大鼠孕期低水平铅暴露对子代学习记忆能力的影响及其机理的研究
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摘要
铅是人类认识和研究的最古老的毒物之一,是常见的环境和生活污染物,可通过呼吸道、消化道、皮肤粘膜等途径进入体内,造成人体多种器官系统的损害,尤其是中枢神经系统,是其毒性作用的主要靶器官之一。
随着人们对铅毒危害认识的不断深入,采取各种保护措施,高水平铅暴露所致的损害已经逐渐减少,但是来自环境和生活中低水平的铅暴露仍然十分常见。其中儿童由于血脑屏障未发育成熟等原因,比成人对铅的神经毒性更为敏感,较低水平的铅暴露即可造成儿童中枢神经系统的功能障碍。对于低水平铅暴露所致的儿童铅损伤尤其是神经系统损伤及其机制的研究,成为当今公共卫生研究领域的一个热点。
学习和记忆是神经系统所具有的基本功能,也是最重要机能之一。海马是学习记忆的关键部位,亦是铅作用的敏感靶部位。铅有很强的发育神经毒性,即使是低水平的铅暴露,发育中的中枢神经系统也很容易受到铅毒性的损害。胎儿和婴幼儿期是脑发育的关键时期,在该时期接触到铅后,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。
在儿童接触铅的众多途径中,母体孕期铅暴露对胎儿脑发育的影响是十分重要的一个方面。研究表明发育早期铅暴露(怀孕/哺乳)所产生的认知和神经行为缺陷,在停止铅暴露后可能会持续影响到成年阶段。胚胎阶段的器官发生期和出生前后一段时期是中枢神经系统发育最迅速、也最易受到外来毒物损害的时期,处于围产期的胎儿或婴幼儿接受铅暴露后神经系统所受的损害可能较其它时期更为严重。但母体孕期低水平铅暴露对其子代中枢神经系统的损害及其机理缺乏深入而系统的研究。本研究采取大鼠孕期低水平铅暴露的方式,测定其子代血铅和海马组织铅的含量,并观察其子代学习记忆机能力的变化,探讨这种变化与铅接触之间的关系,为彻底揭示铅中毒的机理、优生优育和预防并降低儿童学习记忆的损伤,提供科学依据。
第一部分大鼠孕期低水平铅暴露对子代大鼠血液和海马组织铅含量的影响
目的:建立大鼠孕期低水平铅暴露的动物模型,观测大鼠孕期铅暴露后子代血铅和海马铅含量的变化,为分析学习记忆能力的改变与体内铅含量的关系,揭示铅影响学习记忆的机理打下基础。
方法:Wistar大鼠受孕后随机分为4组,3个处理组自怀孕第1天起分别给予醋酸铅含量为125、250和500mg/L的饮水,对照组给予无铅蒸馏水;仔鼠出生后母鼠正常饮水、饮食,仔鼠由母鼠喂养至断乳后与母鼠分笼饲养;仔鼠出生1d时取全脑、21d和60d时取海马组织,采用流动注射氢化物发生-原子吸收光谱法进行铅含量测定。
结果:孕鼠接触不同剂量铅后,各剂量组1d、21d龄的仔鼠血铅、海马组织铅含量显著高于对照组仔鼠,差异有统计学意义(P<0.05,P<0.01),并且仔鼠血铅、海马组织铅含量与孕鼠铅暴露剂量之间有良好的剂量反应关系;至60d龄时,处理组和对照组仔鼠的血铅、海马组织铅含量无明显差异(P>0.05)。说明随着孕鼠铅暴露剂量的增加,进入仔鼠血液和海马组织内的铅也随之增加。
结论:大鼠孕期低水平铅暴露,可使子代大鼠血液和脑组织中的铅含量增加,说明铅易于透过胎盘屏障和血脑屏障,引起子代血铅增高,并蓄积在脑组织中。宫内铅暴露后子代大鼠血铅和海马铅的增高至少可以持续到仔鼠的断乳期,至成熟期时,可下降至正常水平。
第二部分大鼠孕期低水平铅暴露对子代大鼠学习记忆能力的影响
目的:观察大鼠孕期铅暴露后对子代大鼠学习记忆能力的影响,并探讨这种改变与海马组织铅含量的关系,从而进一步判定铅对子代神经系统的毒性作用。
方法:以Morris水迷宫、Y迷宫和避暗穿梭箱实验三种方法,观测仔鼠学习记忆能力的变化。
结果:Morris水迷宫测试结果显示,各处理组21d和60d龄的仔鼠,连续4天训练期间,第2、3、4天时潜伏期均显著高于同期对照组仔鼠,差异有统计学意义(P<0.05, P<0.01)。避暗穿梭箱测试结果显示,各处理组21d和60d龄的仔鼠连续5天训练期间,主动回避次数低于同期对照组仔鼠,差异有统计学意义(P<0.05,P<0.01);而主动回避潜伏期和被动回避潜伏期均高于同期对照组仔鼠,差异有统计学意义(P<0.05 or P<0.01)。Y迷宫测试结果显示,各处理组21d和60d龄的仔鼠,获取记忆的能力、保持记忆的能力和记忆保持率均低于同期对照组仔鼠,差异有统计学意义(P<0.05,P<0.01)。
综合分析海马铅含量和学习记忆能力之间的关系,海马组织铅含量越高,仔鼠的学习记忆能力越差;另外,各处理组仔鼠生长至成熟期(60d)时,血铅和海马铅含量已降至正常水平,但学习记忆能力仍显著低于对照组,未完全恢复,说明铅对仔鼠学习记忆能力的影响至少可持续到仔鼠的成熟期,学习记忆能力的恢复需要较长时间。
结论:大鼠孕期低水平铅暴露,可以损害仔鼠的学习记忆能力,而且这种损害作用至少可以持续到仔鼠的成熟期;仔鼠的学习记忆能力与其海马组织的铅含量有关,铅含量越高,学习记忆能力受损越严重。
第三部分大鼠孕期低水平铅暴露对子代大鼠学习记忆能力影响的机理研究
目的:观察大鼠孕期铅暴露后,对子代大鼠海马组织细胞凋亡、胶质细胞、与生长相关因子情况的影响,并分析上述变化与仔鼠学习记忆能力受损的关系,探讨母体铅暴露对子代学习记忆能力影响的机理。
方法:采用流式细胞技术和末端脱氧核糖核酸转移酶介导的缺口末端标记法(TUNEL),观察大鼠孕期铅暴露后仔鼠海马神经元细胞凋亡发生情况;免疫组织化学和Western blot技术检测海马星形胶质细胞胶质原纤维酸性蛋白(GFAP)表达的变化,原位杂交和荧光定量PCR技术检测海马星形胶质细胞GFAP mRNA表达的变化;免疫组织化学和Western blot技术检测海马细胞神经生长相关蛋白(GAP-43)和神经生长因子(NGF)蛋白表达的变化,原位杂交和荧光定量PCR技术检测海马细胞GAP-43和NGF mRNA表达的变化;分析上述指标变化与学习记忆能力受损之间的关系。
