不同水平铅暴露对生长发育期小鼠学习记忆能力的影响
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摘要
铅是一种具有神经毒性的重金属,它作为一种矿藏广泛存在于自然界,并以良好的柔性和抗腐蚀性得到在工业和日常生活中的广泛应用。铅在环境中可长期蓄积造成污染,通过食物链、水、土壤和空气进入人体。儿童是铅污染的易感人群,铅对儿童的生长发育和智力行为有严重的影响,可出现生长发育落后、智力下降、反应迟钝、多动和注意力集中障碍等症状。
一氧化氮(NO)被认为是典型的逆行信使分子,在学习和记忆中起重要作用,其生物合成主要受一氧化氮合酶(NOS)的调节,目前多以NOS活性来反映NO的含量。已知NOS有三种类型,分别为神经元型NOS(nNOS)、诱导型NOS(iNOS)和内皮型NOS(eNOS),其中nNOS和eNOS合称为结构型NOS(cNOS)。但目前研究对于铅导致脑NO含量及NOS活性降低还是升高方面尚有争议。
本研究拟对小鼠设立正常对照组和不同水平铅暴露组,检测小鼠的血铅和组织铅浓度、Morris水迷宫逃避潜伏期以及脑和血清NO含量、NOS活性的变化情况,探讨不同水平铅暴露对生长发育期小鼠学习记忆能力的影响及脑NO、NOS和血清NO、NOS与小鼠学习记忆能力之间的联系。
材料与方法
1动物模型制备及分组
刚断乳远交群昆明小鼠120只,体重18g～22g,雌雄各半。以含醋酸铅的饮水做铅暴露源,设立0.3g/L组,1.0g/L组,3.0g/L组和正常对照组。每组30只小鼠,雌雄各半,分笼饲养。
2标本的采取
开始染铅记为第0d。分别在第7、14和21d,对全部小鼠采用尾部采血。采血后,每组随机抽取10只小鼠,雌雄各半。断头采血,用于分离血清。解剖小鼠,分离脑、脾、肾、肝、肺和股骨,称重后保存于-20℃冰箱。
3小鼠体重的测定
分别在第0、7、14、21d,用JJ200型精密电子天平测量每组小鼠体重。
4小鼠血铅和组织铅浓度的测定
用Z-5000石墨炉原子吸收光谱仪测小鼠血铅和组织铅浓度。
5小鼠Morris水迷宫试验的测定
在第7、14和21d,每组随机抽取小鼠10只进行测试,3次训练后,测小鼠逃避潜伏期。
6小鼠脑及血清NO含量、NOS活性的测定
在第7、14和21d,用试剂盒测定脑和血清的NO含量,NOS活性。
7统计学分析
用SPSS 12.0统计软件对实验数据进行方差分析、秩和检验(K-W检验)、多个样本均数的两两比较(SNK法检验和Wilcoxon秩和检验)和相关分析。
检验水准α=0.05。
结果
1铅暴露对小鼠一般状况的影响
随着铅暴露时间的增加,正常组小鼠体重呈升高趋势,3组铅暴露小鼠体重的增加较对照组缓慢,差异有统计学意义(P＜0.05);各铅暴露组小鼠的每周体重增长率随铅暴露时间增加均呈下降趋势,均低于正常组,差异有统计学意义(P＜0.05)。
2铅暴露对小鼠血铅和组织铅浓度的影响
各铅暴露组小鼠的血铅、脑铅和骨铅浓度随着铅暴露时间和水平的增加均升高,差异有统计学意义(P＜0.05);肝铅、肾铅、脾铅浓度随着铅暴露水平的增加均升高,差异有统计学意义(P＜0.05);肺铅与正常组小鼠相比,差异无统计学意义。
3铅暴露对小鼠智力的影响
3.1 Morris水迷宫试验
随着铅暴露时间和水平的增加,各铅暴露组小鼠的逃避潜伏期均增加,差异有统计学意义(P＜0.05)。
3.2铅暴露对小鼠脑和血清NO、NOS的影响
3.2.1铅暴露对小鼠脑NO、NOS的影响
各铅暴露组小鼠的脑NO含量随着铅暴露时间的增加呈下降趋势,差异有统计学意义(P＜0.05);在同一时点,随着铅暴露水平的增加,其含量亦呈下降趋势,差异有统计学意义(P＜0.05)。
各铅暴露组小鼠的脑总NOS、iNOS和cNOS活性,随着铅暴露时间的增加呈下降趋势,差异有统计学意义(P＜0.05)。在同一时点,随着铅暴露水平的增加,脑总NOS呈下降趋势,差异有统计学意义(P＜0.05);脑iNOS和脑cNOS活性变化趋势不明显。
3.2.2铅暴露对小鼠血清NO、NOS的影响
各铅暴露组小鼠的血清NO含量随着铅暴露时间的增加呈下降趋势,差异有统计学意义(P＜0.05)。
随着铅暴露时间的增加,各铅暴露组小鼠的血清总NOS和iNOS活性呈升高后又降低的趋势,差异有统计学意义(P＜0.05);血清cNOS活性呈下降趋势,差异有统计学意义(P＜0.05)。在同一时点,随着铅暴露水平的增加,血清总NOS、iNOS和cNOS活性变化差异均有统计学意义(P＜0.05)。
3.3相关分析
小鼠血清cNOS活性,在第7d与血铅浓度呈负相关(r=-0.316,P=0.047);在第14和21d时,小鼠血清cNOS活性与与血铅、脑铅浓度及Morris水迷宫逃避潜伏期均呈负相关(r=-0.365,P=0.020;r=-0.361,P=0.022;r=-0.458,P=0.003;r=-0.731,P=0.000;r=-0.512,P=0.001;r=-0.698,P=0.000)。
结论
1随着铅暴露时间和水平的增加,小鼠体重增长越为迟缓。
2小鼠的学习记忆能力随铅暴露时间和暴露水平增加而降低。
3随着铅暴露时间的增加,小鼠脑和血清的NO含量减少,脑和血清的NOS活性降低,且小鼠血清cNOS活性可能与学习记忆能力有相关性。
OBJECTIVE
Lead widely exists in nature and extensively uesed in the industry and people's daily life because of its flexibility and antisepsis. However, lead is a neurotoxic heavy metal and can pollute the environment by long-term accumulation and enter human body through food chain, water, soil and air. Children are susceptible to lead exposure. Lead can seriously harm children's growth, development and intelligence.
