Zhang Qiong, Zheng Shukai, Shi Xiaoling, Luo Congying, Huang Wenlong, Lin Henghui, Peng Jiajun, Tan Wei, Wu Kusheng
Department of Preventive Medicine, Shantou University Medical College, Shantou 515041, Guangdong, China.
Department of Burns and Plastic Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China.
Environ Int. 2023 Feb;172:107745. doi: 10.1016/j.envint.2023.107745. Epub 2023 Jan 10.
As a substitute for polybrominated diphenyl ethers (PBDEs), organophosphate flame retardant triphenyl phosphate (TPhP) is widely used in our daily products and diffusely exists in our living surroundings, but there is a paucity of information concerning its neurodevelopmental toxicity. Herein, we investigated the effects of TPhP exposure on developmental parameters, locomotor behavior, oxidative stress, apoptosis and transcriptional levels in zebrafish at different developmental stages, so as to explore the effects of TPhP exposure on zebrafish neural development and the underlying molecular mechanisms. TPhP concentration gradient exposure reduced the survival rate, hatchability, heart rate, body length and eye distance of zebrafish embryos/larvae, and caused malformations of zebrafish larvae. TPhP also leads to abnormal locomotor behaviors, such as reduced swimming distance and swimming speed, and impaired panic avoidance reflex to high light stimulation. TPhP caused ROS accumulation in 96 hpf larvae and induced Nrf2-antioxidant response in zebrafish. In addition, TPhP further activated mitochondrial signaling pathways, which affected apoptosis in the zebrafish eye region, resulting in visual impairment. Neurodevelopmental (mbpa, syn2a, foxo3a and pax6a), Retinoid acid metabolism (cyp26a1, raraa, rbp5, rdh1, crabp1a and rbp2a) and apoptosis-related genes (bcl2a, baxa and casp9) revealed the molecular mechanism of abnormal behavior and phenotypic symptoms, and also indicated that 96 hpf larvae are more sensitive than 7 dpf larvae. Thus, in the present study, we revealed the neurotoxic effects of TPhP at different early life stages in zebrafish, and zebrafish locomotor behavior impairments induced by TPhP exposure are attributed to co-regulation of visuomotor dysfunction and neuro-related genes. These results suggest that the safety of TPhP in organisms and even in humans needs to be further studied.
作为多溴二苯醚（PBDEs）的替代品，有机磷酸酯阻燃剂磷酸三苯酯（TPhP）广泛应用于我们的日常用品中，并广泛存在于我们的生活环境中，但关于其神经发育毒性的信息却很少。在此，我们研究了TPhP暴露对不同发育阶段斑马鱼的发育参数、运动行为、氧化应激、细胞凋亡和转录水平的影响，以探讨TPhP暴露对斑马鱼神经发育的影响及其潜在的分子机制。TPhP浓度梯度暴露降低了斑马鱼胚胎/幼体的存活率、孵化率、心率、体长和眼间距，并导致斑马鱼幼体畸形。TPhP还导致异常的运动行为，如游泳距离和游泳速度降低，以及对强光刺激的惊恐回避反射受损。TPhP导致96小时pf幼体中活性氧积累，并诱导斑马鱼中的Nrf2抗氧化反应。此外，TPhP进一步激活线粒体信号通路，影响斑马鱼眼部区域的细胞凋亡，导致视力受损。神经发育（mbpa、syn2a、foxo3a和pax6a）、视黄酸代谢（cyp26a1、raraa、rbp5、rdh1、crabp1a和rbp2a）和凋亡相关基因（bcl2a、baxa和casp9）揭示了异常行为和表型症状的分子机制，也表明96小时pf幼体比7天pf幼体更敏感。因此，在本研究中，我们揭示了TPhP在斑马鱼不同早期生命阶段的神经毒性作用，并且TPhP暴露诱导的斑马鱼运动行为损伤归因于视觉运动功能障碍和神经相关基因的共同调节。这些结果表明，TPhP在生物体甚至人类中的安全性需要进一步研究。