结果:大鼠孕期低水平铅暴露对子代大鼠海马细胞凋亡的影响:流式细胞检测结果显示,各处理组1d、21d和60d龄的仔鼠,海马细胞凋亡率显著高于对照组,差异有统计学意义(P<0.05,P<0.01),并且各时间段细胞凋亡率与海马铅含量之间有良好的剂量反应关系;TUNEL法检测结果显示,1d龄的仔鼠,各处理组海马细胞凋亡指数均显著高于对照组,差异有统计学意义(P <0.05,P<0.01),21d和60d阶段,中、高剂量组海马细胞凋亡指数显著高于对照组(P <0.05,P<0.01),而低剂量组与对照相比未见显著性差异,各时间段仔鼠细胞凋亡指数与海马组织铅含量之间有良好的剂量反应关系;综合分析海马细胞凋亡与学习记忆能力之间的关系,海马细胞凋亡率或凋亡指数越高,仔鼠的学习记忆受损越严重,学习记忆能力越差。
大鼠孕期低水平铅暴露对子代大鼠海马胶质细胞的影响:免疫组化和Western blot技术检测GFAP蛋白表达的结果显示,各处理组1d和21d龄的仔鼠,海马区GFAP免疫阳性反应阳性细胞平均数目、积分光密度和相对灰度值,显著高于同期对照组仔鼠(P <0.05,P<0.01),并与海马组织铅含量有良好的剂量反应关系,至60d时,未见显著性差异。原位杂交和荧光定量PCR技术检测GFAP mRNA表达的结果显示,各处理组1d和21d龄的仔鼠,海马GFAP mRNA阳性细胞数、积分光密度和△CT明显高于对照组,有显著性差异(P<0.05,P<0.01),在60d阶段,未见显著性差异;1天阶段海马组织铅含量与GFAP mRNA阳性细胞数目之间有良好的剂量反应关系,1d和21d阶段海马铅含量与GFAP mRNA积分光密度之间也有良好的剂量反应关系。综合分析海马细胞GFAP表达与学习记忆能力之间的关系,GFAP表达增强后仔鼠的学习记忆能力下降。
大鼠孕期低水平铅暴露对子代大鼠海马生长相关因子的影响:免疫组化检测结果显示,各处理组1d龄的仔鼠,海马组织中GAP-43免疫组化反应物的面密度和积分光密度均显著降低,与对照组相比有显著性差异(P<0.05,P<0.01);21d阶段,中、高剂量组的面密度和积分光密度低于对照组,其差别有显著性(P<0.05,P<0.01),到60d阶段时,各剂量的面密度和积分光密度均无显著性差异;1d和21d阶段海马组织铅含量与GAP-43免疫组化面密度和积分光密度呈明显负相关。Western blot结果显示,各处理组1d和21d龄的仔鼠GAP-43蛋白表达明显低于对照组,具有显著性差异(P<0.05,P<0.01);至60d时,未见显著性差异。原位杂交结果显示,各处理组1d龄的仔鼠,GAP-43 mRNA表达的面密度、积分光密度均低于对照组,差别有显著性(P<0.05,P<0.01);21d阶段中、高剂量组的面密度和积分光密度低于对照组,差别有显著性(P<0.05,P<0.01),且和海马铅含量呈明显负相关;至60d时,各剂量组与对照组相比均无显著性差异。荧光定量PCR结果显示,各处理组1d和21d龄的仔鼠GAP-43 mRNA表达明显降低,与对照组相比具有显著性差异(P<0.01),仔鼠发育至60d时,各剂量组海马区GAP-43 mRNA表达与对照组比较未见显著性差异。
免疫组化和Western blot检测仔鼠海马组织NGF的表达情况,发现各处理组1d和21d龄的仔鼠,NGF免疫组化反应物的面密度、积分光密度和相对灰度值均显著降低,与对照组相比有显著性差异(P<0.05,P<0.01),且与海马组织铅含量程明显负相关;到60d时,均未见显著性差异。原位杂交结果显示,各处理组1d龄的仔鼠,NGF mRNA阳性反应物颗粒的面密度积分光密度均低于对照组,差别有显著性(P<0.05,P<0.01);21d阶段中、高剂量组的面密度和积分光密度低于对照组,差别有显著性(P<0.05,P<0.01);1d和21d阶段海马组织铅含量与NGF mRNA面密度和积分光密度呈明显负相关;荧光定量PCR结果显示,各处理组1d和21d龄的仔鼠NGF mRNA表达显著降低,与对照组相比具有显著性差异(P<0.05,P<0.01);至60d时,未见显著性差异。
综合分析GAP-43和NGF表达与仔鼠学习记忆能力的关系,发现随着海马铅含量的升高,海马组织GAP-43和NGF蛋白及mRNA表达下降,而仔鼠的学习记忆能力也随之降低。
结论:大鼠孕期低水平铅暴露,可以导致仔鼠脑海马区神经细胞凋亡增加,且与海马铅含量呈正相关;可以使仔鼠脑海马区GFAP阳性的胶质细胞数目增多,GFAP蛋白和mRNA表达增加,且与海马铅含量呈正相关,GFAP表达的变化至仔鼠出生60天时消失。可以抑制仔鼠脑海马区GAP-43、NGF蛋白和mRNA表达,且这种抑制作用与海马铅含量呈正相关,蛋白和mRNA表达表达的变化至仔鼠出生60天时消失。提示大鼠孕期低水平铅暴露,可以通过诱导仔鼠海马区神经细胞凋亡、提高GFAP表达水平、降低GAP-43和NGF表达水平等机制,损伤子代的的学习记忆能力。
Lead, the most common environmental daily life pollutant, is one of the oldest of established environmental poisons. Lead can enter into the human’s body and contributes to the damages of functions of many organs and systems. The central nervous system(CNS), especially, is the most important target of lead-mediated toxicity.
