毛细管电泳—化学修饰电极电化学检测方法研究及其在四溴双酚A神经毒性分析中的应用
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摘要
随着人类生产生活的发展,溴系阻燃剂(BFRs)作为目前产量最大、应用最广泛的阻燃剂之一,近年来发展迅速并被广泛应用到国民经济的各个部门及人们的生产生活中。由于其具有难降解性、环境稳定性、高脂溶性等特点,能够通过食物链的转移,使处于高位营养级的生物受到毒害,最终导致对人体健康的危害。在过去的十多年中,溴系阻燃剂的环境安全性问题,特别是多溴联苯醚(PBDEs)、四溴双酚-A(TBBPA)和六溴环十二烷(HBCD)等对环境的影响问题,引起了科学家们的极大关注。然而,对于BFRs神经毒性方面的研究,尚处于起步阶段。
毛细管电泳(capillary electrophoresis,CE)具有分离效率高、分析速度快、检测灵敏度高、样品用量少、能直接进样及易于自动化操作等优点,在生命科学、农业、食品、临床医学、化学等各得到广泛应用。其中,毛细管电泳-安培检测方法具有灵敏度高、选择性好、线性范围宽等特点。随着检测方法的不断完善,不同的电极材料如铂电极金电极等被选做工作电极,毛细管电泳安培检测的对象不断扩大。此外,还可以通过化学修饰的方法在电极表面连接上具有特定活性的化学功能团,赋予电极某种特定的性质,在高选择性和灵敏度方面具有独特的优越性,从而进一步扩大安培检测的范围和适用性。
根据上述研究现状,本论文以重要的生命信息分子为研究对象,建立了用于快速、灵敏、准确检测单胺类神经递质、神经肽类和谷胱甘肽等物质的毛细管电泳-安培检测方法;同时,与化学修饰电极技术相结合,通过对其电催化性质研究和应用,极大地提高毛细管电泳的检测灵敏度。在此基础上,结合国内外溴系阻燃剂研究现状,本论文建立了SD大鼠TBBPA损伤模型,采用毛细管电泳-安培检测方法对上述生物分子水平在受到TBBPA损伤后含量水平的变化进行了一系列的研究工作。
全文共分以下五个部分:
第一章、概述
首先,对溴系阻燃剂的污染现状及其毒性效应进行了综述;其次,分别阐述单胺类神经递质、神经肽类和谷胱甘肽等生物活性分子在生命活动中和疾病诊断治疗中的重要意义;再次,概述了毛细管电泳的发展、现状及前景,对毛细管电泳在环境科学以及生物分析等领域的应用作了较为详尽的论述;最后,以方法的建立、完善和应用领域的拓宽为出发点,提出了本论文的研究内容。
第二章、毛细管电泳-铂纳米修饰电极分离检测单胺类递质的研究及其在TBBPA暴露动物模型中的应用
单胺类神经递质是一类具有广泛生物学活性的物质,作为人体内一类非常重要的神经递质,在神经系统支配体内各个器官,调节各个系统的多种生理功能中处于关键地位,同时单胺类递质也是重要的激素物质,它们和神经冲动、行为及大脑皮质的觉醒和睡眠节律等都有关系,在神经系统中起重要调节作用。
该部分以TBBPA损伤大鼠为模型,应用毛细管电泳电化学检测方法,以铂纳米颗粒修饰电极为工作电极建立了5-羟色胺(serotonin,5-HT)、多巴胺(dopamine,DA)、去甲肾上腺素(norepinephrine,NE)和肾上腺素(epinephrine,E)的分离检测方法。在最佳实验条件下,各物质的浓度在0.01～10 nmol/L内与电流响应呈良好线性关系(相关系数大于0.9997),经铂纳米颗粒修饰的电极灵敏度显著提高,检出限分别可达2.3、2.7、3.1和3.3 pmol/L(S/N=3)。在此基础上,我们按毒性-时间效应、毒性-剂量效应和毒性-时间累积效应三部分分别进行了动物实验,并测定SD大鼠受TBBPA损伤后下丘脑、皮层、海马和小脑四个脑区中5-羟色胺、多巴胺、去甲肾上腺素和肾上腺素的含量的变化,初步探讨了溴系阻燃剂对动物神经毒性的影响。为从分子水平深入研究溴系阻燃剂对动物神经毒性的影响及其毒性的准确评价提供了一种快速、灵敏、有效的方法。
三、毛细管电泳-多壁碳纳米管修饰电极在线衍生法对TBBPA暴露下TRH水平影响的研究
促甲状腺激素释放激素(thyrotropin-releasing hormone,TRH)是一种小分子肽类,主要作用于腺垂体促进促甲状腺激素(thyroid stimulating hormone,TSH)释放,也作为神经递质或调质参与心血管、呼吸、体温等多种生理功能的调节。TRH以神经递质或神经调节物的形式在中枢神经内产生广泛的生理效应,并与阿片肽之间存在一定的相互作用。
