从生化水平探讨MC-RR及蓝藻水华粗提物经口染毒对小鼠肝脏的毒性效应
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摘要
随着世界经济的快速发展，环境水体的污染已成为全世界各国普遍关注的问题。蓝藻水华的频繁发生是导致水环境恶化的主要因素之一，其释放到水体中的大量毒素对人和动物造成了极大危害。微囊藻毒素(Microcystin，MC)是蓝藻水华产生的一组具有肝脏毒性的单环多肽毒素，由于其氨基酸组成的多变性，迄今已发现80多种毒素的异性体，其中以MC-LR、RR和YR最为常见。MC是一类高急性毒性和强促癌性的毒素，其急性毒性是导致动物肝细胞结构破坏、窦状小管结构降解，最终引起肝出血导致个体死亡；而其慢性毒性则是引起慢性肝损伤。此外，MC对动物心、肺、肾以及生殖系统的毒性作用也有广泛报道。人和动物可能通过饮用和进食被毒素污染的水和水生生物经口途径摄入MC，所以在分子水平研究经口暴露MC的毒性作用及致毒机制具有重要的理论和现实意义。
目前公认的MC致毒机制之一是抑制体内重要的蛋白磷酸酶1(PP1)和2A(PP2A)的活性，引起体内蛋白的过度磷酸化，导致众多细胞信号传递通路异常，从而产生多种毒性效应。大量研究发现，MC可诱导多种类型的细胞和动物肝组织发生细胞凋亡，提示MC的凋亡诱导作用可能与其毒性作用密切相关，但具体的凋亡诱导机制还不清楚。研究发现不同浓度的MC暴露在体内引起细胞凋亡的机制存在差异，而氧化应激和线粒体损伤可能是MC诱导细胞凋亡主要原因，线粒体途径可能是MC诱导凋亡的主要通路。
内质网途径是近年才被证明的内源性细胞凋亡通路，由过度的内质网应激引起。当多种因素引起内质网应激发生，且强度超过细胞内质网自稳定范围时，细胞凋亡的内质网通路被开启。目前关于内质网凋亡通路是否参与MC诱导的细胞凋亡还未见报道。
MC家族成员众多，各个成员由于结构的不同，其毒性作用及致毒机制存在差异。MC-RR是蓝藻藻水华释放到水体中主要MC之一，其对生物的毒性作用不可忽视，但目前在活体水平对其经口途径的毒性研究，尤其在哺乳动物中的报道还不多。此外，生活在蓝藻水体爆发水体中生物，并非处于单一毒素的暴露之中，水华释放到水体中的众多有害成分对它们有着复杂的毒性作用。基于此，本研究对MC家族中的重要成员MC-RR以及蓝藻水华粗提物经口途径暴露的毒性作用及致毒机制进行了探讨。
本研究中，MC-RR和蓝藻水华粗提物分别以4.6，23，46，93，186μg／kg和4.6，23，46，93μg／kg·MC(RR+LR)的剂量经灌胃方式连续7天染毒小鼠，第八天处死小鼠后摘取肝脏对MC-RR和蓝藻水华粗提物对肝脏的毒性作用及其凋亡机制进行研究：采用TUNEL法测定MC-RR诱导肝组织细胞的凋亡率，通过检测各种凋亡相关(蛋白因子)在染毒小鼠肝脏中的表达或活性变化来探究它们在细胞凋亡过程中的作用，包括用普通显微镜直接观察MC-RR染毒后小鼠肝组织HE染色的结构变化，通过ROS底物DCFH-DA测定染毒后小鼠肝脏ROS的改变，通过测定MDA的含量来检测毒素暴露小鼠脂质过氧化程度，用calpain和PP2A活性检测试剂盒测定MC-RR染毒小鼠肝组织calpain和PP2A酶活性的变化，用免疫印迹法(western blot)检测PP2A-A和C亚基、Bax、Bcl-2、p53、HSP70以及与内质网应激相关蛋白GRP78和CHOP的表达变化。
实验结果如下：
1．MC-RR染毒小鼠后，小鼠肝组织切片的TUNEL检测结果表明，从46μg／kg染毒组开始，小鼠肝脏细胞的凋亡率出现显著升高并与剂量相关。
2．MC-RR染毒小鼠后，在93μg／kg染毒组小鼠肝脏出现ROS显著升高，但所有染毒组未见MDA的明显改变。
3．MC-RR染毒小鼠后，所有染毒组均未发现小鼠肝组织PP2A活性和其A、C亚基表达的明显改变。
4．MC-RR染毒小鼠后，与对照相比，染毒小鼠肝组织中Bcl-2表达出现下降，并从23μg／kg染毒组开始下降具有显著性；Bax表达在46μg／kg和93μg／kg染毒组出现显著上升；同时Bax／Bcl-2比值从23μg／kg染毒组开始也显著性升高；此外，p53蛋白表达在93μg／kg染毒组出现显著上升。
5．MC-RR染毒小鼠后，与对照组相比，小鼠肝组织GRP78和HSP70均在93μg／染毒组表达显著升高，但在所有染毒组CHOP的表达未见明显变化。
6．MC-RR染毒小鼠后，所有染毒组小鼠肝组织的calpain活性与对照组相比未见明显改变。
7．蓝藻水华粗提物染毒小鼠后，与对照相比，染毒组小鼠肝组织PP2A A亚基表达从23μg／kg染毒组开始出现剂量依赖性显著升高，同时Bax表达呈现明显上升趋势，从23μg／kg染毒组开始表达显著上升；相反，所有染毒组Bcl-2表达改变不明显，但Bax／Bcl-2比值出现显著上升。
8．蓝藻水华粗提物染毒小鼠后，与对照组相比，所有染毒组小鼠肝组织均未发现ROS和MDA的显著变化。
9．蓝藻水华粗提物染毒小鼠后，与对照组相比，小鼠肝组织GRP78和HSP70均在93μg／kg染毒组表达显著升高，但在所有染毒组CHOP的表达未见明显变化。
结论：
MC-RR经口染毒7天未发现明显的氧化损伤及PP2A活性的抑制表明它们可能不是MC-RR对小鼠肝组织产生的主要毒性效应；毒素可诱导小鼠肝组织发生细胞凋亡，诱导效应与染毒剂量相关，而与之同时发生的p53水平升高、促凋亡蛋白Bax的升高、抗凋亡蛋白Bcl-2的下降表明毒素诱导凋亡的机理与线粒体途径密切相关；毒素引起了轻度的内质网应激但内质网凋亡信号通路尚未启动。
蓝藻水华粗提物经口染毒7天可引起小鼠肝组织发生轻度内质网应激并引起Bax、HSP70表达的显著改变；对PP2A A亚基蛋白水平的明显影响表明其毒性作用可能与干扰了PP2A介导的众多细胞信号通路的调节有关。
无论是纯毒素RR还是蓝藻水华粗提物，即使是低剂量经口染毒都可以对小鼠产生影响，预示经口摄入的毒素对动物的毒性是不容忽视的；而蓝藻水华粗提物对同类指标产生的影响与纯毒素相比有类似也有不同，提示对于天然水体水华产生的潜在危害需要进一步全面评价。