The adverse effects from high level lead exposure have been decreased with the deeply knowledgement about lead toxicity and the taking of various preventive measures. But the low level lead exposure from environment and daily life is quite common. Because of the developing immature of blood brain barrier, the children are more sensitive than that of the adult to lead induced insults. So even low level lead exposure can give rise to functional disorder in children. The damage from low level lead exposure to children, especially to CNS and the mechanism of lead actions, is the hot point in public health research areas.
Learning and memory, the basic functions of CNS, is one of the most important functions of CNS. As the key structure for learning and memory, hippocampus is the sensitive target of lead toxicity. It is approved that lead have very strong developmental neurotoxicity, even low level lead exposure can damage the developmental CNS. It is the critical period for development of CNS in fetus and infant. If prenatal lead exposure occurred, 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.
Lead exposure during the gestation period is most responserble for the damage to the developing central nervous system of fetus caused by lead through various ways into the chhildrens’body. Previous studies indicate that impairment of later cognitive and neurobehavioral function result from lead exposure during early developing period(gestation/lactation) could persist long till to adult after the exposure has ceased. The developmental central nervous system (CNS) in organogenetic period and postnatal period are in a state of rapid growth, and more sensitive to toxic metals such as lead. Pb can make more serious damages to fetus and infant brains in prenatal stage than other stages. Despite intensive research, no consensus on the adverse effects and mechanisms of prenatal low level lead exposure to CNS in young offspring has resulted.
In the present study we detected the Pb concentration in blood and content in the hippocampus in offspring rats after low level lead exposure during pregnancy. The changes of learning and memory in offspring rats were examined by Morris water maze test, shuttling and avoiding dark box test, and Y-type maze test. This study attempts to reveal the possible molecular mechanism of Pb induced neural development toxicity and provide the base of aristogenesis as well as prevent to the deficient of learning and memory of children.
Part 1 The effects of prenatal low level lead exposure on the content of lead in blood and hippocampus of offspring rats.
Objective: To establish the animal model of low level lead exposure during pregnancy, and to detect the changes of Pb concentration in blood and hippocampus in offspring rats and analyze the possible relationship between the Pb exposure and the deficient of learning and memory of offspring rats. This study in part provided the base data for revealing the possible mechanism of Pb to reduce the ability of learing and memory.
Methods: The pregnant Wistar rats are housed separately and randomly divided into 4 groups and provided with doubly distilled water in the control group and 125、250、500mg/L lead acetate solution via drinking water in three exposured groups respectively during the pregnancy. The content of lead in blood and hippocampus of 21-day and 60-day old offsprings were measured by flow-injection hydride generation-atomic absorption spectrometry. At 1-day old offspring, the hippocampus was instead by whole brain.
Results: The blood and hippocampus lead concentrations of 1-day old and 21-day old offsprings in the three lead exposed groups were significantly increased compared with the control group (P<0.05, P<0.01), and there was a good dose-response relationship between blood/hippocampus lead concentrations and the maternal exposure dosage. The concentration of Pb in blood and hippocampus of 60-day old offspring was no significantly difference in the lead exposed group compared with control group(P>0.05)。This result suggested that the concentration of Pb in blood and hippocampus of offspring rats increased following the increase of the maternal exposure dosage during pregnancy period.
Conclusion: Prenatal exposure to low level lead make the lead concentrations of blood and hippocampus of the offspring significantly increased compared with the control group, and the increasing changes could continue to weaning at least. When the pups were mature, the concentration of Pb in blood and hippocampus decreased to normal levels.
Part 2 The effects of prenatal low level lead exposure on learning and memory of offspring rats.
Objective: To explore the effects prenatal low level lead exposure on learning and memory of offspring rats, and analyze the relationship between the impairments of learning /memory and lead concentrations in hippocampus. In this part, we want to observe the toxic effects of lead to CNS of offsprings rats.
Methods: The learning and memory ability of the offspring rats were tested by the Morris water maze, Y-type maze, shuttling and avoiding dark box respedtivelty.
Results: In Morris water maze test, the time to find the platform for 21-day old and 60-day old offspring in the three lead exposed groups significantly increased compared with the control group during the 4 days training (P<0.05, P<0.01). In the shuttling and avoiding dark box test, the times of initiative avoiding(TOIA) for 21-day and 60-day old offspring in the three lead exposed groups were significantly decreased, while the latency of the initiative avoiding(LOIA) and latency of the passive avoiding(LOPA) were significantly increased compared with the control group (P<0.05, P<0.01). In Y-type maze test, the ability of learning(A) and memory(B) and the memory retaining rate(C) for 21-day and 60-day old offspring in the three lead exposed groups were significantly decreased compared with control group(P<0.05, P<0.01).
