孕期/哺乳期砷暴露对仔代中枢神经系统发育影响及毒作用机制研究
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摘要
背景和目的慢性砷中毒是一个影响数百万人健康的世界性公共卫生问题。我国饮水型砷中毒病区高砷暴露人群接近300万，已成为受砷中毒危害最为严重的国家之一。慢性砷中毒可致消化系统、神经系统和皮肤等组织器官的病理损害，甚至导致癌症和死亡。由于神经细胞不能再生及其对毒物的毒性作用较其他组织细胞更为敏感，砷对神经系统的毒性影响日益受到高度关注。发育期机体处于快速的细胞生长和分化阶段，同时对体内毒物的清除能力较差，因此对砷的毒作用更加敏感。已被证实，砷是数千种化学物中可以导致神经系统发育紊乱的五种毒物之一。人群调查和动物实验均表明，砷容易通过血脑和胎盘屏障。因此，孕期砷暴露会使胎儿从宫内发育阶段，就面临砷的神经发育毒性作用的风险。流行病学调查和动物实验均表明，脑发育期砷暴露可以导致中枢神经系统发育迟缓及出现学习、记忆等高级神经功能异常，但砷的毒作用机制尚不清楚。已知，孕期和生后早期是脑发育的关键时期。上述时期暴露于有害物质可能影响神经元的发育及正常神经网络的构建，其机制可能与有毒化学物作用于脑发育相关调控蛋白有关。越来越多的证据表明，Rho家族蛋白在神经元形态形成及构成精确的神经网络过程中发挥关键调节作用。酒精等孕期暴露，可导致仔鼠脑组织神经网络构建异常及学习记忆能力下降。而且已被证实，酒精的神经发育毒性与干扰Rho家族蛋白的调控作用有关。那么，砷的神经发育毒性机制是否也与Rho家族蛋白对脑发育调控的紊乱有关，引起我们极大兴趣。本研究通过构建孕期及哺乳期低浓度砷暴露动物模型，观察砷对仔鼠中枢神经系统发育的形态学及对学习记忆等高级神经功能的影响，检测分析神经发育相关蛋白Rho家族多个基因及蛋白的表达，探讨砷对仔鼠脑组织靶基因及相关通路调控的影响，为阐明砷的神经发育毒作用机制以及砷中毒的防治提供依据。
方法
（1）构建孕期/哺乳期砷暴露小鼠模型
昆明孕小鼠随机分为四组，孕0天起全孕期和哺乳期对母鼠以自由饮水方式染毒，含砷饮水中As2O3浓度分别为1mg/L、4mg/L和16mg/L，对照组饮用蒸馏水。仔鼠生后3周断乳。
（2）仔鼠脑组织病理学观察
取新生仔鼠（出生3天）和断乳仔鼠（出生3周）脑组织，石蜡包埋，切片，HE染色，以倒置相差荧光显微镜观察仔鼠脑发育的形态学变化；采用生长相关蛋白（Gap-43）免疫组化法观察仔鼠大脑神经元突起发育。
（3）仔鼠神经行为测试
以Morris水迷宫定向航行实验测试仔鼠学习记忆能力。
（4）仔鼠脑组织神经发育相关基因表达的基因芯片检测。
（5）仔鼠脑组织Rho家族蛋白、基因表达测定
Real-time RT-PCR和Western-blot技术对新生仔鼠和断乳仔鼠脑组织Rho家族多个基因及蛋白表达进行检测。
结果
(一)孕期/哺乳期砷暴露对仔鼠脑发育影响
HE染色切片的镜下观察显示，与对照组比较，染砷新生仔鼠和断乳仔鼠发育中大小脑皮层变薄，小脑外颗粒细胞层和蒲肯野细胞层厚度均显著低于对照组（p<0.05）；染砷新生仔鼠海马出现锥体细胞水肿、核浓缩、锥体细胞层变薄、锥体细胞层数减少等改变；染砷断乳仔鼠海马出现锥体细胞密集、层次减少、锥体细胞层变薄、神经毡空隙增大等改变。
(二)孕期/哺乳期砷暴露对仔鼠脑神经元轴突发育的形态学影响
Gap-43免疫组化法观察显示，与对照组比较，染砷新生仔鼠大脑皮层锥体细胞体积变小、轴突数目减少、形态细小，神经毡染色不均，出现空隙。随染毒剂量增加，染砷断乳仔鼠大脑皮层锥体细胞轴突数目和树突分枝逐渐减少，神经毡着色不均匀，尤其在高剂量组呈现空网状。提示，孕期及哺乳期砷暴露可导致仔鼠大脑神经元发育迟缓，神经网络构建不良。
(三)孕期/哺乳期砷暴露对仔鼠学习记忆能力影响
Morris水迷宫定向航行试验结果显示，4mg/L和16mg/L染砷组仔鼠的逃避潜伏期显著长于对照组(P <0.05)。将平台隐藏后各组小鼠逃避潜伏期之间均没有显著性差异，而平台露出水面后，16mg/L染砷组仔鼠逃避潜伏期显著长于对照组、1mg/L和4mg/L染砷组(p <0.05)。
(四)孕期/哺乳期砷暴露对仔鼠脑发育调控相关基因、蛋白表达影响
基因芯片结果显示，与对照组比较，4mg/L染砷组仔鼠脑组织Rho A、Rac1和Cdc42基因的表达显著上调，Rho A/Rac1比值和Rho A/Cdc42比值均1大于1。Rho下游效应因子Creb和Arp的编码基因表达显著下调。Cbln4、Chd5和Gjb1的表达显著上调，Ncam、Crim、Fgf14、Grik2、Rnf103、Rps6ka3和Sim1的表达显著下调。Real-time RT-PCR和Western-blot检测结果显示，染砷新生仔鼠脑组织Rho A和Rac1的mRNA和蛋白表达均显著下降，而染砷断乳仔鼠脑组织RhoA和Rac1的mRNA和蛋白表达显著升高。尤其，Rho A/Rac1mRNA和蛋白表达的比值，在染砷新生仔鼠和断乳仔鼠均随染砷剂量增加而升高。与对照组比较，染砷仔鼠生后这两个时段脑组织Cdc42的mRNA和蛋白表达均无显著差异。
结论
（1）孕期/哺乳期砷暴露可导致仔鼠大脑和小脑神经元及其突起的形态学异常改变；
（2）孕期/哺乳期砷暴露可导致仔鼠学习记忆功能下降；
（3）孕期/哺乳期砷暴露导致仔鼠脑神经元及其突起的形态学改变可能是砷导致仔鼠学习记忆功能下降的神经解剖学基础；
（4）孕期/哺乳期砷暴露能显著下调新生仔鼠脑组织Rho A和Rac1基因和蛋白表达；
（5）孕期/哺乳期砷暴露能显著上调断乳仔鼠脑组织Rho A和Rac1基因和蛋白表达；
（6）砷诱导小鼠脑组织Rho A/Rac1表达失衡很可能是孕期及哺乳期砷暴露仔鼠脑发育迟缓及学习与记忆功能下降的重要机制。
Background and Objective
