低水平铅暴露对不同发育期大鼠学习记忆及mGlur1、NMDA受体表达的影响
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摘要
随着社会工业进程和现代化步伐的加快,工业垃圾不断倾倒危险品对土壤和水体造成严重污染,其中铅由于在土壤中的持续蓄积和对农产品、人体健康的高毒性,而受到越来越多的关注。铅作为一种常见的金属毒物,对人体多种组织、器官造成损害,尤其对发育中的神经系统造成损害,具有兴奋性神经毒性。它对认知能力影响而引起巨大的公众健康问题。铅可以通过胎盘向胎儿转运,并通过胎儿发育尚不完善的血脑屏障,进入胎儿中枢神经系统,并对中枢神经系统的生长发育造成损害进而影响胎儿出生后的学习记忆能力;也可以通过乳汁进入新生儿体内,造成婴幼儿铅负荷升高;早期铅暴露还将影响儿童和青春期智发育,并且这些影响将持续到成年以后。
在神经系统的发育和再生过程,海马是负责学习记忆的关键脑区,特别是短期记忆和近期记忆。海马长时程增强效应(Long term potentiation,LTP)被认为是海马学习和记忆的储存功能单位。兴奋性神经递质特定受体——谷氨酸触发了LTP。
N-甲基-D-天冬氨酸受体(N–methyl-D-aspartate Receptors,NMDARs)是一种兴奋性氨基酸受体亚单位,在脑的发育、学习与记忆机制中起重要作用。NMDARs作为一个双向受体,可检测到突触受体释放谷氨酸,突触后去极化,使Mg2+阻滞作用消失,通道开放,导致Ca2+内流,激活一系列酶作用反应,同时这些又是构成LTP诱导和维持的物质基础。NMDAR表达存在选择性,主要功能和特性差异源于NR2亚基的不同表达和分布,故此测定NR2。NR2在神经细胞生长发育、突触传递、LTP、神经信号传导和神经递质释放过程中起着重要作用。
生长发育期脑NMDAR是铅作用的重要目标,铅是NMDAR的非竞争性拮抗剂。离体海马神经元电生理研究发现,铅能抑制NMDA激活的全细胞电流,抑制NMDAR单通道的开放频率,且其抑制作用的强度与神经元的成熟程度有关,幼稚神经元对铅的抑制作用更加敏感。但目前还不清楚铅影响NMDA受体mRNA表达的机理,以及暴露水平与影响之间的具体关系。
代谢性谷氨酸受体(Metabotropic glutamate receptors,mGluR)是G蛋白偶联受体(G protein-coupled receptors,GPCR),依据序列的同源性、受体的药理学特性及其所偶联的细胞内第二信使的不同超家族,将8个受体分为中分为三组。代谢性谷氨酸受体亚型1(mGlur1)属于I组,是GPCRs家族的重要成员可能在调节中枢神经系统作用、学习记忆突触的形成和维持、神经元信号转导过程中起重要作用,可引起强烈的兴奋性神经毒性,导致神经元的肿胀和坏死,和神经退行性病变有关,并参与了LTP过程,但具体机理尚不清楚。I组受体和蛋白激酶C偶联,增强NMDA受体通道的开放。mGluR介导的NMDAR活性增强在突触传递和突出可塑性,包括LTP过程中起重要作用。
众所周知,铅毒性通过活性氧族产物诱发氧化损伤,包括超氧离子(O2?),羟基(·OH)和过氧化氢(H2O2)。这些自由基和过氧化物引起膜损伤,常与脂质过氧化有关,影响发育时期暴露于铅的大鼠中枢神经系统。值得注意的是,染铅后大鼠脑组织内可观察到脂质过氧化反应增强,以及抗氧化酶如超氧化物歧化酶(Superoxide dismutase,SOD)、谷胱甘肽超氧化物酶(Glutathione peroxidase,GSH-Px)活性降低。
一氧化氮(Nitric oxide,NO)被认为是典型的逆行信使分子,在学习和记忆中起到重要作用,其生物合成主要受一氧化氮合酶(Nitric oxide synthase,NOS)的调节,目前多是以NOS活性来反映NO的水平。而铅对NOS活性有抑制作用,可使NO减少甚至消失。
目的:
本研究通过建立一系列在生长发育时期的不同阶段低水平大鼠铅暴露模型,检测铅在子代全血和脑组织中的浓度,全血δ-ALAD活性,及不同脑组织中mGlur1、NMDAR亚单位mRNA,SOD,GSH-Px,NOS活性。从一个广泛的角度研究各项指标变化与铅暴露浓度、暴露时间之间的关系,为铅损伤对学习记忆功能及神经行为的改变的研究提供一定的实验依据,进一步探讨醋酸铅的神经毒作用机制。
方法:
1.在不同发育阶段,采用0.2%的醋酸铅溶液自由饮水作为处理因素,建立铅暴露的动物模型,设立正常对照组、孕期暴露组(A组)、哺乳期铅暴露组(B组)、断乳后铅暴露组(C组)。于PND60取材,测量体重及脑重,海马、双侧皮质的重量。
2.用石墨炉-原子吸收光谱法测定血脑组织中铅的含量;用分光光度计测量全血ALAD,评价铅吸收程度。
3.以Morris水迷宫检测不同发育阶段铅暴露后动物的空间学习记忆能力。
4.用半定量RT-PCR方法,结合技术图像分析系统,检测皮层、海马组织中mGlur1及NMDA相关受体mRNA表达量,比较不同时期染毒的变化,观察醋酸铅对大鼠脑组织mGlur1及NMDA受体表达的影响。
5.测定脑组织中的过氧化物酶指标,SOD,GSH-Px和NOS,探讨铅对神经系统损伤的氧化损伤机制。
结果:
1.与对照组相比,染毒剂量组的大鼠体重、脑体重比率差异无显著性(P>0.05),不同时期染毒组之间差异无显著性(P>0.05)。相对于对照组,A组的脑重、海马重量,B组的脑重有显著性减少(P<0.01),A组的皮质重量大于B、C组(P<0.01)。
2.醋酸铅处理后,各剂量染铅组大鼠相对于对照组全血、皮层、海马组织中铅含量显著增加,ALAD活力下降,差异有显著性。A组:与对照组相比,脑铅含量有显著性增加(P<0.01);B组:与对照组相比,血铅升高、ALAD含量降低,差别有显著性(P<0.01,P<0.05);C组:与对照组相比,仔鼠的血铅、脑铅、ALAD含量改变显著,差别有显著性(P<0.01,P<0.05)。
3.在Morris水迷宫测试中,第1天各组动物的测试成绩之间无显著性差异,从第2天起,各染铅组仔鼠的逃避潜伏期(Escape Latency)值均高于对照组,其差别有显著性(P<0.05,P<0.01)。虽然在训练过程中各染铅组的成绩有所提高,但各染铅组后3天的潜伏期曲线始终无法恢复到正常水平,尤其是C组相对于对照组以及其它各组在各象限都有显著性差异(P<0.05)。与对照组相比,A组在第I象限,B组在第I、IV象限的潜伏期时间差异显著(P<0.05)。但是A组在第II、IV象限的潜伏期时间和对照相比无统计学差异(P>0.05)。