该部分以促甲状腺素释放素(TRH)为研究对象,采用毛细管电泳—Cu~(2+)在线衍生电化学检测法,以多壁碳纳米管修饰碳电极为工作电极,建立了促甲状腺激素释放激素(TRH)的测定方法。在含有0.5mmol/L Cu~(2+)的硼酸盐缓冲体系中(pH=10.1),TRH与Cu~(2+)结合形成具有良好电活性的化合物,可以在电化学检测器上被检出。论文对分离和检测的各种影响因素进行了试验,在优化的实验条件下,促甲状腺激素释放激素在浓度1.0×10~(-7)mmol/L到1.0×10~(-9)mol/L范围内,与峰电流呈良好的线性关系,相关系数为0.9992。经多壁碳纳米管修饰的电极灵敏度可提高10倍,检测限为3.0×10_(-10)mol/L(S/N=3)。同时,通过对大鼠腹腔注射TBBPA后脑部TRH含量的变化,初步探讨了四溴双酚A(TBBPA)的神经毒性。结果表明,受TBBPA损伤后,大鼠各个脑区TRH的含量呈现一定的变化规律。该方法灵敏、简单、快速、重现性好,为开展TBBPA对中枢神经系统损伤的研究提供了一个有效的手段。
第四章、毛细管电泳-铂纳米修饰电极在线衍生法对TBBPA暴露下脑啡肽水平影响的研究
脑啡肽物质可作为神经递质或激素单独发挥作用,亦可与其他神经递质共存于同一神经元中而作为神经调制素发挥作用。
该部分建立了四溴双酚A(TBBPA)损伤动物模型,以亮氨酸脑啡肽(L-ENK)和甲硫氨酸脑啡肽(M-ENK)为研究对象,研究了SD大鼠下丘脑,皮层,海马和小脑四个脑区中L-ENK和M-ENK损伤前后水平变化,初步探讨了TBBPA的神经毒性效应。通过电化学聚合法制备了PtNPs修饰电极并作为工作电极,建立了毛细管电化学检测的分离检测上述两种脑啡肽的方法。在优化的分离、检测条件下,L-ENK和M-ENK的电流响应与其浓度在0.1～50 nmol/L的范围内呈良好的线性关系(相关系数为0.999),检出限分别为7和8 pmol/L(S/N=3)。分别按毒性-时间效应,毒性-剂量效应和毒性-时间累积效应三部分进行动物实验,测定L-ENK和M-ENK在受损伤前后的浓度变化。该方法简单、快速、灵敏,为进一步开展溴系阻燃剂对动物神经系统损伤的研究提供了一个有效的手段。
第五章、毛细管电泳-MWCNTs/Mv RuO/RuCN修饰电极对TBBPA暴露下谷胱甘肽的快速测定
谷胱甘肽广泛存在于生物体内,是由谷氨酸、半胱氨酸和甘氨酸组成的含硫醇三肽化合物,半胱氨酸上的巯基为活性基团。谷胱甘肽以还原型(GSH)和氧化型(GSSG)两种形式存在。GSH作为细胞的一种还原剂,参与多种重要的生理过程,可保护细胞免遭氧化损伤,解除药物代谢产物的毒性,调节基因表达和细胞凋亡,并与物质的跨膜转运相关。
该部分以多壁碳纳米管(MWCNTs)、RuCl_3和K_4Ru(CN)_6构筑的MWCNTs-Mv RuO/RuCN修饰电极为工作电极,建立了GSH和GSSG的毛细管电泳电化学检测方法。在最佳实验条件下,各组分的浓度在0.01～10μmol/L内与电流响应成良好线性关系,检出限分别为2.8和1.2 nmol/L(S/N=3)。按毒性-时间效应、毒性-剂量效应和毒性-时间累积效应三部分分别进行了动物实验,建立了TBBPA损伤大鼠模型,并测定了SD大鼠损伤后血清中GSH(还原型谷胱甘肽)和GSSG(氧化型谷胱甘肽)含量,为深入研究溴系阻燃剂的毒性及准确评价提供了一种快速、灵敏、有效的方法。
Brominated flame retardants(BFRs)have been widely used in plastics,textiles,electronic circuitry and other materials to prevent fires.They can accumulate in the environment and biont,and have been proved to be harmful to mammals,birds and fish.Because of their wide spread,stable structures and uncertain risk to human health,great concern has been aroused. Their effects on the hepatic enzyme activities,thyroid gland,nerve system,and immune system have been studied.Recent studies have shown that neonaltal exposure to some of the BFRs produce