Bis(2ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), a replacement for restricted flame retardants, has become ubiquitous in the environment. To reveal the neurotoxicity and underlying mechanism of TBPH, we first evaluated its penetrability through the blood-brain barrier (BBB) using hCMEC/D3 cells as in vitro model, and found TBPH had poor penetrability through BBB with a maximum Papp of 14.8 × 10⁻⁶ cm s⁻¹. Further study using transgenetic zebrafish (Tg flk1: EGFP) as in vivo model confirmed that TBPH could affect the BBB permeability, probably via affecting the transcription of genes encoding tight junction proteins. Finally, wild type zebrafish embryos/larvae were exposed to TBPH to evaluate the neurotoxicity. The neurodevelopment, neurotransmitters and locomotor activity of zebrafish larvae did not changed, which may be because TBPH can hardly cross the BBB to pose direct exposure to the central nervous system. However, the transcription of opsins genes and visual response to light stimulation in zebrafish larvae were inhibited, pointing to additional mechanism that may cause visual impairment indirectly. Above all, these results can help further understand the neurotoxicity and underlying mechanism by TBPH, and also pointed out potential risk of this chemical to aquatic organisms.

双（2乙基己基）-2,3,4,5-四溴邻苯二甲酸酯 (TBPH) 是受限阻燃剂的替代品，已在环境中无处不在。为了揭示 TBPH 的神经毒性和潜在机制，我们首先使用 hCMEC/D3 细胞作为体外模型评估其通过血脑屏障 (BBB) 的穿透性，发现 TBPH 通过 BBB 的穿透性较差，最大 Papp 为 14.8 × 10 ^-6厘米· 秒^-1。使用转基因斑马鱼 ( Tg flk1: EGFP ) 作为体内模型的进一步研究证实 TBPH 可能影响 BBB 通透性，可能通过影响编码紧密连接蛋白的基因的转录。最后，将野生型斑马鱼胚胎/幼虫暴露于 TBPH 以评估神经毒性。斑马鱼幼虫的神经发育、神经递质和运动活动没有改变，这可能是因为TBPH几乎不能穿过血脑屏障直接暴露于中枢神经系统。然而，斑马鱼幼虫中视蛋白基因的转录和对光刺激的视觉反应受到抑制，这表明可能间接导致视力障碍的其他机制。最重要的是，这些结果有助于进一步了解 TBPH 的神经毒性和潜在机制，并指出这种化学物质对水生生物的潜在风险。