发育期慢性低浓度铅暴露对大鼠脑海马、大脑皮质GAP-43表达和学习记忆的影响
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摘要
目的
铅是人们所认识的最古老的毒物之一,是一种对细胞生长,增殖,信号传导无已知必要作用的无机重金属。低浓度的铅暴露亦能引起神经系统的损伤,包括智商、听力、视力的降低和外周神经功能的损害。发育期的神经系统对铅更敏感,即使铅暴露浓度低于儿童铅中毒的下限值10μg/dl也能损伤其神经系统。这与发育期儿童的血脑屏障发育尚未完善,胃肠道对铅的吸收率高及排铅能力低等有关。婴幼儿铅暴露可引起不可逆的神经系统损害,主要表现为学习记忆能力降低和神经行为异常,并且这种损伤可持续到成年阶段,甚至终生。海马是参与学习记忆形成的重要脑区,研究者也已经证实铅通过作用于海马来影响学习记忆功能。近些年来,人们对铅对学习记忆的影响及其细胞和分子学机制做了广泛的研究。但具体的机制仍然不清楚,故开展其相关机制研究具有重要意义。
神经生长相关蛋白(GAP-43)在学习记忆过程中发挥重要作用。发育期低浓度铅暴露是否影响该蛋白在大脑皮质和海马中的表达?其影响机制如何?这些都有待于研究。据此,我们通过孕期开始给予母鼠低浓度铅暴露建立发育期仔鼠铅中毒模型,研究仔鼠不同时间点大脑皮质和海马中GAP-43的表达情况及学习记忆状况,探讨发育期慢性低浓度铅暴露对大鼠学习记忆影响的机制,为儿童铅中毒的预防提供新的理论基础和实验依据。
方法
健康2月龄雌性大鼠30只,按体重随机分成对照组、低剂量铅暴露组1、2,每组10只雌鼠。各组大鼠均伺以普通饲料,饮用双蒸水。适应性喂养1周后雌鼠和正常雄鼠1：1合笼,以次晨发现阴栓或阴道分泌物镜检发现精子者确定为妊娠0天,自怀孕第一天铅低剂量组1、2分别饮用0.05%、0.2%醋酸铅溶液,直到仔鼠出生后28天(PN28)。对照组继续饮用双蒸水。铅暴露组仔鼠断乳前通过母乳饮用醋酸铅,断乳后继续饮用相同浓度醋酸铅。PN1、PN3. PN7、PN14、PN21、PN28解剖动物取出脑海马和大脑皮质,放入液氮中,转存到-70℃冰箱中；PN28测脑铅和血铅；PN56进行水迷宫实验。取出仔鼠海马和大脑皮质标本,免疫组化、Western blot方法检测脑海马、大脑皮质GAP-43蛋白的表达的变化。
结果
1、发育期慢性低浓度铅暴露对大鼠血铅和海马、大脑皮质铅含量的影响
各慢性染铅组仔鼠血铅和脑海马、大脑皮质铅含量明显高于对照组,差异有统计学意义(P<0.01),升高程度与饮用水的铅浓度呈剂量依赖性关系。
2、发育期慢性低浓度铅暴露对大鼠学习记忆能力的影响
在水迷宫实验中,结果表明慢性铅暴露可明显损伤仔鼠的空间定位航行能力,损伤程度与饮用铅的浓度呈剂量依赖性关系。
3、发育期慢性低浓度铅暴露对脑海马和大脑皮质GAP-43蛋白表达的影响
(1)免疫组织化学结果显示：免疫组织化学结果显示,在海马CA1区、CA3区、大脑皮质PN7、PN14、PN21、PN28时和DG区PN7、PN14、PN21时各染铅组的积分光密度值与对照组比差异有统计学意义(P<0.01),即染铅组该蛋白的表达含量低于对照组,CA1区和大脑皮质PN1、PN3时及DG区PN28时低剂量组2与对照组比差异有统计学意义(P<0.05或P<0.01),CA3区PN1、PN3时各染铅组与对照组比较差异有统计学意义(P<0.01)。
(2) Western blot结果显示：与对照组相比,发育期慢性低浓度铅暴露对大鼠脑海马和大脑皮质GAP-43蛋白的表达呈现下降趋势,且其与铅暴露水平有剂量依赖性关系及发育时间表达差异。
结论
1、免疫组织化学和Western Blot结果显示由于铅暴露可导致GAP-43在脑海马和大脑皮质表达减少。
2、铅中毒可降低成年大鼠空间学习记忆能力。
3、铅降低脑海马及大脑皮质GAP-43的表达可能是铅中毒引起学习记忆能力降低的一个机制。
Objective
Lead (Pb2+) is one of the oldest poison,which is a xaenobiotic metal with no known essential function in cellular grown,proliferation,or signaling.low-level lead exposure can also lead to the damage of nervous system,including the reduce of intelligence quotient、hearing、vision and the damage of function of peripheral nerve.Developmental nervous system is more vulnerable to lead toxicity,though nervous system can be damaged with blood lead levels below 10 ug/dl that is the lower limit of lead poisoning in children.It is associated with incompletely developed blood brain barrier, Gastrointestinal high absorptivity and low capacity of the Excretion of lead. Infant' exposure to lead can lead to irreversible damage to the nervous system,mainly showing the reduce of the ability of learning and memory and neurobehavioral abnormalities,and the damage can continue to the adulthood,even the whole life. Researchers have also confirmed that lead is by way of acting on the hippocampus that is one of the key limbic regions involved in learning and memory to influence the learning and memory function.In recent years, the influence of lead on learning and memory function and its cellular and molecular mechanism have been researched widely.However, the specific mechanism is still unclear,so it is significant to study correlative mechanisms.