persisitent aberrations in spontaneous behaviour and affect learning and memory function in the adult mice.These findings suggest that several of the BFRs must be neurotoxic.In order to investigate the neurotoxicity of TBBPA on molecular level,monitoring monoamines,neuropeptide in brain,plasma,urine,and tissue is useful for studying the role of them in neurophysiology,behavioral effects,pathology,disease diagnosis and control.Since the concentrations of these molecules in brain are extremely low,it is important to develop highly sensitive analytical techniques with high resolution for their detections.
Recently,capillary electrophoresis(CE)has exhibited powerful capability for the analysis of complex samples with many advantages,such as the high separation speed and efficiency,low volume sample for analysis,the relatively simple instrumentation and very low running costs.Amperometric detection is an important detection method due to its sensitivity.It has been successfully coupled to CE to detect electroactive analytes.Common amperometric detectors,based on glassy carbon or carbon paste electrodes,exhibit no response for many analytes because of a high overpotential.The benefits of using chemically modified electrodes(CMEs)in these systems include acceleration of electron transfer reactions,permselective transport,reduction in fouling,and preferential accumulation of analyte.
In this dissertation,we laid our emphasis on the research of novel methods of sample analysis in neuroscience by CE-AD couple with chemically modified electrodes(CMEs).To our knowledge,it was the first time by using CE-AD couple with CMEs to determine the monoamine neurotransmitters,neuropeptides in rats' brain after exposure to TBBPA.The dissertation includes five chapters:
Chapter 1.Introduction
In this chapter,it introduced the characteristics of TBBPA,neurotransmitters and CE.The goal and significance of this dissertation are introduced too.
