School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Guangdong, 523-808, China.
Institute for Medical System Biology, Dongguan Scientific Research Center, Guangdong Medical University, Guangdong, 523-808, China.
Chemosphere. 2020 Aug;252:126470. doi: 10.1016/j.chemosphere.2020.126470. Epub 2020 Mar 16.
Concerns have been raised over the neurotoxicity of triphenyl phosphate (TPP), but there have been few studies of the neurotoxic effects of TPP on mammals and the underlying mechanisms. In this study, weaned male mice (C57/BL6) were used and exposed to 0, 50, or 150 mg/kg TPP daily by oral gavage for 30 days. The blood brain barrier (BBB) permeability of TPP and its metabolite diphenyl phosphate (DPP) in the brain, and TPP induced metabolomic and transcriptomic changes of the brain were investigated. The results showed that TPP and DPP can cross the BBB of mice. Histopathological examination of the brain revealed abnormalities in the hippocampus, cortex and thalamus, and mice treated with high doses showed a potential inflammation in the thalamus and hippocampus. Untargeted metabolomic results revealed that the changed level of glutamic acid, N-acetyl CoA metabolites, and organic acid in the brain of treated mice, suggest that amino acid and lipid metabolism was interfered. RNA-seq data indicated that neuronal transcription processes and cell apoptosis pathway (forkhead box (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways) were significantly affected by TPP exposure. RT-PCR showed proinflammation cytokine tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)) levels were increased, while antioxidant genes including nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase1 (HO-1) and superoxide dismutase (SOD1) decreased. These results suggest that TPP could cause a degree of neurotoxicity by inducing neuroinflammation and neuronal apoptosis, which are related to oxidative stress. The potential implications for neurophysiology and behavioral regulation cannot be ignored.
人们对磷酸三苯酯（TPP）的神经毒性表示担忧，但关于 TPP 对哺乳动物的神经毒性影响及其潜在机制的研究较少。在这项研究中，我们使用了断奶雄性小鼠（C57/BL6），并通过口服灌胃每天分别暴露于 0、50 或 150mg/kg TPP 30 天。研究了 TPP 及其代谢物二苯基磷酸酯（DPP）在大脑中的血脑屏障（BBB）通透性，以及 TPP 引起的大脑代谢组学和转录组学变化。结果表明，TPP 和 DPP 可以穿过小鼠的 BBB。大脑的组织病理学检查显示海马体、皮层和丘脑异常，高剂量处理的小鼠丘脑和海马体可能存在炎症。非靶向代谢组学结果表明，受处理的小鼠大脑中谷氨酸、N-乙酰辅酶 A 代谢物和有机酸的变化水平表明，氨基酸和脂质代谢受到干扰。RNA-seq 数据表明，神经元转录过程和细胞凋亡途径（叉头框 (FOXO)和丝裂原激活蛋白激酶 (MAPK)信号通路）受到 TPP 暴露的显著影响。RT-PCR 显示促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的水平升高，而抗氧化基因核因子-E2 相关因子 2（Nrf2）、血红素加氧酶 1（HO-1）和超氧化物歧化酶 1（SOD1）降低。这些结果表明，TPP 通过诱导神经炎症和神经元凋亡引起一定程度的神经毒性，这与氧化应激有关。对神经生理学和行为调节的潜在影响不容忽视。