Nitric oxide (NO) is a retrograde messenger, and plays an important role in learning and memory. Its biosynthesis is modulated by nitric oxide synthase (NOS). By measuring NOS activity, we can estimate the content of NO in the tissue. There are three types of NOS, neurone NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS), among which, nNOS and eNOS are merged as constructional NOS (cNOS). However, the research outcomes on the effects of NO level and NOS activity are still controversy.
The study was aimed to investigate the effects of different lead exposure on lead content, NO levels, NOS activity and learning ability in mice. The relationships between lead exposure level and brain damage as well as the potential correlation between lead exposure and NOS were explored.
MATERIALS AND METHODS
1 Experimental animals
The subjects were weaned KM mice with the body weight at 18g to 22g. The total number of subjects was 120 and half for each gender. They were randomly assigned into non-exposure control group and three levels of lead exposure groups, thirty for each group. The lead exposure was carried out by adding lead acetate in drinking water. The concentrations of lead acetate were 0.3g/L, 1.0g/L and 3.0g/L respectively.
2 Sample collection
The first day of starting lead exposure was assigned as day Zero. On the 7~(th), 14~(th) and 21~(st) days, blood was collected from the mice tail. Ten mice from each of the groups were killed by decapitation. The blood was collected and the serum was separated. The brain, spleen, kidneys, liver, lungs and femurs were dissected and stored at -20℃for future use.
3 Observation on physical development
The mice body weight was recorded once a week.
4 Determination of the lead concentration in blood and tissues
The lead levels in serum, brain and other tissues were measured using Z-5000 graphite furnace atomic absorption spectrometer.
5 Evaluation of learning and memory ability
On day seven, fourteen and twenty-one, of lead exposure, ten mice from each groups were evaluated for their learning and memory function using modified Morris water maze test. After three times training, the duration of escape was recorded.
6 Determination of NO content and NOS activity in serum and brain
At these three time points, after behavior test, the mice were killed. Their serum and brain tissue were analyzed for the NO content and NOS activity.