Chronic arsenic intoxication is a global health problem affecting many millions ofpeople. China is one of most seriously affected countries with the exposed populationabout3million. The detrimental impact of chronic exposure to arsenic on healthincludes pathological damages on skin, digestive system, and peripheral and centralnervous systems, as well as some kinds of cancers. Because the nerve cell has notregeneration capacity and is more sensitive to arsenic toxicity than any other kinds ofcells, increasing concerns have been focused on arsenic toxic effects on the nervoussystem. Developing organisms are undergoing rapid cell growth and extensivedifferentiation and have poor ability to clear toxicant, so are especially sensitive to thetoxic effects of arsenic. Up to now, only five (eg, lead, methylmercury, polychlorinatedbiphenyls, arsenic, and toluene) of the thousands known chemicals has been proven tocause developmental neurotoxicity in humans. Arsenic is one of them. Arsenic easilypasses the blood-brain and placenta barriers in mammal. Thus, the fetus is faced withthe risk of neurodevelopmental toxicity of arsenic from the intrauterine growth stage. Afew epidemiological and animal studies have indicated that exposure to arsenic at earlystage of development led to dysplasia of the central nervous system and abnormalappearance of advanced neural function, such as learning and memory. However, theinfluencing degree and exact mechanism of arsenic neurodevelopmental toxicity isunclear. It is well known that gestation and postnatal early stage are the critical periodsfor brain development. Exposure to harmful substances during the periods mentionedabove may affect the development of neurons and normal construction of neuralnetworks. The mechanism may lie in the interaction of toxicant and key proteins relatedto brain development. More and more evidence showed that Rho proteins played a key role in neuronal morphology and neural networks constitute. It has been documentedthat during rapid brain developing period exposure to alcohol could induce abnormalneural network construction and result in decline of learning and memory. Themechanism describing the above changes has been shown to be associated with alcoholdisturbing the normal regulation effects of Rho proteins. Therefore, whether Rhoproteins are involved in the neurodevelopmental toxicity mechanism of arsenictriggered our great interest. In this study, Kunming mice were chose as experimentalmodel and these experimental animals were exposed to arsenic through drinking waterduring whole pregnancy and lactation. The morphological changes, as well as theimpacts on learning and memory, were observed in offspring of arsenic exposedmothers. The potential target molecules of arsenic neurodevelopment toxicity, Rhoproteins, were explored at gene and protein levels in our study so as to better understandeffect of arsenic on developing nervous system.