Chapter 2.Determination of monoamine neurotransmitters in rats' brain after exposure to TBBPA by CE-AD with Platinum Nanoparticles(PtNPs)modified electrode
Several studies have shown that BFRs affect the dopaminergic system in CNS,especially the synaptosomal and vesicular uptake.It is suggested that such toxins may influence the level of monoamines neurotransmitters.In this chapter,the fabrication and application of CE-AD with the platinum nanoparticles modified electrode were described.The chemically modified electrode had a good catalytic effect on monoamines neurotransmitters.In CE-AD with dopamine(DA),epinephrine(E),norepinephrine(NE)and 5-hydroxytryptamine(5-HT) in rat brain were separated and determined effectively at CMEs.The electrophoresis conditions followed as running voltage was 15 kV,working potential was 1.0 V,running buffer was 160 mmol/L Na_2HPO_4～NaH_2PO_4(pH=5.8)and the injection time was 10 s.A good linear relation was observed in 0.01～10 nmol/L.The detection limits of them was 2.3,2.7,3.1 and 3.3 pmol/L(S/N=3),respectively.The method can be applied directly to the determination the four monoamines neurotransmitters in brain sample with satisfactory results.
Chapter 3.Determination of TRH in rats' brain after exposure to TBBPA by CE-AD with Multiwalled Carbon Nanotubes modified electrode
Studies have shown that neonatal exposure to some brominated flame retardants(BFRs) produces neurobehavioral aberrations.In our study,thyrotropin-releasing hormone(TRH) was used to explore the neurotoxicity of BFRs.Tetrabromobiaphenol-A(TBBPA)was administered intraperitoneally(i.p.)to investigate its effect on TRH levels in rat brain.CE with electrochemical detection(ED)using a carbon nanotubes(CNTs)-modified carbon electrode in conjunction with on-capillary copper complexation was developed for the determination of TRH.TRH forms an electroactive Cu(Ⅱ)complex thus is detectable with the above method.Carbon nanotubes have excellent electrocatalytic activity,so the CNTs-modified carbon electrode was used to improve the sensitivity to at least 10-fold.The detection limit for TRH was 0.3 nmol/L(S/N=3)with the linear calibration curves ranging from 1～100 nmol/L,which enables the possibility for the determination of TRH in biological samples.An increase TRH concentration in different regions of rat brain was observed 24 h after administration of TBBPA in a single dose of 1000 mg/kg body weight.The highest TRH concentration was detected in hippocampus.It was also found that the higher dose of TBBPA affects the TRH level in brain much more.The present study shows that neuropeptides could be used as targets to evaluate the neurotoxicity of BFRs.This rapid,effective and sensitive method can be used to study the neurotoxicity of BFRs via detection of TRH in rat brain.
Chapter 4.Determination of enkephalins in rats' brain after exposure to TBBPA by CE-AD with Platinum Nanoparticles(PtNPs)modified electrode
To observe the changes of M-ENK and L-ENK concentration in the brain regions such as hypothalamus;hippocampus;cerebellum and cortex to explore the neurotoxicity of TBBPA, CE-AD applied with a platinum nanoparticles(PtNPs)modified electrode was developed. This work on M-ENK and L-ENK assays has been established based on the reversible electrochemistry of the Cu(Ⅱ)/Cu(Ⅲ)coupled with M-ENK and L-ENK.Under the optimum condition,M-ENK and L-ENK could be separated in 75 mmol/L Na_2B_4O_7～NaOH(pH=9.8) containing 1.0 mmol/L Cu~(2+).A good linear relation was observed in 0.1～50 nmol/L.The detection limits of them was 7 and 8 pmol/L(S/N=3),respectively.This rapid,effective and sensitive method can be used to study the neurotoxicity of BFRs via detection of enkephalines in rat brain.
Chapter 5.Determination of GSH and GSSG in rats' brain after exposure to TBBPA by CE-AD with Multiwalled Carbon Nanotubes/Mv RuO-RuCN Films modified electrode
Glutathione(GSH)is often involved in protective and detoxifying functions of the cell. Glutathione disulfide(GSSG)is known to be formed in biological systems because of the function of GSH as antioxidant.Analysis of GSH and GSSG is of continuous interest because of their biological significance.To determine concentration of GSH and GSSG,a glassy carbon electrode doped multiwalled carbon nanotube was deposited from a solution containing micromolar concentrations of RuCl_3 and K_4Ru(CN)_6 to fabricate the GC/MWCNTs/mv RuO-RuCN as a working electrode.It was found that the CMEs exhibited efficiently electrocatalytic effect on GSH and GSSG.A good linear relation was observed in 0.01～10μmol/L.The detection limits of them was 2.8 and 1.2nmoI/L(S/N=3),respectively. This rapid,effective and sensitive method can be used to study the toxicity of BFRs via detection of GSH and GSSG in rat serum.