In this part we could found that the higher the Pb contents in hippocampus, the worse the ability of learning and memory of offspring rats. Especially, the deficits of learning and memory of soospring at mature stage(60-day old) in trearment group were still lower than that of control, while the Pb contents in hippocampus had decreased to a normal level. This results indicated the effect of lead to learning and memory could ontinue to the maturation period, and the recovery of the learning and memory might be need a long periods.
Conclusion: Prenantal exposure to low level lead impaired the learning and memory ability of the offspring of the rats, and this kind of influence will continue till the offsprings’maturity. The deficits degrees of learning and memory were corelated with Pb contents in hippocampus of offspring rats. Part 3 The mechanism of prenatal low level lead exposure to learning and memory in young offspring
Objective: To explore the effects of prenatal low level lead exposure to cell apoptosis, glial cells and neuron development of hippocampus of offspring rats. We are interested in the role of apoptosis as well as whether some neuronal specific genes, such as that encoding glial fibrillary acidic protein (GFAP), growth associated protein (GAP-43) and nerve growth factor (NGF), have changes in transcription and/or transcription level in rats after low levels Pb exposure.
Methods: PI labeled apoptosis detection by flow cytometry and Terminal deoxynucleotidyl transferase mediated d-UTP nick end labeling(TUNEL) were utilized to detect the hhippocampal cell apoptosis. The GFAP, GAP-43 and NGF protein expression in hippocampus were observed by immunohistochemistry and western blot, respectively. The GFAP, GAP-43 and NGF mRNA expression in hippocampus were observed by in situ hybridization and real-time PCR.
Results: (1) The effects of prenatal low levels lead exposure on apoptosis of hippocampal cell in offspring rats.
The apoptosis rates in hippocampus for 1-day old, 21-day old and 60-day old offspring examined by flow cytometry in each treatment group were significantly higher than that of control respectively(P<0.05, P<0.01), and there was a good dose-response relationship between apoptosis rates and the Pb concentration in hippocampus. The apoptosis index by TUNEL for 1-day old offspring in each treatment groups were significantly higher than that of control(P<0.05, P<0.01). For 21-day old and 60-day old offspring, the apoptosis index in medium and high dosage treatment groups were significantly higher than that of control group(P<0.05, or P<0.01), and showed a good dose-response relationship. There were positive correlation between apoptosis of hippocampus in offsprings and the deficits of learning and memory.
(2) The effects of prenatal low levels lead exposure on astrocyte of hippocampus in offspring rats.
Immunohistochemistry and Western blot showed that the protein expression of GFAP(include positive cell number, IOD and relative gray value) in hippocampus of 1-day old and 21-day old offspring in each treatment group were significantly higher than that of control(P<0.05, P<0.01), and there was a good dose-response relationship. But there were no significant difference at 60-day old offsprings. In situ hybridization and real time PCR showed that mRNA expression of GFAP(include positive cell number, IOD and△CT ) in hippocampus of 1-day old and 21-day old offspring in each treatment group were significantly higher than that of control(P<0.05, P<0.01), but no significant difference at 60-day old offspringa. The result above indicated that the promotion of GFAP protein and mRNA expression followed by the deficits of learning and memory ability of offsprings.
(3) The effects of prenatal low levels lead exposure on neuron development of hippocampus in offspring rats.
Immunohistochemistry showed showed that the GAP-43 protein expression(include area density and IOD) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01). At 21-day, the value of area density and IOD in medium and high dosage treatment groups were decreased in hippocampus compared with the control group (P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings. There was a good negactive dose-response relationship between the GAP-43 protein expression and lead in hippocampus, respectively. Western blot showed that the GAP-43 protein expression in hippocampus of 1-day old and 21-day old offspring in treatment groups singnificantly decreased compared with control, respectively(P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings. In situ hybridization showed that the GAP-43 mRNA expression(include area density and IOD) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01). At 21-day, the value of area density and IOD in medium and high dosage treatment groups were decreased in hippocampus compared with the control group (P<0.05, P<0.01), and there was a good negective dose-response relationship respectively, and there were no significant difference at 60-day old offsprings. Real time PCR showed that the GAP-43 mRNA expression in hippocampus of 1-day old and 21-day old offspring in treatment groups singnificantly decreased compared with control, respectively(P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings.
Immunohistochemistry and Western blot showed that the NGF protein expression(include area density, IOD and relative gray value) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01), and there was a good negactive dose-response relationship between the NGFprotein expression and lead in hippocampus, respectively. There weas no significant difference at 60-day old offsprings. In situ hybridization showed that the NGF mRNA expression(include area density and IOD) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01). At 21-day, the value of area density and IOD in medium and high dosage treatment groups were decreased in hippocampus compared with the control group (P<0.05, P<0.01), and there was a good negective dose-response relationship respectively, and there were no significant difference at 60-day old offsprings. Real time PCR showed that the NGF mRNA expression in hippocampus of 1-day old and 21-day old offspring in treatment groups singnificantly decreased compared with control, respectively(P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings. The result above indicated that the decrease of GAP-43,NGF protein and mRNA expression could reduce the learning and memory ability of offsprings.
Conclusion: It demonstrates that Pb could induce apoptosis in hippocampus, and increase the GFAP mRNA and protein expression as well as decrease the neuron outgrowth associated protein and factor expression (GAP-43 and NGF). The results in this part possibly implement that the mechanism of deficits of learning and memory of offspring rats after low level lead exposure during pregnancy might be through the apoptosis induction and increased level of GFAP as well as decreased the GAP-43 and NGF expression.