Methods
(1) Animal model of arsenic exposure during pregnant/lactating period: Pregnantmice were randomly divided into four groups. Group1received distilled water(control)，the other three groups received1,4,16mg/L As2O3aqueous solution throughfree drinking water. Mother mice were exposed to arsenic from gestation day0untilweaning. The pops weaned at postnatal21day.
(2) Pathological observation on brain tissue of offspring: The brain tissues ofneonatal and weaned pups were removed, paraffin-embedded, sliced, stained with HE,and observed under inverted fluorescence microscope. The developmental conditions ofneurite in arsenic exposed pups were observed by growth-associated protein (Gap-43)immunohistochemical method.
(3) Neurobehavioral tests: The directional navigation experiment by Morris WaterMaze test was used to examine ability of learning and memory of exposed offspring.
(4) Gene Chip was used to detect genes associated with brain development.
(5) Determination of expression of Rho family in brain tissue of arsenic exposedoffspring: Real-time RT-PCR, and Western-blot detection were used to determineexpression of Rho family members at mRNA and protein levels.
Results
(1) Impact of arsenic exposure during pregnancy/lactation period on braindevelopment: Under microscope, exposed offspring showed thinner cerebral andcerebellar cortical. In hippocampus of exposed neonatal mice, pyramidal cells appeared edema, enrichment nuclear, and pyramidal cell layer became thinner compared withcontrol group.
(2) Impact of arsenic exposure during pregnancy/lactation period on morphologyof neurite: Observing by growth-associated protein (Gap-43) immunohistochemicalmethod, there were some changes in pyramidal cells of cerebral cortex in exposedoffspring compared with the control group, such as decreased baby, reduction in thenumber of axon and dendritic, and uneven stained neuropil. These phenomenasuggested that arsenic exposure during pregnancy and lactation could causes retardedneural growth and poor-constructed neural network.
(3) Impact of arsenic exposure during pregnancy/lactation period on ability oflearning and memory: During the observation period, the escape latency in exposedoffspring of4mg/L and16mg/L groups is significantly longer than the control group.After hiding platform, there is no significant difference in escape latency between allgroups. However, after the platform showing, the escape latency in offspring of16mg/L group is significantly longer than control group,1mg/L and4mg/L exposedgroup.
(4) Impact of arsenic exposure during pregnancy/lactation period on genes andproteins related to brain development: In Gene Chip, expressions of Rho A、Rac1andCdc42gene were significantly increased in brain tissue in offspring of exposed groupcompared with those of the control group. The ratios of Rho A/Rac1and Rho A/Cdc42were both greater than1in exposed group. The genes of downstream effect factorsof Rho, Creb and Arp, were significantly decreased. Expressions of Cbln4, Chd andGjb1gene were significantly increased，and expressions of Ncam, Crim, Fgf14, Grik2,Rnf103, Rps6ka3and Sim1were significantly decreased in exposed group. Comparedwith the control group, expressions of Rho A and Rac1in mRNA and protein levelswere significantly decreased in neonatal offspring, while significantly increased inweaned offspring by Real-time RT-PCR and Western-blot detection. Particularly, Theratios of Rho A/Rac1and Rho A/Cdc42both increased with arsenic exposure doseeither in neonatal or in weaned offspring. Compared with the control group, expressionsof Cdc42in mRNA and protein levels had no significant changes in exposed offspring.