Neuronal growth associated protein (GAP-43) plays a significant role in the process of learning and memory. Whether low-level lead exposure at developmental stage could influence the expression of GAP-43 in hippocampus and cerebral cortex? And what is the influence mechanism? Investigation is necessary to answer these questions. Hereby, in this paper, we built a model of lead poisoning of pup rats at developmental stage by exposing the female rats to lead from the beginning of pregnancy, by which the GAP-43 expression in hippocampus and cerebral cortex at different time points and the state of learning and memory were researched, and the mechanism of the influence that low-level lead exposure exerted on learning and memory function of rats at developmental stage was explored, in order to provide a theoretical basis and an experimental basis for the prevention of lead poisoning of children.
Methods
Female Wistar rats (n=30) aging 2 were randomly divided into three group: control group, low-dose group1(0.05% PbAc), low-dose group2(0.2% PbAc).All the groups were fed normal feeds and double distilled water. After one week adaptive feed, the rats mate according to the pattern in which a female rat mate with one male, and the next morning when vaginal plug appears or sperm was found in vaginal secretion by means of microscopic examination,it was designated as gestation day 0, denoted as GDO. Since the first day of pregnancy, low-dose group 1,2 of lead were consumed 0.05%,0.2%lead acetate solution, until the postnatal day 28 (PN28) of the pups.The control group continued to drink double distilled water with no lead. Pre-weaning the offspring of lead-exposed group drank lead acetate through breast milk,and they continued to drink the same concentration of lead acetate after weaning.At PN1,PN3,PN7,PN14,PN21,PN28,individually the hippocampus and cerebral cortex were got from pups in different groups and stored at fluid nitrogen and then stored at-70℃refrigerator;At PN28,we measured the brain lead and blood lead;Since PN56 the pups began to train in a spatial learning tast using a water maze paradigm.Removing the speciments of the hippocampus and cerebral cortex,we detected the chang of expression of the neuronal growth associated protein using Immunohistochemistry and Western blot.