The frequent occurrences of the toxic cyanobacterial (specifically Microcystisaeruginosa) bloom are becoming a global environmental issue. Microcystin produced bycyanobacteria in diverse water systems is a potent specific hepatotoxin and has beendocumented to induce hepatotoxicity and tumor promotion. There are more than eightyreported microcystins and microcystin-RR (MC-RR) is one of the most widelydistributed variants among the MC family. One of the mechanisms of toxicity of thesetoxins is their inhibition on protein phosphatases 1 and 2A, leading to increased proteinphosphorylation, which is directly related to their cytotoxicity and tumor-promotingactivity. Acute microcystin poisoning in mammals is characterized by disruption ofhepatic architecture due to phosphorylation of cytoskeletal proteins leading to massiveintrahepatic haemorrhage and death in few hours and chronic uptake of microcystinsresults in generalized hepatocyte degeneration with necrosis, progressive fibrosis andmononuclear leukocyte infiltration. At present, the exact mechanisms by which MCinduce hepatotoxicity have not been fully elucidated. Several pieces of evidencesstrongly suggest that apoptosis induced by MC may play a significant role in thepathogenesis of MCs-induced toxicity in mammals, but its detailed mechanism is notclarified so far. It has been documented that oxidative stress and mitochondrial injure are the main elements involved in MC-triggered apoptosis, which means mitochondrialpathway may play a key role in the apoptosis induced by MCs. Nowadays anotherapoptotic pathway, which is iniated by the extress ER stress exceeding the homeostasisof ER, has been proposed by some researchers, however there is little knowledge aboutthe role of ER pathway in the MC- induced apoptosis.
Among the study on MC variants, the toxic effects of MC-RR have not beenstudied extensively, especially in mammals and via oral exposure. Though the toxicityof MC-RR is less than MC-LR, but its toxic effect should be paid attention to sinceaccumulated evidences have shown that MC-RR is the dominant toxin produced bycyanobacterial bloom in some water bodies, especially in China.
Until now, there are varieties of researches related to the toxicity of purifiedmicrocystins, but little is reported on the toxic effects of cyanobacteria crude extract,whose components are most similar to the natural environment water bodies (wherecyanobacteria bloom occurred), but all the organisms are living in a complexcircumstance where multiple effect factors exist. To study the complicated toxic effectof cyanobacteria is very important for us to evaluate the risk of human and animalsexposed to these toxins.