Conclusions
(1) Arsenic exposure during pregnancy/lactation period can cause abnormalmorphology of cerebral and cerebellar tissues in offspring;
(2) Arsenic exposure during pregnancy/lactation period can cause decreased ability of learning and memory in offspring;
(3) Morphological changes in neurons and processes in brain of arsenic exposedoffspring might be the anatomical basis of arsenic neurodevelopmental toxicity;
(4) Arsenic exposure during pregnancy/lactation period can cause expressions ofRho A and Rac1in mRNA and protein levels down regulated in neonatal offspring;
(5) Arsenic exposure during pregnancy/lactation period can cause expressions ofRho A and Rac1in mRNA and protein levels up regulated in weaned offspring;
(6) Arsenic-induced expression imbalance of Rho A/Rac1may be an importantmechanism for slowed brain development and dysfunction of learning and memory.
方法
（1）构建孕期/哺乳期砷暴露小鼠模型
昆明孕小鼠随机分为四组，孕0天起全孕期和哺乳期对母鼠以自由饮水方式染毒，含砷饮水中As2O3浓度分别为1mg/L、4mg/L和16mg/L，对照组饮用蒸馏水。仔鼠生后3周断乳。
（2）仔鼠脑组织病理学观察
取新生仔鼠（出生3天）和断乳仔鼠（出生3周）脑组织，石蜡包埋，切片，HE染色，以倒置相差荧光显微镜观察仔鼠脑发育的形态学变化；采用生长相关蛋白（Gap-43）免疫组化法观察仔鼠大脑神经元突起发育。
（3）仔鼠神经行为测试
以Morris水迷宫定向航行实验测试仔鼠学习记忆能力。
（4）仔鼠脑组织神经发育相关基因表达的基因芯片检测。
（5）仔鼠脑组织Rho家族蛋白、基因表达测定
Real-time RT-PCR和Western-blot技术对新生仔鼠和断乳仔鼠脑组织Rho家族多个基因及蛋白表达进行检测。
结果
(一)孕期/哺乳期砷暴露对仔鼠脑发育影响
HE染色切片的镜下观察显示，与对照组比较，染砷新生仔鼠和断乳仔鼠发育中大小脑皮层变薄，小脑外颗粒细胞层和蒲肯野细胞层厚度均显著低于对照组（p<0.05）；染砷新生仔鼠海马出现锥体细胞水肿、核浓缩、锥体细胞层变薄、锥体细胞层数减少等改变；染砷断乳仔鼠海马出现锥体细胞密集、层次减少、锥体细胞层变薄、神经毡空隙增大等改变。
(二)孕期/哺乳期砷暴露对仔鼠脑神经元轴突发育的形态学影响
Gap-43免疫组化法观察显示，与对照组比较，染砷新生仔鼠大脑皮层锥体细胞体积变小、轴突数目减少、形态细小，神经毡染色不均，出现空隙。随染毒剂量增加，染砷断乳仔鼠大脑皮层锥体细胞轴突数目和树突分枝逐渐减少，神经毡着色不均匀，尤其在高剂量组呈现空网状。提示，孕期及哺乳期砷暴露可导致仔鼠大脑神经元发育迟缓，神经网络构建不良。
(三)孕期/哺乳期砷暴露对仔鼠学习记忆能力影响
Morris水迷宫定向航行试验结果显示，4mg/L和16mg/L染砷组仔鼠的逃避潜伏期显著长于对照组(P <0.05)。将平台隐藏后各组小鼠逃避潜伏期之间均没有显著性差异，而平台露出水面后，16mg/L染砷组仔鼠逃避潜伏期显著长于对照组、1mg/L和4mg/L染砷组(p <0.05)。
(四)孕期/哺乳期砷暴露对仔鼠脑发育调控相关基因、蛋白表达影响
基因芯片结果显示，与对照组比较，4mg/L染砷组仔鼠脑组织Rho A、Rac1和Cdc42基因的表达显著上调，Rho A/Rac1比值和Rho A/Cdc42比值均1大于1。Rho下游效应因子Creb和Arp的编码基因表达显著下调。Cbln4、Chd5和Gjb1的表达显著上调，Ncam、Crim、Fgf14、Grik2、Rnf103、Rps6ka3和Sim1的表达显著下调。Real-time RT-PCR和Western-blot检测结果显示，染砷新生仔鼠脑组织Rho A和Rac1的mRNA和蛋白表达均显著下降，而染砷断乳仔鼠脑组织RhoA和Rac1的mRNA和蛋白表达显著升高。尤其，Rho A/Rac1mRNA和蛋白表达的比值，在染砷新生仔鼠和断乳仔鼠均随染砷剂量增加而升高。与对照组比较，染砷仔鼠生后这两个时段脑组织Cdc42的mRNA和蛋白表达均无显著差异。
结论
（1）孕期/哺乳期砷暴露可导致仔鼠大脑和小脑神经元及其突起的形态学异常改变；
（2）孕期/哺乳期砷暴露可导致仔鼠学习记忆功能下降；
（3）孕期/哺乳期砷暴露导致仔鼠脑神经元及其突起的形态学改变可能是砷导致仔鼠学习记忆功能下降的神经解剖学基础；
（4）孕期/哺乳期砷暴露能显著下调新生仔鼠脑组织Rho A和Rac1基因和蛋白表达；
（5）孕期/哺乳期砷暴露能显著上调断乳仔鼠脑组织Rho A和Rac1基因和蛋白表达；
（6）砷诱导小鼠脑组织Rho A/Rac1表达失衡很可能是孕期及哺乳期砷暴露仔鼠脑发育迟缓及学习与记忆功能下降的重要机制。
Background and Objective