Results
1、Effect of chronic developmental low-level lead exposure on the blood lead and brain(hippocampus and cerebral cortex)lead in rat.
lead levels in blood and brain of the groups of offspring in those two different lead-exposed groups were obviously higher than that in the control group,and the difference was statistically significant (P<0.01),and the extent of increasing showed in lead concentraion dependent manner.
2、Effect of chronic developmental low-level lead exposure on spatial learning and memory in rats at the developmental stage
In the Morris water maze task, results indicated that rats having drunk lead water diplayed significant impairment in their performance,and this extent of impairment showed in lead concentration dependent manner.
3、Effect of chronic developmental low-level lead exposure on GAP-43 expression in rat hippocampus and cerebral cortex
(1) Immunohistochemistry showed:there was statistical significance (P＜0.01) in terms of the difference between the lead-exposed groups and the control group on the integral optical density (IOD) of hippocampal CA1 and CA3 areas, of cerebral cortex on PN7, PN14, PN 21 and PN28 and of DG area on PN7, PN14 and PN21, that was, the content of the protein expression of the lead-exposed groups was lower than that of the control group, compareing that of cerebral hippocampal CA1, and of cerebral cortex on PN1, PN3 and of DG area on PN28, the difference between low dose group 2 and the control group had statistical significance(P＜0.05 or P＜0.01), as well as the difference between the lead-exposed groups and the control group but that of cerebral hippocampal CA3 on PN1, PN3(P<0.01).
(2)Western Blot showed:Rat pups exposed to chronic level-lead during development did express lower levels of GAP-43 expression in hippocampus and cerebral cortex than of the control group and this exhibited in a dose-dependentand developmental expressed differences manner.
Conclusion
1、Immunohistochemistry and Western Blot results showed that chronic developmental low-level lead exposure reduced the expression of GAP-43 in the hippocampus and cerebral cortex.
2、Lead poisoning reduced the ability of learning and memory.
3、Lead on the impact of GAP-43 could be a mechanism that lead poisoning lead to a decreased capacity for learning and memory mechanism.
铅是人们所认识的最古老的毒物之一,是一种对细胞生长,增殖,信号传导无已知必要作用的无机重金属。低浓度的铅暴露亦能引起神经系统的损伤,包括智商、听力、视力的降低和外周神经功能的损害。发育期的神经系统对铅更敏感,即使铅暴露浓度低于儿童铅中毒的下限值10μg/dl也能损伤其神经系统。这与发育期儿童的血脑屏障发育尚未完善,胃肠道对铅的吸收率高及排铅能力低等有关。婴幼儿铅暴露可引起不可逆的神经系统损害,主要表现为学习记忆能力降低和神经行为异常,并且这种损伤可持续到成年阶段,甚至终生。海马是参与学习记忆形成的重要脑区,研究者也已经证实铅通过作用于海马来影响学习记忆功能。近些年来,人们对铅对学习记忆的影响及其细胞和分子学机制做了广泛的研究。但具体的机制仍然不清楚,故开展其相关机制研究具有重要意义。
