三(1,3-二氯-2-丙基)磷酸酯对大鼠的神经毒性效应
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摘要
考察三(1,3-二氯-2-丙基)磷酸酯(TDCPP)对大鼠神经系统的毒性效应及其毒性机制,为有机磷阻燃剂(OPFRs)对哺乳动物神经毒性及其临床防治提供基础数据和科学依据。以Sprague-Dawley (SD)大鼠为受试生物,将TDCPP溶于橄榄油配制不同染毒剂量(125、250和500 mg·kg~(-1)·d~(-1))进行灌胃处理,溶剂对照组以相同体积的橄榄油进行灌胃,空白对照组不做任何处理,染毒周期为12周。结果表明,溶剂对照组和空白对照组的各项检测指标均无显著性差别(P>0.05)。TDCPP染毒组与对照组之间的差异主要表现为(1)体重变化:染毒期间,TDCPP处理组大鼠的体重与对照组相比有下降的趋势,在第12周中剂量染毒组和高剂量染毒组大鼠体重均显著性低于对照组(P<0.05);(2)行为学实验:Morris水迷宫实验结果表明,高剂量的TDCPP对大鼠的空间学习记忆能力造成影响,主要表现为在定位航行实验中,高剂量染毒组大鼠的逃避潜伏期显著性高于对照组和低剂量染毒组(P<0.05),而在空间探索实验中,高剂量染毒组大鼠在目标象限停留时间显著性低于对照组(P<0.05);(3)生化指标检测:各组间纹状体内多巴胺(DA)含量并无显著性差异(P> 0.05),染毒组乙酰胆碱酯酶(ACh E)活性与对照组相比显著性降低(P<0.01)且具有剂量依赖性,高剂量染毒组超氧化物歧化酶(SOD)活性显著性降低,高剂量和中剂量染毒组谷胱甘肽(GSH)含量显著性降低(P<0.05),这表明TDCPP对大鼠脑组织造成了氧化损伤,TDCPP染毒组脑组织的炎症因子(TNF-α)水平均高于对照组,且中剂量与高剂量染毒组TNF-α含量显著性高于对照组(P<0.05),揭示TDCPP能引起大鼠脑部的炎症反应,对脑组织造成损伤;(4)纹状体超微结构:电镜结果表明,TDCPP可导致纹状体细胞受到损伤,主要表现为细胞核固缩、线粒体损伤和突触间隙减小。研究表明,TDCPP可引起大鼠体重明显下降,导致大鼠神经细胞损伤,行为改变,抑制ACh E、SOD活性及GSH含量,使炎症介质增高,引起大鼠脑组织的氧化损伤和炎症反应。
This paper aims to investigate the neurotoxicity of tris( 1,3-dichloro-2-propyl) phosphate( TDCPP) and the mechanism. Rats were used as the animal model; TDCPP was dissolved in olive oil for preparation of different TDCPP doses( 125,250 and 500 mg·kg-1·d-1); the solvent control group was given with the same volume of olive oil. After rats were exposed to TDCPP for 12 weeks,the results showed that there was no difference between solvent control group and blank control group in all indexes. The comparison between TDCPP treatment groups and control group were as follows:( 1) During TDCPP treatment for 12 weeks,the rat body weight in TDCPP-exposed groups showed decreasing tendency compared with blank control and solvent control group. At the end of 12 th week,the body weight of medium dose group and high dose group were statistically decreased compared with control group( P<0.05).( 2) The result of Morris water maze showed that TDCPP can influence the spatial learning and memory ability of rats in high dose group. In positioning navigation experiment,the escape latency of high dose group were statistically higher than control and low dose group( P<0.05); in space exploration experiment,the duration time in target quadrant was statistically lower than control group( P<0.05).( 3) There was no statistical difference in dopamine( DA) content of striatum among all groups( P>0.05); the activity of acetylcholinesterase( AchE) was dose-dependently and statistically decreased in TDCPP-exposed groups compared with control group( P < 0. 05);the activity of superoxide dismutase( SOD) in high dose group was statistically decreased; the levels of glutathione( GSH) was statistically decreased in medium dose group and high dose group( P<0.05),which confirmed that TDCPP induced oxidative stress in the brain of rats; the levels of inflammatory factors( TNF-α) in TDCPP-exposed groups were statistically increased compared with control group( P<0.05),which showed that TDCPP induced inflammatory response in the brain of rats and caused damage to brain tissue.( 4) The results of TEM showed that TDCPP could cause damages to the cells of striatum,mainly including nuclear pyknosis,the damages of mitochondria and the decrease of synaptic gap. The results showed that TDCPP could cause the loss of body weight of rats significantly. TDCPP caused damages in nerve cells and the abnormality of behavior,inhibited the activity of AChE,and induced the oxidative stress and inflammatory response in the brains of rats.