7 Data analysis
The results were analysed using SPSS 12.0. One way ANOVA meathod and rank sum test (K-W test) were used. The significant level was set at 0.05 .
RESULTS
1 The effects of lead exposure on body weight
The mice in both the non-exposure and exposure groups gained body weight, but the later ones gained less and showed the downward weight gain trend (P<0.05); the weekly weight growth rate of the lead-exposued mice showed a downward trend, and all less than the control group's, there were significant differences between them (P<0.05).
2 The effects of exposure on blood and tissue lead levels
The lead levels in blood, brain, bone tissues were increased with the lead exposure time and dosage (P<0.05); liver, kidneys, and spleen tissues were increased with the lead exposure dosage (P<0.05); The lead level in lung tissue was not significantly different between the exposure groups and the control group (P>0.05).
3 The effects of lead exposure on the learning and memory
3.1 Morris water-maze test
The escape latency was significant longer in the lead-exposed groups, the longer and higher dosage exposure, the poor learning performance (P<0.05)
3.2 The effects of lead exposure on NO content and NOS activity in the brain and the serum
3.2.1 The effects of lead exposure on NO content and NOS activity in the brain
Both of the content of NO and total NOS activity were decreased in the lead-exposed mice and more severe declines were observed in the mice with higher dosage and longer time exposure (P<0.05). The changes of the activity of iNOS and cNOS in brain were not obviously.
3.2.2 The effects of lead exposure on NO content and NOS activity in mice serum The content of NO in serum was significantly decreased along with thelead-exposure time (P<0.05).
The overall effect of lead exposure on serum NOS and iNOS activity was decreased. The cNOS activity in serum was decreased in exposed mice (P<0.05).3.3 Correlation analysis
The serum cNOS activity was negatively associated with serum lead on the 7~(th) day (r=-0.316, P=0.047); and serum lead, brain lead as well as the escape latency on 14~(th) day and 21~(st) day (r=-0.365, P=0.020; r=-0.361, P=0.022; r=-0.458, P=0.003; r=-0.731, P=0.000; r=-0.512, P=0.001; r=-0.698, P=0.000 respectively).
CONCLUSION
1 The body weight gain in mice was effected by lead exposure. The higher dosage and the longer time exposure showed more serious effects.
2 The learning and memory performance was impaired in lead exposure mice.
3 The content of NO and the NOS activity in the brain and serum was decreased along with the lead-exposure time, and the serum cNOS activity may be relevant with learning and memory of mice.
一氧化氮(NO)被认为是典型的逆行信使分子,在学习和记忆中起重要作用,其生物合成主要受一氧化氮合酶(NOS)的调节,目前多以NOS活性来反映NO的含量。已知NOS有三种类型,分别为神经元型NOS(nNOS)、诱导型NOS(iNOS)和内皮型NOS(eNOS),其中nNOS和eNOS合称为结构型NOS(cNOS)。但目前研究对于铅导致脑NO含量及NOS活性降低还是升高方面尚有争议。