4. RT-PCR结果显示,染毒组NR2AmRNA在海马和皮层中表达较对照组有不同程度升高,尤其在A组中的表达大于其他各组,有显著性差异(P<0.05);各染毒组NR2BmRNA在海马表达较对照组有不同程度的下降,并有显著性差异(P<0.05),B组的受体在皮质中表达量与对照有显著性差异(P<0.05);NR2CmRNA在皮质中的表达与对照没有统计学差异(P>0.05),A组NR2CmRNA在海马中较对照组表达增加,差异具有统计学意义(P<0.01);与对照组相比,A组在皮质、海马中,以及B组在皮质中的mGlur1受体表达减少,C组正好相反,受体表达不论在皮质还是海马中均高于对照组,两组结果都具有显著性差异(P<0.01)。
5.过氧化物酶测定结果显示,不同时期染毒组SOD活性呈波形趋势,A、B组较对照组不同程度升高,其中B组与对照组、C组差异具有统计学意义(P<0.05),C组较对照组SOD活性降低,但无统计学差异(P>0.05);各染毒组GSH-Px活性较对照组有不同程度升高,尤其B组与对照组、A组差异都具有统计学意义(P<0.05,P<0.01);NOS活性染毒组较同时期对照组有不同程度下降,C组与对照组相比有显著性差异(P<0.05)。
结论:
1.醋酸铅处理后,铅在各染毒组大鼠全血、海马、皮质组织中的含量显著增加,ALAD活性降低。停止铅暴露后,脑组织中的铅含量随年龄增长浓度不断下降。
2.低浓度的铅暴露对学习记忆造成损伤,且损伤将一直持续到成年。
3.孕鼠血中的铅可以通过胎盘屏障进入胎鼠,也可通过发育尚不完善的血脑屏障到达神经系统。在哺乳阶段铅可通过乳汁在子代体内蓄积。通过上述一系列途径,醋酸铅可干扰其子代神经系统的正常生长发育,进而影响仔鼠的学习记忆能力,并且这种损害作用将持续到仔鼠的成熟期。
4.铅可改变脑组织中mGlur1和NMDAR受体mRNA的表达,尤其是低浓度铅暴露使生长发育时期的大鼠脑组织中NR2BmRNA的表达降低,同时可观察到学习记忆能力的下降,所以可以推测mGlur1和NMDAR受体可能是铅神经毒性的机制之一。
5.不同发育期醋酸铅暴露可使脑组织中抗氧化酶类活性升高将加重脑损伤。同时NOS活性的降低可推断NO生成减少,可能是一方面铅作为重金属与NOS的活性中心结合进而产生抑制作用,使NOS酶活性降低或完全失活;另一方面,铅通过影响谷氨酸递质、NMDA受体及Ca2+等进一步抑制NOS酶活性。从某种程度上说,这些作用影响了信号转导和认知能力
With the acceleration of the industrialization and modernization of community, continuous discharge and disposal of industrial waste products containing hazardous materials have resulted in serious contamination of the soil and water bodies, but Pb has grabbed more attention due to its longer persistence in soil and highly toxic effects on both crop production and human health. Lead is a kind of common toxic heavy metal that has obvious and sure damage to apparatus and tissue of individual, especially strong neurotoxicity, which can damage the developmental central nervous system (CNS). It caused major public health problem because of the documented effects on cognitive development. Lead can be transported from mother to fetus through placenta easily and it also can come into the CNS of fetus through the incomplete blood-brain barrier and do harm to the developmental CNS. As a result, the offspring’s ability of learning and memory would be affected; it also can transport into newborn by sucking lacto, which induced to the increase of lead burden in baby body; during the childhood, it can cause destruction of child’s IQ exposed to lead. Furthermore, these destroy will last during the whole life.
During neuronal development and regeneration, hippocampus is an important encephalic region that charge for learning and memory, especially for short-term memory and recent memory. Long-term potentiation (LTP) is a cellular model of the synaptic plasticity that may underlie memory acquisition, which may be representative of learning and memory processes in mammalian brain. LTP is triggered by certain receptors for the excitatory neurotransmitter, glutamate.