毛细管电泳(capillary electrophoresis,CE)具有分离效率高、分析速度快、检测灵敏度高、样品用量少、能直接进样及易于自动化操作等优点,在生命科学、农业、食品、临床医学、化学等各得到广泛应用。其中,毛细管电泳-安培检测方法具有灵敏度高、选择性好、线性范围宽等特点。随着检测方法的不断完善,不同的电极材料如铂电极金电极等被选做工作电极,毛细管电泳安培检测的对象不断扩大。此外,还可以通过化学修饰的方法在电极表面连接上具有特定活性的化学功能团,赋予电极某种特定的性质,在高选择性和灵敏度方面具有独特的优越性,从而进一步扩大安培检测的范围和适用性。
根据上述研究现状,本论文以重要的生命信息分子为研究对象,建立了用于快速、灵敏、准确检测单胺类神经递质、神经肽类和谷胱甘肽等物质的毛细管电泳-安培检测方法;同时,与化学修饰电极技术相结合,通过对其电催化性质研究和应用,极大地提高毛细管电泳的检测灵敏度。在此基础上,结合国内外溴系阻燃剂研究现状,本论文建立了SD大鼠TBBPA损伤模型,采用毛细管电泳-安培检测方法对上述生物分子水平在受到TBBPA损伤后含量水平的变化进行了一系列的研究工作。
全文共分以下五个部分:
第一章、概述
首先,对溴系阻燃剂的污染现状及其毒性效应进行了综述;其次,分别阐述单胺类神经递质、神经肽类和谷胱甘肽等生物活性分子在生命活动中和疾病诊断治疗中的重要意义;再次,概述了毛细管电泳的发展、现状及前景,对毛细管电泳在环境科学以及生物分析等领域的应用作了较为详尽的论述;最后,以方法的建立、完善和应用领域的拓宽为出发点,提出了本论文的研究内容。
第二章、毛细管电泳-铂纳米修饰电极分离检测单胺类递质的研究及其在TBBPA暴露动物模型中的应用
单胺类神经递质是一类具有广泛生物学活性的物质,作为人体内一类非常重要的神经递质,在神经系统支配体内各个器官,调节各个系统的多种生理功能中处于关键地位,同时单胺类递质也是重要的激素物质,它们和神经冲动、行为及大脑皮质的觉醒和睡眠节律等都有关系,在神经系统中起重要调节作用。
该部分以TBBPA损伤大鼠为模型,应用毛细管电泳电化学检测方法,以铂纳米颗粒修饰电极为工作电极建立了5-羟色胺(serotonin,5-HT)、多巴胺(dopamine,DA)、去甲肾上腺素(norepinephrine,NE)和肾上腺素(epinephrine,E)的分离检测方法。在最佳实验条件下,各物质的浓度在0.01～10 nmol/L内与电流响应呈良好线性关系(相关系数大于0.9997),经铂纳米颗粒修饰的电极灵敏度显著提高,检出限分别可达2.3、2.7、3.1和3.3 pmol/L(S/N=3)。在此基础上,我们按毒性-时间效应、毒性-剂量效应和毒性-时间累积效应三部分分别进行了动物实验,并测定SD大鼠受TBBPA损伤后下丘脑、皮层、海马和小脑四个脑区中5-羟色胺、多巴胺、去甲肾上腺素和肾上腺素的含量的变化,初步探讨了溴系阻燃剂对动物神经毒性的影响。为从分子水平深入研究溴系阻燃剂对动物神经毒性的影响及其毒性的准确评价提供了一种快速、灵敏、有效的方法。
三、毛细管电泳-多壁碳纳米管修饰电极在线衍生法对TBBPA暴露下TRH水平影响的研究
促甲状腺激素释放激素(thyrotropin-releasing hormone,TRH)是一种小分子肽类,主要作用于腺垂体促进促甲状腺激素(thyroid stimulating hormone,TSH)释放,也作为神经递质或调质参与心血管、呼吸、体温等多种生理功能的调节。TRH以神经递质或神经调节物的形式在中枢神经内产生广泛的生理效应,并与阿片肽之间存在一定的相互作用。
该部分以促甲状腺素释放素(TRH)为研究对象,采用毛细管电泳—Cu~(2+)在线衍生电化学检测法,以多壁碳纳米管修饰碳电极为工作电极,建立了促甲状腺激素释放激素(TRH)的测定方法。在含有0.5mmol/L Cu~(2+)的硼酸盐缓冲体系中(pH=10.1),TRH与Cu~(2+)结合形成具有良好电活性的化合物,可以在电化学检测器上被检出。论文对分离和检测的各种影响因素进行了试验,在优化的实验条件下,促甲状腺激素释放激素在浓度1.0×10~(-7)mmol/L到1.0×10~(-9)mol/L范围内,与峰电流呈良好的线性关系,相关系数为0.9992。经多壁碳纳米管修饰的电极灵敏度可提高10倍,检测限为3.0×10_(-10)mol/L(S/N=3)。同时,通过对大鼠腹腔注射TBBPA后脑部TRH含量的变化,初步探讨了四溴双酚A(TBBPA)的神经毒性。结果表明,受TBBPA损伤后,大鼠各个脑区TRH的含量呈现一定的变化规律。该方法灵敏、简单、快速、重现性好,为开展TBBPA对中枢神经系统损伤的研究提供了一个有效的手段。
第四章、毛细管电泳-铂纳米修饰电极在线衍生法对TBBPA暴露下脑啡肽水平影响的研究
脑啡肽物质可作为神经递质或激素单独发挥作用,亦可与其他神经递质共存于同一神经元中而作为神经调制素发挥作用。