神经生长相关蛋白(GAP-43)在学习记忆过程中发挥重要作用。发育期低浓度铅暴露是否影响该蛋白在大脑皮质和海马中的表达?其影响机制如何?这些都有待于研究。据此,我们通过孕期开始给予母鼠低浓度铅暴露建立发育期仔鼠铅中毒模型,研究仔鼠不同时间点大脑皮质和海马中GAP-43的表达情况及学习记忆状况,探讨发育期慢性低浓度铅暴露对大鼠学习记忆影响的机制,为儿童铅中毒的预防提供新的理论基础和实验依据。
方法
健康2月龄雌性大鼠30只,按体重随机分成对照组、低剂量铅暴露组1、2,每组10只雌鼠。各组大鼠均伺以普通饲料,饮用双蒸水。适应性喂养1周后雌鼠和正常雄鼠1：1合笼,以次晨发现阴栓或阴道分泌物镜检发现精子者确定为妊娠0天,自怀孕第一天铅低剂量组1、2分别饮用0.05%、0.2%醋酸铅溶液,直到仔鼠出生后28天(PN28)。对照组继续饮用双蒸水。铅暴露组仔鼠断乳前通过母乳饮用醋酸铅,断乳后继续饮用相同浓度醋酸铅。PN1、PN3. PN7、PN14、PN21、PN28解剖动物取出脑海马和大脑皮质,放入液氮中,转存到-70℃冰箱中；PN28测脑铅和血铅；PN56进行水迷宫实验。取出仔鼠海马和大脑皮质标本,免疫组化、Western blot方法检测脑海马、大脑皮质GAP-43蛋白的表达的变化。
结果
1、发育期慢性低浓度铅暴露对大鼠血铅和海马、大脑皮质铅含量的影响
各慢性染铅组仔鼠血铅和脑海马、大脑皮质铅含量明显高于对照组,差异有统计学意义(P<0.01),升高程度与饮用水的铅浓度呈剂量依赖性关系。
2、发育期慢性低浓度铅暴露对大鼠学习记忆能力的影响
在水迷宫实验中,结果表明慢性铅暴露可明显损伤仔鼠的空间定位航行能力,损伤程度与饮用铅的浓度呈剂量依赖性关系。
3、发育期慢性低浓度铅暴露对脑海马和大脑皮质GAP-43蛋白表达的影响
(1)免疫组织化学结果显示：免疫组织化学结果显示,在海马CA1区、CA3区、大脑皮质PN7、PN14、PN21、PN28时和DG区PN7、PN14、PN21时各染铅组的积分光密度值与对照组比差异有统计学意义(P<0.01),即染铅组该蛋白的表达含量低于对照组,CA1区和大脑皮质PN1、PN3时及DG区PN28时低剂量组2与对照组比差异有统计学意义(P<0.05或P<0.01),CA3区PN1、PN3时各染铅组与对照组比较差异有统计学意义(P<0.01)。
(2) Western blot结果显示：与对照组相比,发育期慢性低浓度铅暴露对大鼠脑海马和大脑皮质GAP-43蛋白的表达呈现下降趋势,且其与铅暴露水平有剂量依赖性关系及发育时间表达差异。
结论
1、免疫组织化学和Western Blot结果显示由于铅暴露可导致GAP-43在脑海马和大脑皮质表达减少。
2、铅中毒可降低成年大鼠空间学习记忆能力。
3、铅降低脑海马及大脑皮质GAP-43的表达可能是铅中毒引起学习记忆能力降低的一个机制。
Objective
Lead (Pb2+) is one of the oldest poison,which is a xaenobiotic metal with no known essential function in cellular grown,proliferation,or signaling.low-level lead exposure can also lead to the damage of nervous system,including the reduce of intelligence quotient、hearing、vision and the damage of function of peripheral nerve.Developmental nervous system is more vulnerable to lead toxicity,though nervous system can be damaged with blood lead levels below 10 ug/dl that is the lower limit of lead poisoning in children.It is associated with incompletely developed blood brain barrier, Gastrointestinal high absorptivity and low capacity of the Excretion of lead. Infant' exposure to lead can lead to irreversible damage to the nervous system,mainly showing the reduce of the ability of learning and memory and neurobehavioral abnormalities,and the damage can continue to the adulthood,even the whole life. Researchers have also confirmed that lead is by way of acting on the hippocampus that is one of the key limbic regions involved in learning and memory to influence the learning and memory function.In recent years, the influence of lead on learning and memory function and its cellular and molecular mechanism have been researched widely.However, the specific mechanism is still unclear,so it is significant to study correlative mechanisms.