The N-methyl-D-aspartate (NMDA) receptor receptors are a subclass of excitatory amino acid receptors which play an important role in brain development learning and memory processes. NMDAR on the synaptosome acts as a co-incidence receptor, detecting presynaptically released glutamate, and postsynaptic depolarization, which removes the Mg2+ block leading to Ca2+ influx and the activation of various enzymes involved in LTP. The gene expression of NMDAR subunits differs neuroanatomically and temporally. NMDAR2R play an important role during the course of neuron cell growth and development, synaptogenesis, LTP, neuro signal transduction and the release of neurotransmitter.
The NMDAR in developing brain is an important target of lead. Lead is a potent noncompetitive antagonist of the NMDA receptor. In vitro electro-physiological studies showed that lead could inhibit the NMDA activated whole cell currents, and that lead could also inhibit the opening of the single gate of NMDAR. Immature neurons are more sensitive to lead poison than mature neurons. But it is not known clearly whether Pb impairs the expression level of mRNA of NMDAR subunits. And the relationship between the effects and the exposure level of lead also isn’t known yet.
Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) with eight cloned subtypes classified into three groups based on sequence homology, pharmacology and transduction mechanism. Metabotropic glutamate receptors 1(mGluR1) belonged Group I is an important member of family of GPCRs. The signal transduction induced by mGluR1 plays an important role in the regulation of the central nervous system functions, and is involved in many neurodegenerative diseases participates in LTP; the role of these receptors remains unclear. A pathway linking class I-mGluRs with PKC is sure to enhance the open probability of the NMDAR channel. The mGluR-mediated potentiation of NMDAR activity may play a role in synaptic transmission and plasticity including LTP.
Pb toxicity is also known to induce oxidative stress through over production of reactive oxygen species (ROS) including superoxide radicals (O2?), hydroxyl radicals (·OH) and hydrogen peroxide (H2O2). These free radicals and hydrogen peroxides cause membrane damage (which is often related to lipid peroxidation); which effect the development of central nerve system of rats exposed to lead. We have noted enhanced lipid peroxidation and disorders in the activity of antioxidative enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the brain of rats exposed to Pb.
Nitric oxide (NO) is regarded as typical retrograde messenger, important in learning and memory. Its biosynthesis is modulated by nitric oxide synthase (NOS). At Present, the level of NO is reflected mainly by NOS activity. Lead can inhibit NOS activity and therefore reduce NO.