This paper aims to investigate the neurotoxicity of tris( 1,3-dichloro-2-propyl) phosphate( TDCPP) and the mechanism. Rats were used as the animal model; TDCPP was dissolved in olive oil for preparation of different TDCPP doses( 125,250 and 500 mg·kg-1·d-1); the solvent control group was given with the same volume of olive oil. After rats were exposed to TDCPP for 12 weeks,the results showed that there was no difference between solvent control group and blank control group in all indexes. The comparison between TDCPP treatment groups and control group were as follows:( 1) During TDCPP treatment for 12 weeks,the rat body weight in TDCPP-exposed groups showed decreasing tendency compared with blank control and solvent control group. At the end of 12 th week,the body weight of medium dose group and high dose group were statistically decreased compared with control group( P<0.05).( 2) The result of Morris water maze showed that TDCPP can influence the spatial learning and memory ability of rats in high dose group. In positioning navigation experiment,the escape latency of high dose group were statistically higher than control and low dose group( P<0.05); in space exploration experiment,the duration time in target quadrant was statistically lower than control group( P<0.05).( 3) There was no statistical difference in dopamine( DA) content of striatum among all groups( P>0.05); the activity of acetylcholinesterase( AchE) was dose-dependently and statistically decreased in TDCPP-exposed groups compared with control group( P < 0. 05);the activity of superoxide dismutase( SOD) in high dose group was statistically decreased; the levels of glutathione( GSH) was statistically decreased in medium dose group and high dose group( P<0.05),which confirmed that TDCPP induced oxidative stress in the brain of rats; the levels of inflammatory factors( TNF-α) in TDCPP-exposed groups were statistically increased compared with control group( P<0.05),which showed that TDCPP induced inflammatory response in the brain of rats and caused damage to brain tissue.( 4) The results of TEM showed that TDCPP could cause damages to the cells of striatum,mainly including nuclear pyknosis,the damages of mitochondria and the decrease of synaptic gap. The results showed that TDCPP could cause the loss of body weight of rats significantly. TDCPP caused damages in nerve cells and the abnormality of behavior,inhibited the activity of AChE,and induced the oxidative stress and inflammatory response in the brains of rats.