Chronic arsenic intoxication is a global health problem affecting many millions ofpeople. China is one of most seriously affected countries with the exposed populationabout3million. The detrimental impact of chronic exposure to arsenic on healthincludes pathological damages on skin, digestive system, and peripheral and centralnervous systems, as well as some kinds of cancers. Because the nerve cell has notregeneration capacity and is more sensitive to arsenic toxicity than any other kinds ofcells, increasing concerns have been focused on arsenic toxic effects on the nervoussystem. Developing organisms are undergoing rapid cell growth and extensivedifferentiation and have poor ability to clear toxicant, so are especially sensitive to thetoxic effects of arsenic. Up to now, only five (eg, lead, methylmercury, polychlorinatedbiphenyls, arsenic, and toluene) of the thousands known chemicals has been proven tocause developmental neurotoxicity in humans. Arsenic is one of them. Arsenic easilypasses the blood-brain and placenta barriers in mammal. Thus, the fetus is faced withthe risk of neurodevelopmental toxicity of arsenic from the intrauterine growth stage. Afew epidemiological and animal studies have indicated that exposure to arsenic at earlystage of development led to dysplasia of the central nervous system and abnormalappearance of advanced neural function, such as learning and memory. However, theinfluencing degree and exact mechanism of arsenic neurodevelopmental toxicity isunclear. It is well known that gestation and postnatal early stage are the critical periodsfor brain development. Exposure to harmful substances during the periods mentionedabove may affect the development of neurons and normal construction of neuralnetworks. The mechanism may lie in the interaction of toxicant and key proteins relatedto brain development. More and more evidence showed that Rho proteins played a key role in neuronal morphology and neural networks constitute. It has been documentedthat during rapid brain developing period exposure to alcohol could induce abnormalneural network construction and result in decline of learning and memory. Themechanism describing the above changes has been shown to be associated with alcoholdisturbing the normal regulation effects of Rho proteins. Therefore, whether Rhoproteins are involved in the neurodevelopmental toxicity mechanism of arsenictriggered our great interest. In this study, Kunming mice were chose as experimentalmodel and these experimental animals were exposed to arsenic through drinking waterduring whole pregnancy and lactation. The morphological changes, as well as theimpacts on learning and memory, were observed in offspring of arsenic exposedmothers. The potential target molecules of arsenic neurodevelopment toxicity, Rhoproteins, were explored at gene and protein levels in our study so as to better understandeffect of arsenic on developing nervous system.
