Environmentally
Relevant Concentrations of Tetrabromobisphenol
A Exposure Impends Neurovascular Formation through Perturbing Mitochondrial
Metabolism in Zebrafish Embryos and Human Primary Endothelial Cells
posted on 2024-03-13, 20:30authored byXiangyu Zeng, Shengtao Ma, Yijun Luo, Yangjian Zhang, Qi Wang, Zhuyi Zhang, Weijian Ke, Ya Ma, Haichen Hu, Thomas Hartung, Yanhong Wei, Xiali Zhong
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.