淀山湖类毒素-A污染状况及其神经毒性研究
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摘要
随着水体富营养化的日益加剧,淡水“水华”和海水“赤潮”不断暴发,藻类〔包括藻毒素〕污染已成为迫切的公共卫生问题之一。藻毒素能引起多脏器的损伤。类毒素-A(anatoxin-a, ANTX-A)是一种常见的神经藻毒素。已有ANTX-A引起家禽、家畜和野生动物急性中毒死亡的许多报道。许多国家湖泊和水库中都检测出不同程度的ANTX-A污染,且传统氯化饮水消毒技术尚不能完全去除水中的ANTX-A,造成人们低剂量反复接触ANTX-A的可能性。毒理学试验也提示了低剂量ANTX-A的中枢神经毒性。因此,需要全面认识A NTX-A的低剂量神经毒性。
本研究从淀山湖ANTX-A污染调查、ANTX-A体内神经毒性试验及体外神经毒性试验三方面,对ANTX-A在我国淀山湖的污染状况以及低剂量亚急性暴露ANTX-A对中枢神经系统的影响和可能毒作用机理进行探讨。
第一部分 淀山湖类毒素-A污染状况调查
目的:研究淀山湖富营养化状况和ANTX-A在淀山湖的分布情况,并探讨ANTX-A与各项环境因素的相关性。方法:在2002年夏秋季节,测定湖水中与水体富营养化有关的各项理化指标、藻细胞总数、水中和水华藻中ANTX-A含量(高效液相色谱法),分析水中ANTX-A与各项环境因素的相关性(广义估计方程)。结果:水中总氮和总磷均超过地面水环境质量标准III级限值,水中藻细胞总数均值达到3×106个/L。湖中ANTX-A平均污染水平为7ng/L,7月污染最严重。水华藻中ANTX-A含量为15ng/mg干藻。ANTX-A与照度、浊度、总磷、叶绿素A有明显的相关关系,浊度作用较强(p<0.01)。结论:淀山湖呈现严重富营养化。存在ANTX-A污染,7月污染较严重。水体浊度与ANTX-A污染呈正相关。
第二部分 类毒素-A体内神经毒性实验研究
目的:研究ANTX-A亚急性暴露对小鼠中枢神经系统的影响,并探讨其毒作用机理。方法:小鼠每日腹腔染毒ANTX-A 0,12.5,50,200 ug/kg.bw,连续一月,观察体重增长情况,用小鼠避暗试验和水迷宫试验测定小鼠神经行为改变,并观察中枢神经系统病理学改变。测定脑组织中钙调信号传导系统包括细胞内钙离子、ATPase、钙调神经磷脂酶(PP2B)、c-fos、NGFI-A和CREB
-1变化,以及自由基信号系统包括NO和活性氧变化。结果:ANTX-A 200μg/kg.bw组小鼠体重增长缓慢(p<0.05)。ANTX-A 200μg/kg.bw组小鼠被动回避反应和空间学习记忆能力降低(p<0.05)。ANTX-A 200μg/kg.bw组小鼠皮质和海马区有散在的神经元变性或坏死。其余ANTX-A剂量组未见上述改变。ANTX-A 12.5μg/kg.bw、50μg/kg.bw、200μg/kg.bw各剂量组动物脑组织内钙离子浓度明显升高(p<0.01);ANTX-A 200μg/kg.bw组小鼠脑组织PP2B活性、c-fos基因和蛋白表达、CREB-1蛋白表达均有增高(p<0.05);ANTX-A 50μg/kg.bw、200μg/kg.bw组小鼠脑组织内Ca2+-ATP酶活性均有降低(p<0.05)。ANTX-A 200μg/kg.bw组小鼠脑组织活性氧含量增高(p<0.05)。结论:亚急性ANTX-A暴露对小鼠学习记忆能力有一定抑制作用。ANTX-A可能通过钙调信号传导通路和活性氧产生中枢毒作用。
第三部分 类毒素-A体外神经毒性实验研究
目的:研究ANTX-A对神经元烟碱型乙酰胆碱受体(nAChRs)的毒作用及其作用机制。方法:用[H3]-NA释放试验来检测ANTX-A对PC12细胞nAChRs的激活和脱敏作用,研究PC12细胞激活和脱敏状态时胞内钙调信号传导通路和活性氧变化。结果:10-9M～10-7M ANTX-A刺激PC12细胞1小时可激活PC12细胞,有剂量反应关系。10-7M ANTX-A刺激PC12细胞30min～120min可激活PC12细胞,有时间效应关系。ANTX-A激活PC12细胞时,胞内钙离子浓度、c-fos和NGFI-A基因表达明显增加(p<0.05); Ca2+-ATP酶和PP2B活性降低(p<0.05)。ANTX-A两相刺激可诱导PC12细胞脱敏。ANTX-A诱导PC12细胞脱敏时,胞内钙离子浓度、PP2B活性、c-fos、NGFI-A基因表达和活性氧含量显著增加(p<0.05);Ca2+-ATP酶活性显著降低(p<0.05)。美加明(MEC)--烟碱受体拮抗剂和环孢菌素A(CsA)――PP2B抑制剂可抑制ANTX-A诱导细胞脱敏的产生(p<0.05)。维拉帕米(VRP)―― L型-电压敏感的钙通道拮抗剂可拮抗ANTX-A增加胞内钙离子浓度的作用。结论:ANTX-A在体外可激活和脱敏神经元烟碱型乙酰胆碱受体,钙调信号传导通路可能在ANTX-A诱导nAChRs激活和脱敏中起重要调控作用,活性氧在ANTX-A诱导nAChRs脱敏中可能有重要调控作用。
With progressive eutrophication of surface water, water bloom and red tide break out frequently in freshwater and seawater. Contamination of algae (including algal toxins) has been an important public health concern. Algal toxins can give birth to the damage of many tissues. Anatoxin-a (ANTX-A) is one of the most familiar neurotoxical algal toxins. There were lots of domestic fowls and livestock and wild animals poisoning incidents caused by ANTX-A. Different amounts of ANTX-A were detected from lakes and reservoirs in many countries. Moreover, conventional chlorination water treatment procedure is not sufficient to totally remove ANTX-A, humans are potentially exposed to low-level ANTX-A. Some toxicological tests suggested that low-dose ANTX-A might be associated with central nerve system toxicity. Therefore, it’s necessary to study the low-dose neurotoxicity of ANTX-A.