Objectives:
We established a series of rat models exposure to low-level Lead in different developmental stages, and then measured the concentration of lead in the blood and brain,δ-ALAD in blood, determinate the changes of mRNA expression of mGlur1、NMDAR-2R in different brain regions(hippocampus, cortex), evaluate SOD, GSH-Px, NOS activity. From a widespread domain, research the relationship among the change of each index and lead level, time of exposure, and provid experiment evidences on how lead harms learning and memory function, explore the likely mechanism for the lead neurotoxicology.
Methods:
1. The rat models were established by exposing rats to 0.2% mg/ml lead acetate solution via drinking water respectively in different developing stages and divided into control group, lead exposure during pregnancy group (GroupA), lead exposure lactation period group (GroupB), and lead exposure after ablactation (GroupC). The samples were taken on 60th～68th day, the body, brain, hippocampus and cerebral cortex weights were measured respectively.
2. The contents of lead in blood, hippocampus and cerebral cortex were measured by graphite furnace atomic absorption spectrometry; the activities of ALAD in blood were measured by spectra photometer.
3. The ability of learning and memory was tested by Morris water maze.
4. Expression of NMDA receptor 2A, 2B, 2C subunits mRNA and mGlur1 mRNA in rat cerebral cortex and hippocampus were measured by semi-quantitative reverse transcript polymerase-chain reaction (RT-PCR), withβ-actin as standard.
5. Hippocampus and cerebral cortex tissue respectively were detected activity of SOD, GSH-Px and NOS by commercial kits.
Results:
1. Compare with the control, no differences in body weights, brain/body of dams were measured between any two groups (P>0.05). Compare with the control, hippocampus weights, brain weights of GroupA, brain weights of GroupB were decrease (P<0.01), Cortex weights of GroupA were higher than those of GroupB and GroupC (P<0.01).
2. The blood and brain lead level of Pb-exposed dams were higher than those of control group; the activity of ALAD were lower than those of control group, especially the GroupC (P<0.01, P<0.05). Compare with the control, lead concentra- tion in both hippocampus and cerebral cortex is elevated significantly in GroupA (P<0.01); lead concentration in blood is increase (P<0.01) and the activity of ALAD in blood is decrease (P<0.05).
3. The results of Morris water maze showed that the escape latencies in all groups were not significantly different in the first day of the test. In the last three days of the test, the escape latencies in treatment groups were significantly longer than the control group, particularly the GroupC, the average escape latency was significantly elevated compared with the control, while it is different from any other group in any quadrant (P<0.05); Compared with the control, the escape latencies is long in I quadrant of GroupA, and in I, IV quadrant of GroupB (P<0.05). But there was no significant difference between GroupA and the control group (P>0.05) in II and IV quadrant.
4. The expression levels of NR2A mRNA in treatment groups were significantly higher than the control group, particularly the GroupA were highest of groups; The expression levels of NR2B mRNA in hippocampus were significantly decreased compared the control (P<0.05), contrary to the control, the expression levels of NR2B mRNA of the GroupB in cerebral cortex were decrease (P<0.05); The expression levels of NR2C mRNA in hippocampus of GroupA were higher than the control (P<0.01).
Contrary to the control, the expression of mGlur1 mRNA were significantly lower in both cerebral cortex and hippocampus of GroupA and cortex of GroupB (P<0.01). But contrary to the control, expression of mGlur1 mRNA in cerebral cortex and hippocampus of GroupC were significantly elevated (P<0.01).
5. The activity of SOD in GroupA and B increased compared with the control, especially the GroupB is higher than the control and GroupC (P<0.05); Compared with the control, the activity of GSH-Px is elevated, GroupB is higher than the control and GroupA (P<0.05, P<0.01). The activity of NOS is decrease, GroupC is lower than the control (P<0.05).
Conclusions:
1. The contents of lead in blood, cerebral cortex and hippocampus were significantly increased in treatment groups. Lead acetate could inhabit the concentration of ALAD. Concentration of Pb in brain would decrease with time went by once without Pb exposure.
2. The low level Pb do exposure would result in impairment of learning and memory ability for life long.
3. The lead in blood in the pregnant rat can come into the body of fetus through the placenta. It also can come across the incomplete blood-brain barrier and reach to nervous system. Lead poisoning can also through latex accumulate in offspring during sucking period. By this way, the abilities of learning and memory would be affected. Further more, the effects would last to the period of maturation.
4. Lead could change the expression of mGlur1and NMDAR mRNA in brain. Developmental low level lead exposure of rats can decrease the expression level of NR2BmRNA in brain. Meantime, the abilities of learning and memory would be affected. So, effects on NMDAR, mGlur1may be one of the neurotoxic mechanisms of lead.
