Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, Guangdong, China.
Department of Forensic Medicine, Shantou University Medical College, Shantou 515041, Guangdong, China.
Ecotoxicol Environ Saf. 2024 Feb;271:115960. doi: 10.1016/j.ecoenv.2024.115960. Epub 2024 Jan 13.
Triphenyl phosphate (TPhP) serves as a major organophosphorus flame retardant, and its induced neurodevelopmental toxicity has attracted widespread attention, but the mechanism remains unclear. In this study, we involved zebrafish to explore the new mechanism of TPhP inducing oxidative stress and ferroptosis to promote neurodevelopmental toxicity. The results suggested that TPhP affected the embryonic development, reduced the number of new neurons, and led to abnormal neural behavior in zebrafish larvae. TPhP also induced ROS accumulation, activated the antioxidant defense signal Nrf2 and Keap1, and significantly changed the activities of Acetylcholinesterase (AChE), Adenosine triphosphatase (ATPase) and glutathione S-transferase (GST). In addition, TPhP induced ferroptosis in zebrafish, which was reflected in the increase of Fe content, the abnormal expression of GPX4 protein and genes related to iron metabolism (gpx4a, slc7a11, acsl4b, tfa, slc40a1, fth1b, tfr2, tfr1a, tfr1b and ncoa4). Astaxanthin intervention specifically inhibited ROS levels, and reversed SLC7A11 and GPX4 expression levels and Fe metabolism thus alleviating ferroptosis induced by TPhP. Astaxanthin also partially reversed the activity of AChE, GST and the expression of neurodevelopmental-related genes (gap43, gfap, neurog1 and syn2a), so as to partially rescue the embryonic developmental abnormalities and motor behavior disorders induced by TPhP. More interestingly, the expression of mitochondrial apoptosis-related protein BAX, anti-apoptotic protein BCL-2, Caspase3 and Caspase9 was significantly altered in the TPhP exposed group, which could be also reversed by Astaxanthin intervention. In summary, our results suggested that TPhP exposure can induce oxidative stress and ferroptosis, thereby causing neurodevelopment toxicity to zebrafish, while Astaxanthin can partially reverse oxidative stress and reduce the neurodevelopmental toxicity of zebrafish larvae by activating Nrf2/Keap1/HO-1 signaling pathway.
磷酸三苯酯（TPhP）作为一种主要的有机磷阻燃剂，其诱导的神经发育毒性引起了广泛关注，但具体机制尚不清楚。在本研究中，我们使用斑马鱼来探索 TPhP 诱导氧化应激和铁死亡从而促进神经发育毒性的新机制。结果表明，TPhP 影响胚胎发育，减少新神经元的数量，并导致斑马鱼幼虫神经行为异常。TPhP 还诱导 ROS 积累，激活抗氧化防御信号 Nrf2 和 Keap1，并显著改变乙酰胆碱酯酶（AChE）、三磷酸腺苷酶（ATPase）和谷胱甘肽 S-转移酶（GST）的活性。此外，TPhP 诱导斑马鱼发生铁死亡，表现为铁含量增加、GPX4 蛋白及铁代谢相关基因（gpx4a、slc7a11、acsl4b、tfa、slc40a1、fth1b、tfr2、tfr1a、tfr1b 和 ncoa4）异常表达。虾青素干预特异性抑制 ROS 水平，并逆转 SLC7A11 和 GPX4 表达水平及铁代谢，从而缓解 TPhP 诱导的铁死亡。虾青素还部分逆转了 AChE、GST 和神经发育相关基因（gap43、gfap、neurog1 和 syn2a）的活性，从而部分挽救 TPhP 诱导的胚胎发育异常和运动行为障碍。更有趣的是，TPhP 暴露组中与线粒体凋亡相关的蛋白 BAX、抗凋亡蛋白 BCL-2、Caspase3 和 Caspase9 的表达明显改变，虾青素干预也可以逆转这种改变。总之，我们的结果表明，TPhP 暴露可诱导氧化应激和铁死亡，从而导致斑马鱼神经发育毒性，而虾青素可通过激活 Nrf2/Keap1/HO-1 信号通路部分逆转氧化应激，降低斑马鱼幼虫的神经发育毒性。