本研究拟对小鼠设立正常对照组和不同水平铅暴露组,检测小鼠的血铅和组织铅浓度、Morris水迷宫逃避潜伏期以及脑和血清NO含量、NOS活性的变化情况,探讨不同水平铅暴露对生长发育期小鼠学习记忆能力的影响及脑NO、NOS和血清NO、NOS与小鼠学习记忆能力之间的联系。
材料与方法
1动物模型制备及分组
刚断乳远交群昆明小鼠120只,体重18g～22g,雌雄各半。以含醋酸铅的饮水做铅暴露源,设立0.3g/L组,1.0g/L组,3.0g/L组和正常对照组。每组30只小鼠,雌雄各半,分笼饲养。
2标本的采取
开始染铅记为第0d。分别在第7、14和21d,对全部小鼠采用尾部采血。采血后,每组随机抽取10只小鼠,雌雄各半。断头采血,用于分离血清。解剖小鼠,分离脑、脾、肾、肝、肺和股骨,称重后保存于-20℃冰箱。
3小鼠体重的测定
分别在第0、7、14、21d,用JJ200型精密电子天平测量每组小鼠体重。
4小鼠血铅和组织铅浓度的测定
用Z-5000石墨炉原子吸收光谱仪测小鼠血铅和组织铅浓度。
5小鼠Morris水迷宫试验的测定
在第7、14和21d,每组随机抽取小鼠10只进行测试,3次训练后,测小鼠逃避潜伏期。
6小鼠脑及血清NO含量、NOS活性的测定
在第7、14和21d,用试剂盒测定脑和血清的NO含量,NOS活性。
7统计学分析
用SPSS 12.0统计软件对实验数据进行方差分析、秩和检验(K-W检验)、多个样本均数的两两比较(SNK法检验和Wilcoxon秩和检验)和相关分析。
检验水准α=0.05。
结果
1铅暴露对小鼠一般状况的影响
随着铅暴露时间的增加,正常组小鼠体重呈升高趋势,3组铅暴露小鼠体重的增加较对照组缓慢,差异有统计学意义(P＜0.05);各铅暴露组小鼠的每周体重增长率随铅暴露时间增加均呈下降趋势,均低于正常组,差异有统计学意义(P＜0.05)。
2铅暴露对小鼠血铅和组织铅浓度的影响
各铅暴露组小鼠的血铅、脑铅和骨铅浓度随着铅暴露时间和水平的增加均升高,差异有统计学意义(P＜0.05);肝铅、肾铅、脾铅浓度随着铅暴露水平的增加均升高,差异有统计学意义(P＜0.05);肺铅与正常组小鼠相比,差异无统计学意义。
3铅暴露对小鼠智力的影响
3.1 Morris水迷宫试验
随着铅暴露时间和水平的增加,各铅暴露组小鼠的逃避潜伏期均增加,差异有统计学意义(P＜0.05)。
3.2铅暴露对小鼠脑和血清NO、NOS的影响
3.2.1铅暴露对小鼠脑NO、NOS的影响
各铅暴露组小鼠的脑NO含量随着铅暴露时间的增加呈下降趋势,差异有统计学意义(P＜0.05);在同一时点,随着铅暴露水平的增加,其含量亦呈下降趋势,差异有统计学意义(P＜0.05)。
各铅暴露组小鼠的脑总NOS、iNOS和cNOS活性,随着铅暴露时间的增加呈下降趋势,差异有统计学意义(P＜0.05)。在同一时点,随着铅暴露水平的增加,脑总NOS呈下降趋势,差异有统计学意义(P＜0.05);脑iNOS和脑cNOS活性变化趋势不明显。
3.2.2铅暴露对小鼠血清NO、NOS的影响
各铅暴露组小鼠的血清NO含量随着铅暴露时间的增加呈下降趋势,差异有统计学意义(P＜0.05)。
随着铅暴露时间的增加,各铅暴露组小鼠的血清总NOS和iNOS活性呈升高后又降低的趋势,差异有统计学意义(P＜0.05);血清cNOS活性呈下降趋势,差异有统计学意义(P＜0.05)。在同一时点,随着铅暴露水平的增加,血清总NOS、iNOS和cNOS活性变化差异均有统计学意义(P＜0.05)。
3.3相关分析
小鼠血清cNOS活性,在第7d与血铅浓度呈负相关(r=-0.316,P=0.047);在第14和21d时,小鼠血清cNOS活性与与血铅、脑铅浓度及Morris水迷宫逃避潜伏期均呈负相关(r=-0.365,P=0.020;r=-0.361,P=0.022;r=-0.458,P=0.003;r=-0.731,P=0.000;r=-0.512,P=0.001;r=-0.698,P=0.000)。
结论
1随着铅暴露时间和水平的增加,小鼠体重增长越为迟缓。
2小鼠的学习记忆能力随铅暴露时间和暴露水平增加而降低。
3随着铅暴露时间的增加,小鼠脑和血清的NO含量减少,脑和血清的NOS活性降低,且小鼠血清cNOS活性可能与学习记忆能力有相关性。
OBJECTIVE
Lead widely exists in nature and extensively uesed in the industry and people's daily life because of its flexibility and antisepsis. However, lead is a neurotoxic heavy metal and can pollute the environment by long-term accumulation and enter human body through food chain, water, soil and air. Children are susceptible to lead exposure. Lead can seriously harm children's growth, development and intelligence.
Nitric oxide (NO) is a retrograde messenger, and plays an important role in learning and memory. Its biosynthesis is modulated by nitric oxide synthase (NOS). By measuring NOS activity, we can estimate the content of NO in the tissue. There are three types of NOS, neurone NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS), among which, nNOS and eNOS are merged as constructional NOS (cNOS). However, the research outcomes on the effects of NO level and NOS activity are still controversy.