5. The activity of anti-oxidative enzymes increase after Pb exposure, which would attribute to oxidative injury in brain; the activity of NOS depress indicated that there would be a decrease production of NO. It may be because that lead as a kind of heave mental can inhibit the production of NO by combining with the centre activity of NOS, or it would affect glutamic acid and NMDA receptor as messenger leading to excitatory neurotoxicity. Changes in cognitive ability were perhaps dependent on these results in some degree.
在神经系统的发育和再生过程,海马是负责学习记忆的关键脑区,特别是短期记忆和近期记忆。海马长时程增强效应(Long term potentiation,LTP)被认为是海马学习和记忆的储存功能单位。兴奋性神经递质特定受体——谷氨酸触发了LTP。
N-甲基-D-天冬氨酸受体(N–methyl-D-aspartate Receptors,NMDARs)是一种兴奋性氨基酸受体亚单位,在脑的发育、学习与记忆机制中起重要作用。NMDARs作为一个双向受体,可检测到突触受体释放谷氨酸,突触后去极化,使Mg2+阻滞作用消失,通道开放,导致Ca2+内流,激活一系列酶作用反应,同时这些又是构成LTP诱导和维持的物质基础。NMDAR表达存在选择性,主要功能和特性差异源于NR2亚基的不同表达和分布,故此测定NR2。NR2在神经细胞生长发育、突触传递、LTP、神经信号传导和神经递质释放过程中起着重要作用。
生长发育期脑NMDAR是铅作用的重要目标,铅是NMDAR的非竞争性拮抗剂。离体海马神经元电生理研究发现,铅能抑制NMDA激活的全细胞电流,抑制NMDAR单通道的开放频率,且其抑制作用的强度与神经元的成熟程度有关,幼稚神经元对铅的抑制作用更加敏感。但目前还不清楚铅影响NMDA受体mRNA表达的机理,以及暴露水平与影响之间的具体关系。
代谢性谷氨酸受体(Metabotropic glutamate receptors,mGluR)是G蛋白偶联受体(G protein-coupled receptors,GPCR),依据序列的同源性、受体的药理学特性及其所偶联的细胞内第二信使的不同超家族,将8个受体分为中分为三组。代谢性谷氨酸受体亚型1(mGlur1)属于I组,是GPCRs家族的重要成员可能在调节中枢神经系统作用、学习记忆突触的形成和维持、神经元信号转导过程中起重要作用,可引起强烈的兴奋性神经毒性,导致神经元的肿胀和坏死,和神经退行性病变有关,并参与了LTP过程,但具体机理尚不清楚。I组受体和蛋白激酶C偶联,增强NMDA受体通道的开放。mGluR介导的NMDAR活性增强在突触传递和突出可塑性,包括LTP过程中起重要作用。
众所周知,铅毒性通过活性氧族产物诱发氧化损伤,包括超氧离子(O2?),羟基(·OH)和过氧化氢(H2O2)。这些自由基和过氧化物引起膜损伤,常与脂质过氧化有关,影响发育时期暴露于铅的大鼠中枢神经系统。值得注意的是,染铅后大鼠脑组织内可观察到脂质过氧化反应增强,以及抗氧化酶如超氧化物歧化酶(Superoxide dismutase,SOD)、谷胱甘肽超氧化物酶(Glutathione peroxidase,GSH-Px)活性降低。
一氧化氮(Nitric oxide,NO)被认为是典型的逆行信使分子,在学习和记忆中起到重要作用,其生物合成主要受一氧化氮合酶(Nitric oxide synthase,NOS)的调节,目前多是以NOS活性来反映NO的水平。而铅对NOS活性有抑制作用,可使NO减少甚至消失。
目的:
本研究通过建立一系列在生长发育时期的不同阶段低水平大鼠铅暴露模型,检测铅在子代全血和脑组织中的浓度,全血δ-ALAD活性,及不同脑组织中mGlur1、NMDAR亚单位mRNA,SOD,GSH-Px,NOS活性。从一个广泛的角度研究各项指标变化与铅暴露浓度、暴露时间之间的关系,为铅损伤对学习记忆功能及神经行为的改变的研究提供一定的实验依据,进一步探讨醋酸铅的神经毒作用机制。
方法:
1.在不同发育阶段,采用0.2%的醋酸铅溶液自由饮水作为处理因素,建立铅暴露的动物模型,设立正常对照组、孕期暴露组(A组)、哺乳期铅暴露组(B组)、断乳后铅暴露组(C组)。于PND60取材,测量体重及脑重,海马、双侧皮质的重量。
2.用石墨炉-原子吸收光谱法测定血脑组织中铅的含量;用分光光度计测量全血ALAD,评价铅吸收程度。
3.以Morris水迷宫检测不同发育阶段铅暴露后动物的空间学习记忆能力。
4.用半定量RT-PCR方法,结合技术图像分析系统,检测皮层、海马组织中mGlur1及NMDA相关受体mRNA表达量,比较不同时期染毒的变化,观察醋酸铅对大鼠脑组织mGlur1及NMDA受体表达的影响。
5.测定脑组织中的过氧化物酶指标,SOD,GSH-Px和NOS,探讨铅对神经系统损伤的氧化损伤机制。
结果:
1.与对照组相比,染毒剂量组的大鼠体重、脑体重比率差异无显著性(P>0.05),不同时期染毒组之间差异无显著性(P>0.05)。相对于对照组,A组的脑重、海马重量,B组的脑重有显著性减少(P<0.01),A组的皮质重量大于B、C组(P<0.01)。
2.醋酸铅处理后,各剂量染铅组大鼠相对于对照组全血、皮层、海马组织中铅含量显著增加,ALAD活力下降,差异有显著性。A组:与对照组相比,脑铅含量有显著性增加(P<0.01);B组:与对照组相比,血铅升高、ALAD含量降低,差别有显著性(P<0.01,P<0.05);C组:与对照组相比,仔鼠的血铅、脑铅、ALAD含量改变显著,差别有显著性(P<0.01,P<0.05)。