引文
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[2] Betts K S. New details on organophosphate flame retardants[J]. Environmental Health Perspectives,2013,121(5):A168
[3]徐怀洲，王智志，张圣虎，等．有机磷酸酯类阻燃剂毒性效应研究进展[J]．生态毒理学报，2018,13(3):19-30Xu H Z,Wang Z Z,Zhang S H,et al. Research progress on toxic effects of organophosphate flame retardants[J].Asian Journal of Ecotoxicology,2018,13(3):19-30(in Chinese)
[4] Hartmann P C,Burgi D,Giger W. Organophosphate flame retardants and plasticizers in indoor air[J].Chemosphere,2004,57(8):781-787
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[6] Bacaloni A,Cavaliere C,Nazzari M,et al. Liquid chromatography/tandem mass spectrometry determination of organophosphorus flame retardants and plasticizers in drinking and surface waters[J]. Rapid Communications in Mass Spectrometry,2007,21(7):1123-1130
[7] Cao S,Zeng X Y,Song H,et al. Levels and distributions of organophosphate flame retardants and plasticizers in sediment from Taihu Lake,China[J]. Environmental Toxicology and Chemistry,2012,31(7):1478-1484
[8] Sundkvist A M,Olofsson U,Haglund P. Organophosphorus flame retardants and plasticizers in marine and fresh water biota and in human milk[J]. Journal of Environmental Monitoring,2010,12:943-951
[9]高小中，许宜平，王子健．有机磷酸酯阻燃剂的环境暴露与迁移转化研究进展[J]．生态毒理学报，2015,10(2):56-68Gao X Z,Xu Y P,Wang Z J. Research progress on environmental exposure,migration and transformation of organophosphate flame retardants[J]. Asian Journal of Ecotoxicology,2015,10(2):56-68(in Chinese)
[10] Office of Environmental Health Hazard Assessment(OEHHA). Evidence on the carcinogenicity of tris(1,3-dichloro-2-propyl)phosphate[R]. Sacramento,CA:Reproductive and Cancer Hazard Assessment Branch,Office of Environmental Health Hazard Assessment,California Environmental Protection Agency,2011
[11] National Research Council(NRC). Toxicological risks of selected flame-retardant chemicals[R]. Washington,DC:Subcommittee on Flame Retardant Chemicals,National Research Council,National Academy of Sciences,National Academy Press,2000
[12] Liu C S,Su G Y,Giesy J P,et al. Acute exposure to tris(1,3-dichloro-2-propyl)phosphate(TDCIPP)causes hepatic inflammation and leads to hepatotoxicity in zebrafish[J]. Scientific Reports,2016,6(1):19045
[13]周启星，赵梦阳，来子阳，等．有机磷阻燃剂的环境暴露与动物毒性效应[J]．生态毒理学报，2017,12(5):1-11Zhou Q X,Zhao M Y,Lai Z Y,et al. Researching progress in toxic effects of organophosphorus flame retardants released into the environment[J].Asian Journal of Ecotoxicology,2017,12(5):1-11(in Chinese)
[14] Farhat A,Crump D,Chiu S,et al. In ovo effects of two organophosphate flame retardants—TCPP and TDCIPP—on pipping success,development,mRNA expression,and thyroid hormone levels in chicken embryos[J]. Toxicological Sciences,2013,134(1):92-102
[15] Liu X,Ji K,Choi K. Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish[J]. Aquatic Toxicology,2012,114:173-181
[16] Venerosi A,Ricceri L,Tait S,et al. Sexdimorphic behaviors as markers of neuroendocrine disruption by environmental chemicals:The case of chlorpyrifos[J].Neurotoxicology,2012,33(6):1420-1426
[17] Munoz-Quezada M T,Lucero B A,Barr D B,et al.Neurodevelopmental effects in children associated with exposure to organophosphate pesticides:A systematic review[J]. Neurotoxicology,2013,39:158-168
[18]周贵珍，曾涛，张利平，等．磷酸三邻甲苯酯对母鸡中枢神经组织ATP含量的影响[J]．环境与职业医学，2009,26(1):20-23Zhou G Z,Zeng T,Zhang L P,et al. Effects of tri-o-cresyl phosphate(TOCP)on ATP concentration in hen’s central nervous tissues[J]. Journal of Environmental and Occupational Medicine,2009,26(1):20-23(in Chinese)
[19] Fu J,Han J,Zhou B S,et al. Toxicogenomic responses of zebrafish embryos/larvae to tris(1,3-dichloro-2-propyl)phosphate(TDCIPP)reveal possible molecular mechanisms of developmental toxicity[J]. Environmental Science&Technology,2013,47(18):10574-10582
[20]张利平，郭新，王青山，等．三邻甲苯基磷酸酯诱导母鸡坐骨神经动作电位特性的时效性变化[J]．中国药理学与毒理学杂志，2005,19(5):387-392Zhang L P,Guo X,Wang Q S,et al. Time-dependent changes in compound action potential in hen sciatic nerve treated with tri-ortho-cresyl phosphate[J]. Chinese Journal of Pharmacology&Toxicology,2005,19(5):387-392(in Chinese)
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