随着人们对铅毒危害认识的不断深入,采取各种保护措施,高水平铅暴露所致的损害已经逐渐减少,但是来自环境和生活中低水平的铅暴露仍然十分常见。其中儿童由于血脑屏障未发育成熟等原因,比成人对铅的神经毒性更为敏感,较低水平的铅暴露即可造成儿童中枢神经系统的功能障碍。对于低水平铅暴露所致的儿童铅损伤尤其是神经系统损伤及其机制的研究,成为当今公共卫生研究领域的一个热点。
学习和记忆是神经系统所具有的基本功能,也是最重要机能之一。海马是学习记忆的关键部位,亦是铅作用的敏感靶部位。铅有很强的发育神经毒性,即使是低水平的铅暴露,发育中的中枢神经系统也很容易受到铅毒性的损害。胎儿和婴幼儿期是脑发育的关键时期,在该时期接触到铅后,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。
在儿童接触铅的众多途径中,母体孕期铅暴露对胎儿脑发育的影响是十分重要的一个方面。研究表明发育早期铅暴露(怀孕/哺乳)所产生的认知和神经行为缺陷,在停止铅暴露后可能会持续影响到成年阶段。胚胎阶段的器官发生期和出生前后一段时期是中枢神经系统发育最迅速、也最易受到外来毒物损害的时期,处于围产期的胎儿或婴幼儿接受铅暴露后神经系统所受的损害可能较其它时期更为严重。但母体孕期低水平铅暴露对其子代中枢神经系统的损害及其机理缺乏深入而系统的研究。本研究采取大鼠孕期低水平铅暴露的方式,测定其子代血铅和海马组织铅的含量,并观察其子代学习记忆机能力的变化,探讨这种变化与铅接触之间的关系,为彻底揭示铅中毒的机理、优生优育和预防并降低儿童学习记忆的损伤,提供科学依据。
第一部分大鼠孕期低水平铅暴露对子代大鼠血液和海马组织铅含量的影响
目的:建立大鼠孕期低水平铅暴露的动物模型,观测大鼠孕期铅暴露后子代血铅和海马铅含量的变化,为分析学习记忆能力的改变与体内铅含量的关系,揭示铅影响学习记忆的机理打下基础。
方法:Wistar大鼠受孕后随机分为4组,3个处理组自怀孕第1天起分别给予醋酸铅含量为125、250和500mg/L的饮水,对照组给予无铅蒸馏水;仔鼠出生后母鼠正常饮水、饮食,仔鼠由母鼠喂养至断乳后与母鼠分笼饲养;仔鼠出生1d时取全脑、21d和60d时取海马组织,采用流动注射氢化物发生-原子吸收光谱法进行铅含量测定。
结果:孕鼠接触不同剂量铅后,各剂量组1d、21d龄的仔鼠血铅、海马组织铅含量显著高于对照组仔鼠,差异有统计学意义(P<0.05,P<0.01),并且仔鼠血铅、海马组织铅含量与孕鼠铅暴露剂量之间有良好的剂量反应关系;至60d龄时,处理组和对照组仔鼠的血铅、海马组织铅含量无明显差异(P>0.05)。说明随着孕鼠铅暴露剂量的增加,进入仔鼠血液和海马组织内的铅也随之增加。
结论:大鼠孕期低水平铅暴露,可使子代大鼠血液和脑组织中的铅含量增加,说明铅易于透过胎盘屏障和血脑屏障,引起子代血铅增高,并蓄积在脑组织中。宫内铅暴露后子代大鼠血铅和海马铅的增高至少可以持续到仔鼠的断乳期,至成熟期时,可下降至正常水平。
第二部分大鼠孕期低水平铅暴露对子代大鼠学习记忆能力的影响
目的:观察大鼠孕期铅暴露后对子代大鼠学习记忆能力的影响,并探讨这种改变与海马组织铅含量的关系,从而进一步判定铅对子代神经系统的毒性作用。
方法:以Morris水迷宫、Y迷宫和避暗穿梭箱实验三种方法,观测仔鼠学习记忆能力的变化。
结果:Morris水迷宫测试结果显示,各处理组21d和60d龄的仔鼠,连续4天训练期间,第2、3、4天时潜伏期均显著高于同期对照组仔鼠,差异有统计学意义(P<0.05, P<0.01)。避暗穿梭箱测试结果显示,各处理组21d和60d龄的仔鼠连续5天训练期间,主动回避次数低于同期对照组仔鼠,差异有统计学意义(P<0.05,P<0.01);而主动回避潜伏期和被动回避潜伏期均高于同期对照组仔鼠,差异有统计学意义(P<0.05 or P<0.01)。Y迷宫测试结果显示,各处理组21d和60d龄的仔鼠,获取记忆的能力、保持记忆的能力和记忆保持率均低于同期对照组仔鼠,差异有统计学意义(P<0.05,P<0.01)。
综合分析海马铅含量和学习记忆能力之间的关系,海马组织铅含量越高,仔鼠的学习记忆能力越差;另外,各处理组仔鼠生长至成熟期(60d)时,血铅和海马铅含量已降至正常水平,但学习记忆能力仍显著低于对照组,未完全恢复,说明铅对仔鼠学习记忆能力的影响至少可持续到仔鼠的成熟期,学习记忆能力的恢复需要较长时间。
结论:大鼠孕期低水平铅暴露,可以损害仔鼠的学习记忆能力,而且这种损害作用至少可以持续到仔鼠的成熟期;仔鼠的学习记忆能力与其海马组织的铅含量有关,铅含量越高,学习记忆能力受损越严重。
第三部分大鼠孕期低水平铅暴露对子代大鼠学习记忆能力影响的机理研究
目的:观察大鼠孕期铅暴露后,对子代大鼠海马组织细胞凋亡、胶质细胞、与生长相关因子情况的影响,并分析上述变化与仔鼠学习记忆能力受损的关系,探讨母体铅暴露对子代学习记忆能力影响的机理。
方法:采用流式细胞技术和末端脱氧核糖核酸转移酶介导的缺口末端标记法(TUNEL),观察大鼠孕期铅暴露后仔鼠海马神经元细胞凋亡发生情况;免疫组织化学和Western blot技术检测海马星形胶质细胞胶质原纤维酸性蛋白(GFAP)表达的变化,原位杂交和荧光定量PCR技术检测海马星形胶质细胞GFAP mRNA表达的变化;免疫组织化学和Western blot技术检测海马细胞神经生长相关蛋白(GAP-43)和神经生长因子(NGF)蛋白表达的变化,原位杂交和荧光定量PCR技术检测海马细胞GAP-43和NGF mRNA表达的变化;分析上述指标变化与学习记忆能力受损之间的关系。