该部分建立了四溴双酚A(TBBPA)损伤动物模型,以亮氨酸脑啡肽(L-ENK)和甲硫氨酸脑啡肽(M-ENK)为研究对象,研究了SD大鼠下丘脑,皮层,海马和小脑四个脑区中L-ENK和M-ENK损伤前后水平变化,初步探讨了TBBPA的神经毒性效应。通过电化学聚合法制备了PtNPs修饰电极并作为工作电极,建立了毛细管电化学检测的分离检测上述两种脑啡肽的方法。在优化的分离、检测条件下,L-ENK和M-ENK的电流响应与其浓度在0.1～50 nmol/L的范围内呈良好的线性关系(相关系数为0.999),检出限分别为7和8 pmol/L(S/N=3)。分别按毒性-时间效应,毒性-剂量效应和毒性-时间累积效应三部分进行动物实验,测定L-ENK和M-ENK在受损伤前后的浓度变化。该方法简单、快速、灵敏,为进一步开展溴系阻燃剂对动物神经系统损伤的研究提供了一个有效的手段。
第五章、毛细管电泳-MWCNTs/Mv RuO/RuCN修饰电极对TBBPA暴露下谷胱甘肽的快速测定
谷胱甘肽广泛存在于生物体内,是由谷氨酸、半胱氨酸和甘氨酸组成的含硫醇三肽化合物,半胱氨酸上的巯基为活性基团。谷胱甘肽以还原型(GSH)和氧化型(GSSG)两种形式存在。GSH作为细胞的一种还原剂,参与多种重要的生理过程,可保护细胞免遭氧化损伤,解除药物代谢产物的毒性,调节基因表达和细胞凋亡,并与物质的跨膜转运相关。
该部分以多壁碳纳米管(MWCNTs)、RuCl_3和K_4Ru(CN)_6构筑的MWCNTs-Mv RuO/RuCN修饰电极为工作电极,建立了GSH和GSSG的毛细管电泳电化学检测方法。在最佳实验条件下,各组分的浓度在0.01～10μmol/L内与电流响应成良好线性关系,检出限分别为2.8和1.2 nmol/L(S/N=3)。按毒性-时间效应、毒性-剂量效应和毒性-时间累积效应三部分分别进行了动物实验,建立了TBBPA损伤大鼠模型,并测定了SD大鼠损伤后血清中GSH(还原型谷胱甘肽)和GSSG(氧化型谷胱甘肽)含量,为深入研究溴系阻燃剂的毒性及准确评价提供了一种快速、灵敏、有效的方法。
Brominated flame retardants(BFRs)have been widely used in plastics,textiles,electronic circuitry and other materials to prevent fires.They can accumulate in the environment and biont,and have been proved to be harmful to mammals,birds and fish.Because of their wide spread,stable structures and uncertain risk to human health,great concern has been aroused. Their effects on the hepatic enzyme activities,thyroid gland,nerve system,and immune system have been studied.Recent studies have shown that neonaltal exposure to some of the BFRs produce persisitent aberrations in spontaneous behaviour and affect learning and memory function in the adult mice.These findings suggest that several of the BFRs must be neurotoxic.In order to investigate the neurotoxicity of TBBPA on molecular level,monitoring monoamines,neuropeptide in brain,plasma,urine,and tissue is useful for studying the role of them in neurophysiology,behavioral effects,pathology,disease diagnosis and control.Since the concentrations of these molecules in brain are extremely low,it is important to develop highly sensitive analytical techniques with high resolution for their detections.
