Isopropylate Triphenyl Phosphate (IPPP), a novel organophosphorus flame retardant, has become a widespread environmental pollutant. However, the toxic effects and mechanisms of IPPP remain unclear. In this study, we evaluated the neurodevelopmental toxicity effects of IPPP on zebrafish embryonic development, neurobehavior, and physiological and transcriptomic changes. The results showed that IPPP induced adverse developments such as low survival rates and hatching rates, decreased body length and eye distance, and also led to increased heart rates and embryonic malformation rates. The developmental defects mainly included typical pericardial edema, eye deformities, and a reduction in the number of newborn neurons. Mitochondrial energy metabolism disorders and apoptosis of cardiomyocytes may be responsible for heart malformation. Behavioral results showed that IPPP caused abnormal changes in swimming speed, total swimming distance and trajectory, and showed a low-dose effect. In addition, the decreased activity of neurotransmitters such as acetylcholinesterase (AchE) and dopamine (DA), and the changes in genes related to the central nervous system (CNS) and metabolism pathway may be the causes of neurodevelopmental toxicity of IPPP. Meanwhile, IPPP induced oxidative stress and apoptosis, and changed the ATPase activity of zebrafish larvae by altering nuclear factor erythroid2-related factor 2 (Nrf2) and mitochondrial signaling pathways, respectively. Transcriptome sequencing results indicated that Cytochrome P450 and drug metabolism, Energy metabolism-related pathways, Glutathione metabolism, Retinoid acid (RA) and REDOX signaling pathways were significantly enriched, and most of the genes in these pathways were up-regulated after IPPP treatment, which may be new targets for IPPP-induced neurodevelopment. In summary, the results of this study provide an important reference for a comprehensive assessment of the toxic effects and health risks of the new pollutant IPPP.

中文翻译：

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斑马鱼 (Danio rerio) 对磷酸三苯异丙酯 (IPPP) 暴露的反应的生理和转录组变化


磷酸三苯异丙酯（IPPP）是一种新型有机磷阻燃剂，已成为一种广泛的环境污染物。然而，IPPP的毒性作用和机制仍不清楚。在本研究中，我们评估了 IPPP 对斑马鱼胚胎发育、神经行为以及生理和转录组变化的神经发育毒性影响。结果表明，IPPP会导致诸如存活率和孵化率低、体长和眼距缩短等不良发育，并导致心率和胚胎畸形率增加。发育缺陷主要包括典型的心包水肿、眼睛畸形和新生神经元数量减少。线粒体能量代谢紊乱和心肌细胞凋亡可能是心脏畸形的原因。行为结果显示，IPPP引起游泳速度、总游泳距离和轨迹的异常变化，并表现出低剂量效应。此外，乙酰胆碱酯酶（AchE）和多巴胺（DA）等神经递质活性的降低，以及中枢神经系统（CNS）和代谢途径相关基因的改变可能是IPPP神经发育毒性的原因。同时，IPPP分别通过改变核因子红细胞2相关因子2（Nrf2）和线粒体信号通路来诱导氧化应激和细胞凋亡，并改变斑马鱼幼虫的ATP酶活性。 转录组测序结果表明，细胞色素P450与药物代谢、能量代谢相关通路、谷胱甘肽代谢、维甲酸（RA）和氧化还原信号通路显着富集，且这些通路中的大部分基因在IPPP治疗后上调，可能是 IPPP 诱导神经发育的新目标。综上所述，本研究结果为综合评估新污染物IPPP的毒性效应和健康风险提供了重要参考。