结果:大鼠孕期低水平铅暴露对子代大鼠海马细胞凋亡的影响:流式细胞检测结果显示,各处理组1d、21d和60d龄的仔鼠,海马细胞凋亡率显著高于对照组,差异有统计学意义(P<0.05,P<0.01),并且各时间段细胞凋亡率与海马铅含量之间有良好的剂量反应关系;TUNEL法检测结果显示,1d龄的仔鼠,各处理组海马细胞凋亡指数均显著高于对照组,差异有统计学意义(P <0.05,P<0.01),21d和60d阶段,中、高剂量组海马细胞凋亡指数显著高于对照组(P <0.05,P<0.01),而低剂量组与对照相比未见显著性差异,各时间段仔鼠细胞凋亡指数与海马组织铅含量之间有良好的剂量反应关系;综合分析海马细胞凋亡与学习记忆能力之间的关系,海马细胞凋亡率或凋亡指数越高,仔鼠的学习记忆受损越严重,学习记忆能力越差。
大鼠孕期低水平铅暴露对子代大鼠海马胶质细胞的影响:免疫组化和Western blot技术检测GFAP蛋白表达的结果显示,各处理组1d和21d龄的仔鼠,海马区GFAP免疫阳性反应阳性细胞平均数目、积分光密度和相对灰度值,显著高于同期对照组仔鼠(P <0.05,P<0.01),并与海马组织铅含量有良好的剂量反应关系,至60d时,未见显著性差异。原位杂交和荧光定量PCR技术检测GFAP mRNA表达的结果显示,各处理组1d和21d龄的仔鼠,海马GFAP mRNA阳性细胞数、积分光密度和△CT明显高于对照组,有显著性差异(P<0.05,P<0.01),在60d阶段,未见显著性差异;1天阶段海马组织铅含量与GFAP mRNA阳性细胞数目之间有良好的剂量反应关系,1d和21d阶段海马铅含量与GFAP mRNA积分光密度之间也有良好的剂量反应关系。综合分析海马细胞GFAP表达与学习记忆能力之间的关系,GFAP表达增强后仔鼠的学习记忆能力下降。
大鼠孕期低水平铅暴露对子代大鼠海马生长相关因子的影响:免疫组化检测结果显示,各处理组1d龄的仔鼠,海马组织中GAP-43免疫组化反应物的面密度和积分光密度均显著降低,与对照组相比有显著性差异(P<0.05,P<0.01);21d阶段,中、高剂量组的面密度和积分光密度低于对照组,其差别有显著性(P<0.05,P<0.01),到60d阶段时,各剂量的面密度和积分光密度均无显著性差异;1d和21d阶段海马组织铅含量与GAP-43免疫组化面密度和积分光密度呈明显负相关。Western blot结果显示,各处理组1d和21d龄的仔鼠GAP-43蛋白表达明显低于对照组,具有显著性差异(P<0.05,P<0.01);至60d时,未见显著性差异。原位杂交结果显示,各处理组1d龄的仔鼠,GAP-43 mRNA表达的面密度、积分光密度均低于对照组,差别有显著性(P<0.05,P<0.01);21d阶段中、高剂量组的面密度和积分光密度低于对照组,差别有显著性(P<0.05,P<0.01),且和海马铅含量呈明显负相关;至60d时,各剂量组与对照组相比均无显著性差异。荧光定量PCR结果显示,各处理组1d和21d龄的仔鼠GAP-43 mRNA表达明显降低,与对照组相比具有显著性差异(P<0.01),仔鼠发育至60d时,各剂量组海马区GAP-43 mRNA表达与对照组比较未见显著性差异。
免疫组化和Western blot检测仔鼠海马组织NGF的表达情况,发现各处理组1d和21d龄的仔鼠,NGF免疫组化反应物的面密度、积分光密度和相对灰度值均显著降低,与对照组相比有显著性差异(P<0.05,P<0.01),且与海马组织铅含量程明显负相关;到60d时,均未见显著性差异。原位杂交结果显示,各处理组1d龄的仔鼠,NGF mRNA阳性反应物颗粒的面密度积分光密度均低于对照组,差别有显著性(P<0.05,P<0.01);21d阶段中、高剂量组的面密度和积分光密度低于对照组,差别有显著性(P<0.05,P<0.01);1d和21d阶段海马组织铅含量与NGF mRNA面密度和积分光密度呈明显负相关;荧光定量PCR结果显示,各处理组1d和21d龄的仔鼠NGF mRNA表达显著降低,与对照组相比具有显著性差异(P<0.05,P<0.01);至60d时,未见显著性差异。
综合分析GAP-43和NGF表达与仔鼠学习记忆能力的关系,发现随着海马铅含量的升高,海马组织GAP-43和NGF蛋白及mRNA表达下降,而仔鼠的学习记忆能力也随之降低。
结论:大鼠孕期低水平铅暴露,可以导致仔鼠脑海马区神经细胞凋亡增加,且与海马铅含量呈正相关;可以使仔鼠脑海马区GFAP阳性的胶质细胞数目增多,GFAP蛋白和mRNA表达增加,且与海马铅含量呈正相关,GFAP表达的变化至仔鼠出生60天时消失。可以抑制仔鼠脑海马区GAP-43、NGF蛋白和mRNA表达,且这种抑制作用与海马铅含量呈正相关,蛋白和mRNA表达表达的变化至仔鼠出生60天时消失。提示大鼠孕期低水平铅暴露,可以通过诱导仔鼠海马区神经细胞凋亡、提高GFAP表达水平、降低GAP-43和NGF表达水平等机制,损伤子代的的学习记忆能力。
Lead, the most common environmental daily life pollutant, is one of the oldest of established environmental poisons. Lead can enter into the human’s body and contributes to the damages of functions of many organs and systems. The central nervous system(CNS), especially, is the most important target of lead-mediated toxicity.