Methods
(1) Animal model of arsenic exposure during pregnant/lactating period: Pregnantmice were randomly divided into four groups. Group1received distilled water(control)，the other three groups received1,4,16mg/L As2O3aqueous solution throughfree drinking water. Mother mice were exposed to arsenic from gestation day0untilweaning. The pops weaned at postnatal21day.
(2) Pathological observation on brain tissue of offspring: The brain tissues ofneonatal and weaned pups were removed, paraffin-embedded, sliced, stained with HE,and observed under inverted fluorescence microscope. The developmental conditions ofneurite in arsenic exposed pups were observed by growth-associated protein (Gap-43)immunohistochemical method.
(3) Neurobehavioral tests: The directional navigation experiment by Morris WaterMaze test was used to examine ability of learning and memory of exposed offspring.
(4) Gene Chip was used to detect genes associated with brain development.
(5) Determination of expression of Rho family in brain tissue of arsenic exposedoffspring: Real-time RT-PCR, and Western-blot detection were used to determineexpression of Rho family members at mRNA and protein levels.
Results
(1) Impact of arsenic exposure during pregnancy/lactation period on braindevelopment: Under microscope, exposed offspring showed thinner cerebral andcerebellar cortical. In hippocampus of exposed neonatal mice, pyramidal cells appeared edema, enrichment nuclear, and pyramidal cell layer became thinner compared withcontrol group.
(2) Impact of arsenic exposure during pregnancy/lactation period on morphologyof neurite: Observing by growth-associated protein (Gap-43) immunohistochemicalmethod, there were some changes in pyramidal cells of cerebral cortex in exposedoffspring compared with the control group, such as decreased baby, reduction in thenumber of axon and dendritic, and uneven stained neuropil. These phenomenasuggested that arsenic exposure during pregnancy and lactation could causes retardedneural growth and poor-constructed neural network.
(3) Impact of arsenic exposure during pregnancy/lactation period on ability oflearning and memory: During the observation period, the escape latency in exposedoffspring of4mg/L and16mg/L groups is significantly longer than the control group.After hiding platform, there is no significant difference in escape latency between allgroups. However, after the platform showing, the escape latency in offspring of16mg/L group is significantly longer than control group,1mg/L and4mg/L exposedgroup.
(4) Impact of arsenic exposure during pregnancy/lactation period on genes andproteins related to brain development: In Gene Chip, expressions of Rho A、Rac1andCdc42gene were significantly increased in brain tissue in offspring of exposed groupcompared with those of the control group. The ratios of Rho A/Rac1and Rho A/Cdc42were both greater than1in exposed group. The genes of downstream effect factorsof Rho, Creb and Arp, were significantly decreased. Expressions of Cbln4, Chd andGjb1gene were significantly increased，and expressions of Ncam, Crim, Fgf14, Grik2,Rnf103, Rps6ka3and Sim1were significantly decreased in exposed group. Comparedwith the control group, expressions of Rho A and Rac1in mRNA and protein levelswere significantly decreased in neonatal offspring, while significantly increased inweaned offspring by Real-time RT-PCR and Western-blot detection. Particularly, Theratios of Rho A/Rac1and Rho A/Cdc42both increased with arsenic exposure doseeither in neonatal or in weaned offspring. Compared with the control group, expressionsof Cdc42in mRNA and protein levels had no significant changes in exposed offspring.
Conclusions
(1) Arsenic exposure during pregnancy/lactation period can cause abnormalmorphology of cerebral and cerebellar tissues in offspring;
(2) Arsenic exposure during pregnancy/lactation period can cause decreased ability of learning and memory in offspring;
(3) Morphological changes in neurons and processes in brain of arsenic exposedoffspring might be the anatomical basis of arsenic neurodevelopmental toxicity;
(4) Arsenic exposure during pregnancy/lactation period can cause expressions ofRho A and Rac1in mRNA and protein levels down regulated in neonatal offspring;
(5) Arsenic exposure during pregnancy/lactation period can cause expressions ofRho A and Rac1in mRNA and protein levels up regulated in weaned offspring;
(6) Arsenic-induced expression imbalance of Rho A/Rac1may be an importantmechanism for slowed brain development and dysfunction of learning and memory.
引文
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