The present study is aimed to investigate the distribution of ANTX-A from Dianshan Lake and to explore the effect of ANTX-A on CNS and its possible mechanism. This study includes three parts: 1) investigation on the pollution of ANTX-A in Dianshan Lake; 2) in vivo neurotoxical test of ANTX-A; 3) in vitro neurotoxical test of ANTX-A.
Part 1: Investigation on the Pollution of Anatoxin-a in Dianshan Lake
Objectives: To study the eutrophication status and the distribution of ANTX-A in Dianshan Lake, and discuss the correlation between ANTX-A and various environmental elements. Methods: During the summer and autumn in 2002, some physical-chemical elements associated to eutrophication and algae cell density were investigated, the concentration of ANTX-A in the lake and water-bloom algae were measured by the high-performance liquid chromatography (HPLC), the correlation between ANTX-A and environmental elements was analyzed by general estimated equations (GEE). Results: The concentration of total nitrogen (TN) and total phosphorus (TP) in the Lake were higher than the III level guideline of surface water environmental quality standard. The average algae cell density was 3×106
/liter. The average level of ANTX-A in the lake was 7 ng/liter. And the pollution of ANTX-A was most serious in July. The concentration of ANTX-A in water-bloom algae was 15ng/mg dry algae. The level of ANTX-A was correlated with illumination, turbidity, TP and chlorophyll a (Chla). And the correlation between turbidity and ANTX-A was more significant than others (p<0.05). Conclusion: Dianshan Lake presented serious eutriphication. There was the pollution of ANTX-A, and it was most serious in July. The concentration of ANTX-A was significant correlative with turbidity of lake.
Part 2: in vivo Neurotoxical Test of Anatoxin-a
Objectives: To study the effect of sub-acute exposure of ANTX-A on CNS in mouse and explore its possible mechanism. Methods: Mice were administered by i.p. with ANTX-A at the concentrations of 0, 12.5, 50, 200ug/kg.bw/day for 30 days. Body weight increase was observed during the administration period, neurobehavioral function was measured using step-through test and Morris water maze test, the CNS neuropathological changes were examined. The changes of calcium-mediated signal transduction system including intracellular calcium, ATPase, calcineurin (PP2B), c-fos and CREB-1 and free radical signal system comprised of reactive oxygen species (ROS) and nitric oxide (NO) were measured. Results: The body weight increase of the mice in ANTX-A 200ug/kg.bw group decreased obviously (p<0.05). The passive evade activity and special learning and memory function of the mice in ANTX-A 200ug/kg.bw group weakened significantly (p<0.05). Degeneration and necrosis of neuron were observed in the cortex and hippocampus of ANTX-A 200ug/kg.bw-treated mice. And no such changes were observed in the other ANTX-A group. In ANTX-A 12.5ug/kg.bw, 50ug/kg.bw, 200ug/kg.bw group, the concentration of intracellular calcium in the brain increased significantly (p<0.05). The activity of PP2B and the gene and protein expression of c-fos and CREB-1 improved in ANTX-A 200ug/kg.
