Tetrabromobisphenol A (TBBPA), the most extensively utilized brominated flame retardant, has raised growing concerns regarding its environmental and health risks. Neurovascular formation is essential for metabolically supporting neuronal networks. However, previous studies primarily concerned the neuronal injuries of TBBPA, its impact on the neurovascularture, and molecular mechanism, which are yet to be elucidated. In this study, 5, 30, 100, 300 μg/L of TBBPA were administered to Tg (fli1a: eGFP) zebrafish larvae at 2–72 h postfertilization (hpf). The findings revealed that TBBPA impaired cerebral and ocular angiogenesis in zebrafish. Metabolomics analysis showed that TBBPA-treated neuroendothelial cells exhibited disruption of the TCA cycle and the Warburg effect pathway. TBBPA induced a significant reduction in glycolysis and mitochondrial ATP production rates, accompanied by mitochondrial fragmentation and an increase in mitochondrial reactive oxygen species (mitoROS) production in neuroendothelial cells. The supplementation of alpha-ketoglutaric acid, a key metabolite of the TCA cycle, mitigated TBBPA-induced mitochondrial damage, reduced mitoROS production, and restored angiogenesis in zebrafish larvae. Our results suggested that TBBPA exposure impeded neurovascular injury via mitochondrial metabolic perturbation mediated by mitoROS signaling, providing novel insight into the neurovascular toxicity and mode of action of TBBPA.

中文翻译：

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环境相关浓度的四溴双酚 A 暴露通过扰乱斑马鱼胚胎和人原代内皮细胞的线粒体代谢来阻碍神经血管的形成

四溴双酚 A (TBBPA) 是使用最广泛的溴化阻燃剂，其环境和健康风险引起了越来越多的关注。神经血管的形成对于代谢支持神经元网络至关重要。然而，以往的研究主要集中在TBBPA对神经元的损伤、对神经血管的影响以及分子机制等方面，尚待阐明。在本研究中，在受精后 2-72 小时 (hpf) 时，对Tg (fli1a: eGFP) 斑马鱼幼虫施用 5、30、100、300 μg/L 的 TBBPA 。研究结果表明，TBBPA 会损害斑马鱼的脑部和眼部血管生成。代谢组学分析表明，TBBPA 处理的神经内皮细胞表现出 TCA 循环和 Warburg 效应途径的破坏。 TBBPA 诱导糖酵解和线粒体 ATP 生成速率显着降低，并伴有神经内皮细胞中线粒体断裂和线粒体活性氧 (mitoROS) 生成增加。补充α-酮戊二酸（TCA 循环的关键代谢物）可减轻 TBBPA 诱导的线粒体损伤，减少 mitoROS 的产生，并恢复斑马鱼幼虫的血管生成。我们的结果表明，TBBPA 暴露通过 mitoROS 信号传导介导的线粒体代谢扰动阻止神经血管损伤，为 TBBPA 的神经血管毒性和作用模式提供了新的见解。