3.在Morris水迷宫测试中,第1天各组动物的测试成绩之间无显著性差异,从第2天起,各染铅组仔鼠的逃避潜伏期(Escape Latency)值均高于对照组,其差别有显著性(P<0.05,P<0.01)。虽然在训练过程中各染铅组的成绩有所提高,但各染铅组后3天的潜伏期曲线始终无法恢复到正常水平,尤其是C组相对于对照组以及其它各组在各象限都有显著性差异(P<0.05)。与对照组相比,A组在第I象限,B组在第I、IV象限的潜伏期时间差异显著(P<0.05)。但是A组在第II、IV象限的潜伏期时间和对照相比无统计学差异(P>0.05)。
4. RT-PCR结果显示,染毒组NR2AmRNA在海马和皮层中表达较对照组有不同程度升高,尤其在A组中的表达大于其他各组,有显著性差异(P<0.05);各染毒组NR2BmRNA在海马表达较对照组有不同程度的下降,并有显著性差异(P<0.05),B组的受体在皮质中表达量与对照有显著性差异(P<0.05);NR2CmRNA在皮质中的表达与对照没有统计学差异(P>0.05),A组NR2CmRNA在海马中较对照组表达增加,差异具有统计学意义(P<0.01);与对照组相比,A组在皮质、海马中,以及B组在皮质中的mGlur1受体表达减少,C组正好相反,受体表达不论在皮质还是海马中均高于对照组,两组结果都具有显著性差异(P<0.01)。
5.过氧化物酶测定结果显示,不同时期染毒组SOD活性呈波形趋势,A、B组较对照组不同程度升高,其中B组与对照组、C组差异具有统计学意义(P<0.05),C组较对照组SOD活性降低,但无统计学差异(P>0.05);各染毒组GSH-Px活性较对照组有不同程度升高,尤其B组与对照组、A组差异都具有统计学意义(P<0.05,P<0.01);NOS活性染毒组较同时期对照组有不同程度下降,C组与对照组相比有显著性差异(P<0.05)。
结论:
1.醋酸铅处理后,铅在各染毒组大鼠全血、海马、皮质组织中的含量显著增加,ALAD活性降低。停止铅暴露后,脑组织中的铅含量随年龄增长浓度不断下降。
2.低浓度的铅暴露对学习记忆造成损伤,且损伤将一直持续到成年。
3.孕鼠血中的铅可以通过胎盘屏障进入胎鼠,也可通过发育尚不完善的血脑屏障到达神经系统。在哺乳阶段铅可通过乳汁在子代体内蓄积。通过上述一系列途径,醋酸铅可干扰其子代神经系统的正常生长发育,进而影响仔鼠的学习记忆能力,并且这种损害作用将持续到仔鼠的成熟期。
4.铅可改变脑组织中mGlur1和NMDAR受体mRNA的表达,尤其是低浓度铅暴露使生长发育时期的大鼠脑组织中NR2BmRNA的表达降低,同时可观察到学习记忆能力的下降,所以可以推测mGlur1和NMDAR受体可能是铅神经毒性的机制之一。
5.不同发育期醋酸铅暴露可使脑组织中抗氧化酶类活性升高将加重脑损伤。同时NOS活性的降低可推断NO生成减少,可能是一方面铅作为重金属与NOS的活性中心结合进而产生抑制作用,使NOS酶活性降低或完全失活;另一方面,铅通过影响谷氨酸递质、NMDA受体及Ca2+等进一步抑制NOS酶活性。从某种程度上说,这些作用影响了信号转导和认知能力
With the acceleration of the industrialization and modernization of community, continuous discharge and disposal of industrial waste products containing hazardous materials have resulted in serious contamination of the soil and water bodies, but Pb has grabbed more attention due to its longer persistence in soil and highly toxic effects on both crop production and human health. Lead is a kind of common toxic heavy metal that has obvious and sure damage to apparatus and tissue of individual, especially strong neurotoxicity, which can damage the developmental central nervous system (CNS). It caused major public health problem because of the documented effects on cognitive development. Lead can be transported from mother to fetus through placenta easily and it also can come into the CNS of fetus through the incomplete blood-brain barrier and do harm to the developmental CNS. As a result, the offspring’s ability of learning and memory would be affected; it also can transport into newborn by sucking lacto, which induced to the increase of lead burden in baby body; during the childhood, it can cause destruction of child’s IQ exposed to lead. Furthermore, these destroy will last during the whole life.