The adverse effects from high level lead exposure have been decreased with the deeply knowledgement about lead toxicity and the taking of various preventive measures. But the low level lead exposure from environment and daily life is quite common. Because of the developing immature of blood brain barrier, the children are more sensitive than that of the adult to lead induced insults. So even low level lead exposure can give rise to functional disorder in children. The damage from low level lead exposure to children, especially to CNS and the mechanism of lead actions, is the hot point in public health research areas.
Learning and memory, the basic functions of CNS, is one of the most important functions of CNS. As the key structure for learning and memory, hippocampus is the sensitive target of lead toxicity. It is approved that lead have very strong developmental neurotoxicity, even low level lead exposure can damage the developmental CNS. It is the critical period for development of CNS in fetus and infant. If prenatal lead exposure occurred, 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.
Lead exposure during the gestation period is most responserble for the damage to the developing central nervous system of fetus caused by lead through various ways into the chhildrens’body. Previous studies indicate that impairment of later cognitive and neurobehavioral function result from lead exposure during early developing period(gestation/lactation) could persist long till to adult after the exposure has ceased. The developmental central nervous system (CNS) in organogenetic period and postnatal period are in a state of rapid growth, and more sensitive to toxic metals such as lead. Pb can make more serious damages to fetus and infant brains in prenatal stage than other stages. Despite intensive research, no consensus on the adverse effects and mechanisms of prenatal low level lead exposure to CNS in young offspring has resulted.
In the present study we detected the Pb concentration in blood and content in the hippocampus in offspring rats after low level lead exposure during pregnancy. The changes of learning and memory in offspring rats were examined by Morris water maze test, shuttling and avoiding dark box test, and Y-type maze test. This study attempts to reveal the possible molecular mechanism of Pb induced neural development toxicity and provide the base of aristogenesis as well as prevent to the deficient of learning and memory of children.
Part 1 The effects of prenatal low level lead exposure on the content of lead in blood and hippocampus of offspring rats.
Objective: To establish the animal model of low level lead exposure during pregnancy, and to detect the changes of Pb concentration in blood and hippocampus in offspring rats and analyze the possible relationship between the Pb exposure and the deficient of learning and memory of offspring rats. This study in part provided the base data for revealing the possible mechanism of Pb to reduce the ability of learing and memory.
Methods: The pregnant Wistar rats are housed separately and randomly divided into 4 groups and provided with doubly distilled water in the control group and 125、250、500mg/L lead acetate solution via drinking water in three exposured groups respectively during the pregnancy. The content of lead in blood and hippocampus of 21-day and 60-day old offsprings were measured by flow-injection hydride generation-atomic absorption spectrometry. At 1-day old offspring, the hippocampus was instead by whole brain.
Results: The blood and hippocampus lead concentrations of 1-day old and 21-day old offsprings in the three lead exposed groups were significantly increased compared with the control group (P<0.05, P<0.01), and there was a good dose-response relationship between blood/hippocampus lead concentrations and the maternal exposure dosage. The concentration of Pb in blood and hippocampus of 60-day old offspring was no significantly difference in the lead exposed group compared with control group(P>0.05)。This result suggested that the concentration of Pb in blood and hippocampus of offspring rats increased following the increase of the maternal exposure dosage during pregnancy period.
Conclusion: Prenatal exposure to low level lead make the lead concentrations of blood and hippocampus of the offspring significantly increased compared with the control group, and the increasing changes could continue to weaning at least. When the pups were mature, the concentration of Pb in blood and hippocampus decreased to normal levels.
Part 2 The effects of prenatal low level lead exposure on learning and memory of offspring rats.
Objective: To explore the effects prenatal low level lead exposure on learning and memory of offspring rats, and analyze the relationship between the impairments of learning /memory and lead concentrations in hippocampus. In this part, we want to observe the toxic effects of lead to CNS of offsprings rats.
Methods: The learning and memory ability of the offspring rats were tested by the Morris water maze, Y-type maze, shuttling and avoiding dark box respedtivelty.
Results: In Morris water maze test, the time to find the platform for 21-day old and 60-day old offspring in the three lead exposed groups significantly increased compared with the control group during the 4 days training (P<0.05, P<0.01). In the shuttling and avoiding dark box test, the times of initiative avoiding(TOIA) for 21-day and 60-day old offspring in the three lead exposed groups were significantly decreased, while the latency of the initiative avoiding(LOIA) and latency of the passive avoiding(LOPA) were significantly increased compared with the control group (P<0.05, P<0.01). In Y-type maze test, the ability of learning(A) and memory(B) and the memory retaining rate(C) for 21-day and 60-day old offspring in the three lead exposed groups were significantly decreased compared with control group(P<0.05, P<0.01).