Neuronal growth associated protein (GAP-43) plays a significant role in the process of learning and memory. Whether low-level lead exposure at developmental stage could influence the expression of GAP-43 in hippocampus and cerebral cortex? And what is the influence mechanism? Investigation is necessary to answer these questions. Hereby, in this paper, we built a model of lead poisoning of pup rats at developmental stage by exposing the female rats to lead from the beginning of pregnancy, by which the GAP-43 expression in hippocampus and cerebral cortex at different time points and the state of learning and memory were researched, and the mechanism of the influence that low-level lead exposure exerted on learning and memory function of rats at developmental stage was explored, in order to provide a theoretical basis and an experimental basis for the prevention of lead poisoning of children.
Methods
Female Wistar rats (n=30) aging 2 were randomly divided into three group: control group, low-dose group1(0.05% PbAc), low-dose group2(0.2% PbAc).All the groups were fed normal feeds and double distilled water. After one week adaptive feed, the rats mate according to the pattern in which a female rat mate with one male, and the next morning when vaginal plug appears or sperm was found in vaginal secretion by means of microscopic examination,it was designated as gestation day 0, denoted as GDO. Since the first day of pregnancy, low-dose group 1,2 of lead were consumed 0.05%,0.2%lead acetate solution, until the postnatal day 28 (PN28) of the pups.The control group continued to drink double distilled water with no lead. Pre-weaning the offspring of lead-exposed group drank lead acetate through breast milk,and they continued to drink the same concentration of lead acetate after weaning.At PN1,PN3,PN7,PN14,PN21,PN28,individually the hippocampus and cerebral cortex were got from pups in different groups and stored at fluid nitrogen and then stored at-70℃refrigerator;At PN28,we measured the brain lead and blood lead;Since PN56 the pups began to train in a spatial learning tast using a water maze paradigm.Removing the speciments of the hippocampus and cerebral cortex,we detected the chang of expression of the neuronal growth associated protein using Immunohistochemistry and Western blot.
Results
1、Effect of chronic developmental low-level lead exposure on the blood lead and brain(hippocampus and cerebral cortex)lead in rat.
lead levels in blood and brain of the groups of offspring in those two different lead-exposed groups were obviously higher than that in the control group,and the difference was statistically significant (P<0.01),and the extent of increasing showed in lead concentraion dependent manner.
2、Effect of chronic developmental low-level lead exposure on spatial learning and memory in rats at the developmental stage
In the Morris water maze task, results indicated that rats having drunk lead water diplayed significant impairment in their performance,and this extent of impairment showed in lead concentration dependent manner.
3、Effect of chronic developmental low-level lead exposure on GAP-43 expression in rat hippocampus and cerebral cortex
(1) Immunohistochemistry showed:there was statistical significance (P＜0.01) in terms of the difference between the lead-exposed groups and the control group on the integral optical density (IOD) of hippocampal CA1 and CA3 areas, of cerebral cortex on PN7, PN14, PN 21 and PN28 and of DG area on PN7, PN14 and PN21, that was, the content of the protein expression of the lead-exposed groups was lower than that of the control group, compareing that of cerebral hippocampal CA1, and of cerebral cortex on PN1, PN3 and of DG area on PN28, the difference between low dose group 2 and the control group had statistical significance(P＜0.05 or P＜0.01), as well as the difference between the lead-exposed groups and the control group but that of cerebral hippocampal CA3 on PN1, PN3(P<0.01).
(2)Western Blot showed:Rat pups exposed to chronic level-lead during development did express lower levels of GAP-43 expression in hippocampus and cerebral cortex than of the control group and this exhibited in a dose-dependentand developmental expressed differences manner.
Conclusion
1、Immunohistochemistry and Western Blot results showed that chronic developmental low-level lead exposure reduced the expression of GAP-43 in the hippocampus and cerebral cortex.
2、Lead poisoning reduced the ability of learning and memory.
3、Lead on the impact of GAP-43 could be a mechanism that lead poisoning lead to a decreased capacity for learning and memory mechanism.
引文
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