During neuronal development and regeneration, hippocampus is an important encephalic region that charge for learning and memory, especially for short-term memory and recent memory. Long-term potentiation (LTP) is a cellular model of the synaptic plasticity that may underlie memory acquisition, which may be representative of learning and memory processes in mammalian brain. LTP is triggered by certain receptors for the excitatory neurotransmitter, glutamate.
The N-methyl-D-aspartate (NMDA) receptor receptors are a subclass of excitatory amino acid receptors which play an important role in brain development learning and memory processes. NMDAR on the synaptosome acts as a co-incidence receptor, detecting presynaptically released glutamate, and postsynaptic depolarization, which removes the Mg2+ block leading to Ca2+ influx and the activation of various enzymes involved in LTP. The gene expression of NMDAR subunits differs neuroanatomically and temporally. NMDAR2R play an important role during the course of neuron cell growth and development, synaptogenesis, LTP, neuro signal transduction and the release of neurotransmitter.
The NMDAR in developing brain is an important target of lead. Lead is a potent noncompetitive antagonist of the NMDA receptor. In vitro electro-physiological studies showed that lead could inhibit the NMDA activated whole cell currents, and that lead could also inhibit the opening of the single gate of NMDAR. Immature neurons are more sensitive to lead poison than mature neurons. But it is not known clearly whether Pb impairs the expression level of mRNA of NMDAR subunits. And the relationship between the effects and the exposure level of lead also isn’t known yet.
Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) with eight cloned subtypes classified into three groups based on sequence homology, pharmacology and transduction mechanism. Metabotropic glutamate receptors 1(mGluR1) belonged Group I is an important member of family of GPCRs. The signal transduction induced by mGluR1 plays an important role in the regulation of the central nervous system functions, and is involved in many neurodegenerative diseases participates in LTP; the role of these receptors remains unclear. A pathway linking class I-mGluRs with PKC is sure to enhance the open probability of the NMDAR channel. The mGluR-mediated potentiation of NMDAR activity may play a role in synaptic transmission and plasticity including LTP.
Pb toxicity is also known to induce oxidative stress through over production of reactive oxygen species (ROS) including superoxide radicals (O2?), hydroxyl radicals (·OH) and hydrogen peroxide (H2O2). These free radicals and hydrogen peroxides cause membrane damage (which is often related to lipid peroxidation); which effect the development of central nerve system of rats exposed to lead. We have noted enhanced lipid peroxidation and disorders in the activity of antioxidative enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the brain of rats exposed to Pb.
Nitric oxide (NO) is regarded as typical retrograde messenger, important in learning and memory. Its biosynthesis is modulated by nitric oxide synthase (NOS). At Present, the level of NO is reflected mainly by NOS activity. Lead can inhibit NOS activity and therefore reduce NO.
Objectives:
We established a series of rat models exposure to low-level Lead in different developmental stages, and then measured the concentration of lead in the blood and brain,δ-ALAD in blood, determinate the changes of mRNA expression of mGlur1、NMDAR-2R in different brain regions(hippocampus, cortex), evaluate SOD, GSH-Px, NOS activity. From a widespread domain, research the relationship among the change of each index and lead level, time of exposure, and provid experiment evidences on how lead harms learning and memory function, explore the likely mechanism for the lead neurotoxicology.