本研究从淀山湖ANTX-A污染调查、ANTX-A体内神经毒性试验及体外神经毒性试验三方面,对ANTX-A在我国淀山湖的污染状况以及低剂量亚急性暴露ANTX-A对中枢神经系统的影响和可能毒作用机理进行探讨。
第一部分 淀山湖类毒素-A污染状况调查
目的:研究淀山湖富营养化状况和ANTX-A在淀山湖的分布情况,并探讨ANTX-A与各项环境因素的相关性。方法:在2002年夏秋季节,测定湖水中与水体富营养化有关的各项理化指标、藻细胞总数、水中和水华藻中ANTX-A含量(高效液相色谱法),分析水中ANTX-A与各项环境因素的相关性(广义估计方程)。结果:水中总氮和总磷均超过地面水环境质量标准III级限值,水中藻细胞总数均值达到3×106个/L。湖中ANTX-A平均污染水平为7ng/L,7月污染最严重。水华藻中ANTX-A含量为15ng/mg干藻。ANTX-A与照度、浊度、总磷、叶绿素A有明显的相关关系,浊度作用较强(p<0.01)。结论:淀山湖呈现严重富营养化。存在ANTX-A污染,7月污染较严重。水体浊度与ANTX-A污染呈正相关。
第二部分 类毒素-A体内神经毒性实验研究
目的:研究ANTX-A亚急性暴露对小鼠中枢神经系统的影响,并探讨其毒作用机理。方法:小鼠每日腹腔染毒ANTX-A 0,12.5,50,200 ug/kg.bw,连续一月,观察体重增长情况,用小鼠避暗试验和水迷宫试验测定小鼠神经行为改变,并观察中枢神经系统病理学改变。测定脑组织中钙调信号传导系统包括细胞内钙离子、ATPase、钙调神经磷脂酶(PP2B)、c-fos、NGFI-A和CREB
-1变化,以及自由基信号系统包括NO和活性氧变化。结果:ANTX-A 200μg/kg.bw组小鼠体重增长缓慢(p<0.05)。ANTX-A 200μg/kg.bw组小鼠被动回避反应和空间学习记忆能力降低(p<0.05)。ANTX-A 200μg/kg.bw组小鼠皮质和海马区有散在的神经元变性或坏死。其余ANTX-A剂量组未见上述改变。ANTX-A 12.5μg/kg.bw、50μg/kg.bw、200μg/kg.bw各剂量组动物脑组织内钙离子浓度明显升高(p<0.01);ANTX-A 200μg/kg.bw组小鼠脑组织PP2B活性、c-fos基因和蛋白表达、CREB-1蛋白表达均有增高(p<0.05);ANTX-A 50μg/kg.bw、200μg/kg.bw组小鼠脑组织内Ca2+-ATP酶活性均有降低(p<0.05)。ANTX-A 200μg/kg.bw组小鼠脑组织活性氧含量增高(p<0.05)。结论:亚急性ANTX-A暴露对小鼠学习记忆能力有一定抑制作用。ANTX-A可能通过钙调信号传导通路和活性氧产生中枢毒作用。
第三部分 类毒素-A体外神经毒性实验研究
目的:研究ANTX-A对神经元烟碱型乙酰胆碱受体(nAChRs)的毒作用及其作用机制。方法:用[H3]-NA释放试验来检测ANTX-A对PC12细胞nAChRs的激活和脱敏作用,研究PC12细胞激活和脱敏状态时胞内钙调信号传导通路和活性氧变化。结果:10-9M～10-7M ANTX-A刺激PC12细胞1小时可激活PC12细胞,有剂量反应关系。10-7M ANTX-A刺激PC12细胞30min～120min可激活PC12细胞,有时间效应关系。ANTX-A激活PC12细胞时,胞内钙离子浓度、c-fos和NGFI-A基因表达明显增加(p<0.05); Ca2+-ATP酶和PP2B活性降低(p<0.05)。ANTX-A两相刺激可诱导PC12细胞脱敏。ANTX-A诱导PC12细胞脱敏时,胞内钙离子浓度、PP2B活性、c-fos、NGFI-A基因表达和活性氧含量显著增加(p<0.05);Ca2+-ATP酶活性显著降低(p<0.05)。美加明(MEC)--烟碱受体拮抗剂和环孢菌素A(CsA)――PP2B抑制剂可抑制ANTX-A诱导细胞脱敏的产生(p<0.05)。维拉帕米(VRP)―― L型-电压敏感的钙通道拮抗剂可拮抗ANTX-A增加胞内钙离子浓度的作用。结论:ANTX-A在体外可激活和脱敏神经元烟碱型乙酰胆碱受体,钙调信号传导通路可能在ANTX-A诱导nAChRs激活和脱敏中起重要调控作用,活性氧在ANTX-A诱导nAChRs脱敏中可能有重要调控作用。
With progressive eutrophication of surface water, water bloom and red tide break out frequently in freshwater and seawater. Contamination of algae (including algal toxins) has been an important public health concern. Algal toxins can give birth to the damage of many tissues. Anatoxin-a (ANTX-A) is one of the most familiar neurotoxical algal toxins. There were lots of domestic fowls and livestock and wild animals poisoning incidents caused by ANTX-A. Different amounts of ANTX-A were detected from lakes and reservoirs in many countries. Moreover, conventional chlorination water treatment procedure is not sufficient to totally remove ANTX-A, humans are potentially exposed to low-level ANTX-A. Some toxicological tests suggested that low-dose ANTX-A might be associated with central nerve system toxicity. Therefore, it’s necessary to study the low-dose neurotoxicity of ANTX-A.
The present study is aimed to investigate the distribution of ANTX-A from Dianshan Lake and to explore the effect of ANTX-A on CNS and its possible mechanism. This study includes three parts: 1) investigation on the pollution of ANTX-A in Dianshan Lake; 2) in vivo neurotoxical test of ANTX-A; 3) in vitro neurotoxical test of ANTX-A.