Recently,capillary electrophoresis(CE)has exhibited powerful capability for the analysis of complex samples with many advantages,such as the high separation speed and efficiency,low volume sample for analysis,the relatively simple instrumentation and very low running costs.Amperometric detection is an important detection method due to its sensitivity.It has been successfully coupled to CE to detect electroactive analytes.Common amperometric detectors,based on glassy carbon or carbon paste electrodes,exhibit no response for many analytes because of a high overpotential.The benefits of using chemically modified electrodes(CMEs)in these systems include acceleration of electron transfer reactions,permselective transport,reduction in fouling,and preferential accumulation of analyte.
In this dissertation,we laid our emphasis on the research of novel methods of sample analysis in neuroscience by CE-AD couple with chemically modified electrodes(CMEs).To our knowledge,it was the first time by using CE-AD couple with CMEs to determine the monoamine neurotransmitters,neuropeptides in rats' brain after exposure to TBBPA.The dissertation includes five chapters:
Chapter 1.Introduction
In this chapter,it introduced the characteristics of TBBPA,neurotransmitters and CE.The goal and significance of this dissertation are introduced too.
Chapter 2.Determination of monoamine neurotransmitters in rats' brain after exposure to TBBPA by CE-AD with Platinum Nanoparticles(PtNPs)modified electrode
Several studies have shown that BFRs affect the dopaminergic system in CNS,especially the synaptosomal and vesicular uptake.It is suggested that such toxins may influence the level of monoamines neurotransmitters.In this chapter,the fabrication and application of CE-AD with the platinum nanoparticles modified electrode were described.The chemically modified electrode had a good catalytic effect on monoamines neurotransmitters.In CE-AD with dopamine(DA),epinephrine(E),norepinephrine(NE)and 5-hydroxytryptamine(5-HT) in rat brain were separated and determined effectively at CMEs.The electrophoresis conditions followed as running voltage was 15 kV,working potential was 1.0 V,running buffer was 160 mmol/L Na_2HPO_4～NaH_2PO_4(pH=5.8)and the injection time was 10 s.A good linear relation was observed in 0.01～10 nmol/L.The detection limits of them was 2.3,2.7,3.1 and 3.3 pmol/L(S/N=3),respectively.The method can be applied directly to the determination the four monoamines neurotransmitters in brain sample with satisfactory results.