Methods:
1. The rat models were established by exposing rats to 0.2% mg/ml lead acetate solution via drinking water respectively in different developing stages and divided into control group, lead exposure during pregnancy group (GroupA), lead exposure lactation period group (GroupB), and lead exposure after ablactation (GroupC). The samples were taken on 60th～68th day, the body, brain, hippocampus and cerebral cortex weights were measured respectively.
2. The contents of lead in blood, hippocampus and cerebral cortex were measured by graphite furnace atomic absorption spectrometry; the activities of ALAD in blood were measured by spectra photometer.
3. The ability of learning and memory was tested by Morris water maze.
4. Expression of NMDA receptor 2A, 2B, 2C subunits mRNA and mGlur1 mRNA in rat cerebral cortex and hippocampus were measured by semi-quantitative reverse transcript polymerase-chain reaction (RT-PCR), withβ-actin as standard.
5. Hippocampus and cerebral cortex tissue respectively were detected activity of SOD, GSH-Px and NOS by commercial kits.
Results:
1. Compare with the control, no differences in body weights, brain/body of dams were measured between any two groups (P>0.05). Compare with the control, hippocampus weights, brain weights of GroupA, brain weights of GroupB were decrease (P<0.01), Cortex weights of GroupA were higher than those of GroupB and GroupC (P<0.01).
2. The blood and brain lead level of Pb-exposed dams were higher than those of control group; the activity of ALAD were lower than those of control group, especially the GroupC (P<0.01, P<0.05). Compare with the control, lead concentra- tion in both hippocampus and cerebral cortex is elevated significantly in GroupA (P<0.01); lead concentration in blood is increase (P<0.01) and the activity of ALAD in blood is decrease (P<0.05).
3. The results of Morris water maze showed that the escape latencies in all groups were not significantly different in the first day of the test. In the last three days of the test, the escape latencies in treatment groups were significantly longer than the control group, particularly the GroupC, the average escape latency was significantly elevated compared with the control, while it is different from any other group in any quadrant (P<0.05); Compared with the control, the escape latencies is long in I quadrant of GroupA, and in I, IV quadrant of GroupB (P<0.05). But there was no significant difference between GroupA and the control group (P>0.05) in II and IV quadrant.
4. The expression levels of NR2A mRNA in treatment groups were significantly higher than the control group, particularly the GroupA were highest of groups; The expression levels of NR2B mRNA in hippocampus were significantly decreased compared the control (P<0.05), contrary to the control, the expression levels of NR2B mRNA of the GroupB in cerebral cortex were decrease (P<0.05); The expression levels of NR2C mRNA in hippocampus of GroupA were higher than the control (P<0.01).
Contrary to the control, the expression of mGlur1 mRNA were significantly lower in both cerebral cortex and hippocampus of GroupA and cortex of GroupB (P<0.01). But contrary to the control, expression of mGlur1 mRNA in cerebral cortex and hippocampus of GroupC were significantly elevated (P<0.01).
5. The activity of SOD in GroupA and B increased compared with the control, especially the GroupB is higher than the control and GroupC (P<0.05); Compared with the control, the activity of GSH-Px is elevated, GroupB is higher than the control and GroupA (P<0.05, P<0.01). The activity of NOS is decrease, GroupC is lower than the control (P<0.05).
Conclusions:
1. The contents of lead in blood, cerebral cortex and hippocampus were significantly increased in treatment groups. Lead acetate could inhabit the concentration of ALAD. Concentration of Pb in brain would decrease with time went by once without Pb exposure.
2. The low level Pb do exposure would result in impairment of learning and memory ability for life long.
3. The lead in blood in the pregnant rat can come into the body of fetus through the placenta. It also can come across the incomplete blood-brain barrier and reach to nervous system. Lead poisoning can also through latex accumulate in offspring during sucking period. By this way, the abilities of learning and memory would be affected. Further more, the effects would last to the period of maturation.
4. Lead could change the expression of mGlur1and NMDAR mRNA in brain. Developmental low level lead exposure of rats can decrease the expression level of NR2BmRNA in brain. Meantime, the abilities of learning and memory would be affected. So, effects on NMDAR, mGlur1may be one of the neurotoxic mechanisms of lead.
5. The activity of anti-oxidative enzymes increase after Pb exposure, which would attribute to oxidative injury in brain; the activity of NOS depress indicated that there would be a decrease production of NO. It may be because that lead as a kind of heave mental can inhibit the production of NO by combining with the centre activity of NOS, or it would affect glutamic acid and NMDA receptor as messenger leading to excitatory neurotoxicity. Changes in cognitive ability were perhaps dependent on these results in some degree.
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