The study was aimed to investigate the effects of different lead exposure on lead content, NO levels, NOS activity and learning ability in mice. The relationships between lead exposure level and brain damage as well as the potential correlation between lead exposure and NOS were explored.
MATERIALS AND METHODS
1 Experimental animals
The subjects were weaned KM mice with the body weight at 18g to 22g. The total number of subjects was 120 and half for each gender. They were randomly assigned into non-exposure control group and three levels of lead exposure groups, thirty for each group. The lead exposure was carried out by adding lead acetate in drinking water. The concentrations of lead acetate were 0.3g/L, 1.0g/L and 3.0g/L respectively.
2 Sample collection
The first day of starting lead exposure was assigned as day Zero. On the 7~(th), 14~(th) and 21~(st) days, blood was collected from the mice tail. Ten mice from each of the groups were killed by decapitation. The blood was collected and the serum was separated. The brain, spleen, kidneys, liver, lungs and femurs were dissected and stored at -20℃for future use.
3 Observation on physical development
The mice body weight was recorded once a week.
4 Determination of the lead concentration in blood and tissues
The lead levels in serum, brain and other tissues were measured using Z-5000 graphite furnace atomic absorption spectrometer.
5 Evaluation of learning and memory ability
On day seven, fourteen and twenty-one, of lead exposure, ten mice from each groups were evaluated for their learning and memory function using modified Morris water maze test. After three times training, the duration of escape was recorded.
6 Determination of NO content and NOS activity in serum and brain
At these three time points, after behavior test, the mice were killed. Their serum and brain tissue were analyzed for the NO content and NOS activity.
7 Data analysis
The results were analysed using SPSS 12.0. One way ANOVA meathod and rank sum test (K-W test) were used. The significant level was set at 0.05 .
RESULTS
1 The effects of lead exposure on body weight
The mice in both the non-exposure and exposure groups gained body weight, but the later ones gained less and showed the downward weight gain trend (P<0.05); the weekly weight growth rate of the lead-exposued mice showed a downward trend, and all less than the control group's, there were significant differences between them (P<0.05).
2 The effects of exposure on blood and tissue lead levels
The lead levels in blood, brain, bone tissues were increased with the lead exposure time and dosage (P<0.05); liver, kidneys, and spleen tissues were increased with the lead exposure dosage (P<0.05); The lead level in lung tissue was not significantly different between the exposure groups and the control group (P>0.05).
3 The effects of lead exposure on the learning and memory
3.1 Morris water-maze test
The escape latency was significant longer in the lead-exposed groups, the longer and higher dosage exposure, the poor learning performance (P<0.05)
3.2 The effects of lead exposure on NO content and NOS activity in the brain and the serum
3.2.1 The effects of lead exposure on NO content and NOS activity in the brain
Both of the content of NO and total NOS activity were decreased in the lead-exposed mice and more severe declines were observed in the mice with higher dosage and longer time exposure (P<0.05). The changes of the activity of iNOS and cNOS in brain were not obviously.
3.2.2 The effects of lead exposure on NO content and NOS activity in mice serum The content of NO in serum was significantly decreased along with thelead-exposure time (P<0.05).
The overall effect of lead exposure on serum NOS and iNOS activity was decreased. The cNOS activity in serum was decreased in exposed mice (P<0.05).3.3 Correlation analysis
The serum cNOS activity was negatively associated with serum lead on the 7~(th) day (r=-0.316, P=0.047); and serum lead, brain lead as well as the escape latency on 14~(th) day and 21~(st) day (r=-0.365, P=0.020; r=-0.361, P=0.022; r=-0.458, P=0.003; r=-0.731, P=0.000; r=-0.512, P=0.001; r=-0.698, P=0.000 respectively).
CONCLUSION
1 The body weight gain in mice was effected by lead exposure. The higher dosage and the longer time exposure showed more serious effects.
2 The learning and memory performance was impaired in lead exposure mice.
3 The content of NO and the NOS activity in the brain and serum was decreased along with the lead-exposure time, and the serum cNOS activity may be relevant with learning and memory of mice.
引文
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