Chapter 3.Determination of TRH in rats' brain after exposure to TBBPA by CE-AD with Multiwalled Carbon Nanotubes modified electrode
Studies have shown that neonatal exposure to some brominated flame retardants(BFRs) produces neurobehavioral aberrations.In our study,thyrotropin-releasing hormone(TRH) was used to explore the neurotoxicity of BFRs.Tetrabromobiaphenol-A(TBBPA)was administered intraperitoneally(i.p.)to investigate its effect on TRH levels in rat brain.CE with electrochemical detection(ED)using a carbon nanotubes(CNTs)-modified carbon electrode in conjunction with on-capillary copper complexation was developed for the determination of TRH.TRH forms an electroactive Cu(Ⅱ)complex thus is detectable with the above method.Carbon nanotubes have excellent electrocatalytic activity,so the CNTs-modified carbon electrode was used to improve the sensitivity to at least 10-fold.The detection limit for TRH was 0.3 nmol/L(S/N=3)with the linear calibration curves ranging from 1～100 nmol/L,which enables the possibility for the determination of TRH in biological samples.An increase TRH concentration in different regions of rat brain was observed 24 h after administration of TBBPA in a single dose of 1000 mg/kg body weight.The highest TRH concentration was detected in hippocampus.It was also found that the higher dose of TBBPA affects the TRH level in brain much more.The present study shows that neuropeptides could be used as targets to evaluate the neurotoxicity of BFRs.This rapid,effective and sensitive method can be used to study the neurotoxicity of BFRs via detection of TRH in rat brain.
Chapter 4.Determination of enkephalins in rats' brain after exposure to TBBPA by CE-AD with Platinum Nanoparticles(PtNPs)modified electrode
To observe the changes of M-ENK and L-ENK concentration in the brain regions such as hypothalamus;hippocampus;cerebellum and cortex to explore the neurotoxicity of TBBPA, CE-AD applied with a platinum nanoparticles(PtNPs)modified electrode was developed. This work on M-ENK and L-ENK assays has been established based on the reversible electrochemistry of the Cu(Ⅱ)/Cu(Ⅲ)coupled with M-ENK and L-ENK.Under the optimum condition,M-ENK and L-ENK could be separated in 75 mmol/L Na_2B_4O_7～NaOH(pH=9.8) containing 1.0 mmol/L Cu~(2+).A good linear relation was observed in 0.1～50 nmol/L.The detection limits of them was 7 and 8 pmol/L(S/N=3),respectively.This rapid,effective and sensitive method can be used to study the neurotoxicity of BFRs via detection of enkephalines in rat brain.
Chapter 5.Determination of GSH and GSSG in rats' brain after exposure to TBBPA by CE-AD with Multiwalled Carbon Nanotubes/Mv RuO-RuCN Films modified electrode
Glutathione(GSH)is often involved in protective and detoxifying functions of the cell. Glutathione disulfide(GSSG)is known to be formed in biological systems because of the function of GSH as antioxidant.Analysis of GSH and GSSG is of continuous interest because of their biological significance.To determine concentration of GSH and GSSG,a glassy carbon electrode doped multiwalled carbon nanotube was deposited from a solution containing micromolar concentrations of RuCl_3 and K_4Ru(CN)_6 to fabricate the GC/MWCNTs/mv RuO-RuCN as a working electrode.It was found that the CMEs exhibited efficiently electrocatalytic effect on GSH and GSSG.A good linear relation was observed in 0.01～10μmol/L.The detection limits of them was 2.8 and 1.2nmoI/L(S/N=3),respectively. This rapid,effective and sensitive method can be used to study the toxicity of BFRs via detection of GSH and GSSG in rat serum.
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