朱亭^1,2,3,
严骁²,
邹忠杰⁴,
王美欢²,
唐斌²,
许榕发²,
郑晶^2,,,
麦碧娴¹,
于云江²
1. 中国科学院广州地球化学研究所, 有机地球化学国家重点实验室, 广州 510640;
2. 生态环境部华南环境科学研究所, 国家环境保护环境污染健康风险评价重点实验室, 广州 510655;
3. 中国科学院大学, 北京 100049;
4. 广东药科大学中药学院, 广州 510006

作者简介: 朱亭(1993-),女,博士,研究方向为环境污染与健康,E-mail:ztzoe_093@163.com.

通讯作者: 郑晶,zhengjing@scies.org ;

基金项目: 广州市科技计划项目（201804010074）；中央级公益性科研院所基本科研业务费专项资金资助项目（PM-zx703-201904-122）；国家自然科学基金重点项目（41931290）


中图分类号: X171.5

A Potential Target Research of Neurotoxicity Induced by Tris(1,3-dichloro-2-propyl) Phosphate (TDCPP) in Mice

Zhu Ting^1,2,3,
Yan Xiao²,
Zou Zhongjie⁴,
Wang Meihuan²,
Tang Bin²,
Xu Rongfa²,
Zheng Jing^2,,,
Mai Bixian¹,
Yu Yunjiang²
1. State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China;
2. State Environmental Protection Key Laboratory of Environmental Pollution Health Risk Assessment, South China Institute of Environmental Sciences, Ministry of Ecology and Environment, Guangzhou 510655, China;
3. University of Chinese Academy of Sciences, Beijing 100049, China;
4. School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China

Corresponding author: Zheng Jing,zhengjing@scies.org ;

CLC number: X171.5

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摘要:磷酸三（1，3-二氯-2-丙基）酯（TDCPP）在环境介质及生物样本中被广泛检出，为探究TDCPP的潜在神经毒性以及作用机制，以C57BL/6小鼠为动物模型，考察经300 mg·kg^-1·d^-1的TDCPP持续染毒35 d后，小鼠大脑皮层神经功能相关因子及血清代谢组学的变化。结果显示，小鼠在TDCPP染毒35 d后，大脑皮层中5-羟色胺（5-HT）含量和乙酰胆碱酯酶（AChE）活性无显著变化（P>0.05），而促炎性细胞因子白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、诱导型一氧化氮合酶（iNOS）及胶质细胞源性神经营养因子（GDNF）基因表达水平显著上调（P<0.05），神经营养因子-3（Ntf3）基因表达水平显著下调（P<0.05）；同时，TDCPP染毒显著干扰了小鼠的代谢过程，引起异亮氨酸、谷氨酸、甘氨酸和β-葡萄糖等多种神经性疾病相关生物标志物的改变，以及氨基酸代谢、糖类代谢和脂质代谢紊乱。研究结果表明，TDCPP的神经毒性效应与神经炎症和神经元损伤相关因子转录水平改变，以及代谢失衡引起的信号紊乱有关。
关键词: 磷酸三(1,3-二氯-2-丙基)酯/
小鼠/
神经毒性/
代谢组学/
生物标志物

Abstract:Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) was widely detected in a variety of environmental media and biota samples. C57BL/6 mice were used as an animal model to study the potential neurotoxicity mechanisms caused by TDCPP. Changes of the neural function related factors in cerebral cortex and serum metabolomics in mice were investigated after continuous exposure to TDCPP at 300 mg·kg^-1·d^-1 for 35 d. The results showed that, after 35 d of TDCPP exposure, the concentrations of 5-hydroxytryptamine (5-HT) and activities of acetylcholinesterase (AChE) in the cerebral cortex had no significant change (P>0.05). Significant up-regulations of the gene expression levels of the proinflammatory cytokine interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and glial cell line-derived neurotrophic factor (GDNF) were observed (P<0.05) in exposed mice. However, the gene expression level of neurotrophic factor-3 (Ntf3) was significantly down-regulated (P<0.05). Meanwhile, TDCPP exposure interfered with the metabolic process of amino acid metabolism, glycometabolism and lipid metabolism, leading to changes in the levels of biomarkers such as isoleucine, glutamate, glycine and β-glucose, which were associated with a variety of neurological diseases. The results showed that the neurotoxic effects of TDCPP were related to changes in the transcriptional levels of neuroinflammation and neuronal damage-related factors as well as the metabolic signal disorder caused by metabolic imbalance.
Key words:tris(1,3-dichloro-2-propyl) phosphate/
mouse/
neurotoxicity/
metabolomics/
biomarkers.

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