, less understood mechanisms, possibly involving epigenetic modifications or compensatory neuronal adaptations. These findings underscore the complexity of low-dose toxicity and the need for further research into the molecular pathways underlying the neurotoxic effects of TBBPA and its derivatives, particularly at environmentally relevant concentrations.