Part 1: Investigation on the Pollution of Anatoxin-a in Dianshan Lake
Objectives: To study the eutrophication status and the distribution of ANTX-A in Dianshan Lake, and discuss the correlation between ANTX-A and various environmental elements. Methods: During the summer and autumn in 2002, some physical-chemical elements associated to eutrophication and algae cell density were investigated, the concentration of ANTX-A in the lake and water-bloom algae were measured by the high-performance liquid chromatography (HPLC), the correlation between ANTX-A and environmental elements was analyzed by general estimated equations (GEE). Results: The concentration of total nitrogen (TN) and total phosphorus (TP) in the Lake were higher than the III level guideline of surface water environmental quality standard. The average algae cell density was 3×106
/liter. The average level of ANTX-A in the lake was 7 ng/liter. And the pollution of ANTX-A was most serious in July. The concentration of ANTX-A in water-bloom algae was 15ng/mg dry algae. The level of ANTX-A was correlated with illumination, turbidity, TP and chlorophyll a (Chla). And the correlation between turbidity and ANTX-A was more significant than others (p<0.05). Conclusion: Dianshan Lake presented serious eutriphication. There was the pollution of ANTX-A, and it was most serious in July. The concentration of ANTX-A was significant correlative with turbidity of lake.
Part 2: in vivo Neurotoxical Test of Anatoxin-a
Objectives: To study the effect of sub-acute exposure of ANTX-A on CNS in mouse and explore its possible mechanism. Methods: Mice were administered by i.p. with ANTX-A at the concentrations of 0, 12.5, 50, 200ug/kg.bw/day for 30 days. Body weight increase was observed during the administration period, neurobehavioral function was measured using step-through test and Morris water maze test, the CNS neuropathological changes were examined. The changes of calcium-mediated signal transduction system including intracellular calcium, ATPase, calcineurin (PP2B), c-fos and CREB-1 and free radical signal system comprised of reactive oxygen species (ROS) and nitric oxide (NO) were measured. Results: The body weight increase of the mice in ANTX-A 200ug/kg.bw group decreased obviously (p<0.05). The passive evade activity and special learning and memory function of the mice in ANTX-A 200ug/kg.bw group weakened significantly (p<0.05). Degeneration and necrosis of neuron were observed in the cortex and hippocampus of ANTX-A 200ug/kg.bw-treated mice. And no such changes were observed in the other ANTX-A group. In ANTX-A 12.5ug/kg.bw, 50ug/kg.bw, 200ug/kg.bw group, the concentration of intracellular calcium in the brain increased significantly (p<0.05). The activity of PP2B and the gene and protein expression of c-fos and CREB-1 improved in ANTX-A 200ug/kg.
引文
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许绍芬. 主编. 神经生物学. 第二版. 上海医科大学出版社. 1999, 66
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