In this part we could found that the higher the Pb contents in hippocampus, the worse the ability of learning and memory of offspring rats. Especially, the deficits of learning and memory of soospring at mature stage(60-day old) in trearment group were still lower than that of control, while the Pb contents in hippocampus had decreased to a normal level. This results indicated the effect of lead to learning and memory could ontinue to the maturation period, and the recovery of the learning and memory might be need a long periods.
Conclusion: Prenantal exposure to low level lead impaired the learning and memory ability of the offspring of the rats, and this kind of influence will continue till the offsprings’maturity. The deficits degrees of learning and memory were corelated with Pb contents in hippocampus of offspring rats. Part 3 The mechanism of prenatal low level lead exposure to learning and memory in young offspring
Objective: To explore the effects of prenatal low level lead exposure to cell apoptosis, glial cells and neuron development of hippocampus of offspring rats. We are interested in the role of apoptosis as well as whether some neuronal specific genes, such as that encoding glial fibrillary acidic protein (GFAP), growth associated protein (GAP-43) and nerve growth factor (NGF), have changes in transcription and/or transcription level in rats after low levels Pb exposure.
Methods: PI labeled apoptosis detection by flow cytometry and Terminal deoxynucleotidyl transferase mediated d-UTP nick end labeling(TUNEL) were utilized to detect the hhippocampal cell apoptosis. The GFAP, GAP-43 and NGF protein expression in hippocampus were observed by immunohistochemistry and western blot, respectively. The GFAP, GAP-43 and NGF mRNA expression in hippocampus were observed by in situ hybridization and real-time PCR.
Results: (1) The effects of prenatal low levels lead exposure on apoptosis of hippocampal cell in offspring rats.
The apoptosis rates in hippocampus for 1-day old, 21-day old and 60-day old offspring examined by flow cytometry in each treatment group were significantly higher than that of control respectively(P<0.05, P<0.01), and there was a good dose-response relationship between apoptosis rates and the Pb concentration in hippocampus. The apoptosis index by TUNEL for 1-day old offspring in each treatment groups were significantly higher than that of control(P<0.05, P<0.01). For 21-day old and 60-day old offspring, the apoptosis index in medium and high dosage treatment groups were significantly higher than that of control group(P<0.05, or P<0.01), and showed a good dose-response relationship. There were positive correlation between apoptosis of hippocampus in offsprings and the deficits of learning and memory.
(2) The effects of prenatal low levels lead exposure on astrocyte of hippocampus in offspring rats.
Immunohistochemistry and Western blot showed that the protein expression of GFAP(include positive cell number, IOD and relative gray value) in hippocampus of 1-day old and 21-day old offspring in each treatment group were significantly higher than that of control(P<0.05, P<0.01), and there was a good dose-response relationship. But there were no significant difference at 60-day old offsprings. In situ hybridization and real time PCR showed that mRNA expression of GFAP(include positive cell number, IOD and△CT ) in hippocampus of 1-day old and 21-day old offspring in each treatment group were significantly higher than that of control(P<0.05, P<0.01), but no significant difference at 60-day old offspringa. The result above indicated that the promotion of GFAP protein and mRNA expression followed by the deficits of learning and memory ability of offsprings.
(3) The effects of prenatal low levels lead exposure on neuron development of hippocampus in offspring rats.
Immunohistochemistry showed showed that the GAP-43 protein expression(include area density and IOD) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01). At 21-day, the value of area density and IOD in medium and high dosage treatment groups were decreased in hippocampus compared with the control group (P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings. There was a good negactive dose-response relationship between the GAP-43 protein expression and lead in hippocampus, respectively. Western blot showed that the GAP-43 protein expression in hippocampus of 1-day old and 21-day old offspring in treatment groups singnificantly decreased compared with control, respectively(P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings. In situ hybridization showed that the GAP-43 mRNA expression(include area density and IOD) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01). At 21-day, the value of area density and IOD in medium and high dosage treatment groups were decreased in hippocampus compared with the control group (P<0.05, P<0.01), and there was a good negective dose-response relationship respectively, and there were no significant difference at 60-day old offsprings. Real time PCR showed that the GAP-43 mRNA expression in hippocampus of 1-day old and 21-day old offspring in treatment groups singnificantly decreased compared with control, respectively(P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings.
Immunohistochemistry and Western blot showed that the NGF protein expression(include area density, IOD and relative gray value) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01), and there was a good negactive dose-response relationship between the NGFprotein expression and lead in hippocampus, respectively. There weas no significant difference at 60-day old offsprings. In situ hybridization showed that the NGF mRNA expression(include area density and IOD) in hippocampus of 1-day old offspring in each treatment group were significantly lower than that of control(P<0.05, P<0.01). At 21-day, the value of area density and IOD in medium and high dosage treatment groups were decreased in hippocampus compared with the control group (P<0.05, P<0.01), and there was a good negective dose-response relationship respectively, and there were no significant difference at 60-day old offsprings. Real time PCR showed that the NGF mRNA expression in hippocampus of 1-day old and 21-day old offspring in treatment groups singnificantly decreased compared with control, respectively(P<0.05, P<0.01), and there were no significant difference at 60-day old offsprings. The result above indicated that the decrease of GAP-43,NGF protein and mRNA expression could reduce the learning and memory ability of offsprings.
Conclusion: It demonstrates that Pb could induce apoptosis in hippocampus, and increase the GFAP mRNA and protein expression as well as decrease the neuron outgrowth associated protein and factor expression (GAP-43 and NGF). The results in this part possibly implement that the mechanism of deficits of learning and memory of offspring rats after low level lead exposure during pregnancy might be through the apoptosis induction and increased level of GFAP as well as decreased the GAP-43 and NGF expression.
引文
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