In this work, an in vivo approach was applied to administrate MC-RR andcyanobacterial bloom extract orally to mice and multiple indicators were measured. Theaim of this work is to investigate the toxic effect of MC-RR and cyanobacteria bloomextract on mice liver. In current work, the two kinds of preparation of microcystinhave been administered orally to ICR mice for 7 days with different dosages. In MC-RRtreated mice, apoptotie cell death in liver was detected by TUNEL assay, and theexpression levels of Bcl-2, Bax and p53, GRP 78 and CHOP which have been reportedto be related to apoptosis and ER stress were determined via western-blot. The activityof PP2A was measured using the serine-threonine phosphatase assay system, and PP2AA subunit and C subunit expression is measured by western blot, the oxidative stress isdetermined by ROS and MDA assay, and the calpain activity is investigated todetermine its role in MC-RR induced apoptosis. In cyanobacteria bloom extract-treatedmice, the expression levels of Bcl-2, Bax, GRP 78 and CHOP, HSP 70, PP2A-A subunit were determined via western-blot ; the oxidative stress is determined by ROS and MDAassay.
The results were showed as below:
1. MC-RR exposure has induced significant apoptosis in mice liver.
2. MC-RR exposure has no significant effect on ROS lever in mice liver, except for93μg/kg treated group. There is no distinct change on MDA content in anyMC-RR treated group.
3. MC-RR exposure has no distinct effect on PP2A activity or its A/C subunitexpression level in mice livers.
4. MC-RR exposure significantly increased the expression level of p53 and Bax anddecreased the level of Bcl-2 in mice livers. The ratio of Bax/Bcl-2 was increaseddistinctly.
5. MC-RR exposure significantly increased the expression level of liSP70 and GRP78,and the level of CHOP had not changed obviously..
6. MC-RR exposure has no distinct effect on calpain activity in mice livers.
7. Cyanobacteria bloom extract exposure significantly increased the expression levelof Bax and PP2A A subunit in a dose-dependent manner, but there was no distincteffect on Bcl-2 level in mice liver. However, the ratio of Bax/Bcl-2 was increasedobviously.
8. Cyanobacteria bloom extract exposure has no obviously effect on oxidative stresssystem in mice livers, based on ROS level and MDA content in mice liver.
9. Cyanobacteria bloom extract exposure obviously increased the expression level ofHSP70 and GRP78, but there was no distinct effect on CHOP expression level inmice livers.
Conclusions:
There is no significant change in PP2A activity or subunit expression level after themice were orally exposed to MC-RR for 7 days. In this study, the inhibition of PP2Aand the induced oxidative stress is not a major mechanism of the MC-RR toxic effect.The apoptosis in MC-RR treated mouse livers is proportional to MC-RR dosage, andaccompanied with increased expression level of p53 and Bax and decreased level ofBcl-2. This suggests that the apoptosis is closely related to the mitochondrial pathway.MC-RR exposure can induced moderate ER stress and the ER apoptotic pathway hasnot initiated.
Cyanobacteria bloom extract can induce moderate ER stress and increase theexpression level of Bax, and HSP70. The obvious change of PP2A A subunit indicatedthat the toxic effects exerted by cyanobacteria bloom may be related with its interferingon signal pathways regulated by PP2A.
This study concludes that both pure MC and cyanobacteria bloom have negativerole on mice, even at a low dosage. The toxicity of oral exposure to MC can not benegligible. The toxic effect of cyanobacteria bloom is not exactly the same with puretoxin. A comprehensive assessment of its toxicity is necessary and will be our futurework.
目前公认的MC致毒机制之一是抑制体内重要的蛋白磷酸酶1(PP1)和2A(PP2A)的活性，引起体内蛋白的过度磷酸化，导致众多细胞信号传递通路异常，从而产生多种毒性效应。大量研究发现，MC可诱导多种类型的细胞和动物肝组织发生细胞凋亡，提示MC的凋亡诱导作用可能与其毒性作用密切相关，但具体的凋亡诱导机制还不清楚。研究发现不同浓度的MC暴露在体内引起细胞凋亡的机制存在差异，而氧化应激和线粒体损伤可能是MC诱导细胞凋亡主要原因，线粒体途径可能是MC诱导凋亡的主要通路。
内质网途径是近年才被证明的内源性细胞凋亡通路，由过度的内质网应激引起。当多种因素引起内质网应激发生，且强度超过细胞内质网自稳定范围时，细胞凋亡的内质网通路被开启。目前关于内质网凋亡通路是否参与MC诱导的细胞凋亡还未见报道。
MC家族成员众多，各个成员由于结构的不同，其毒性作用及致毒机制存在差异。MC-RR是蓝藻藻水华释放到水体中主要MC之一，其对生物的毒性作用不可忽视，但目前在活体水平对其经口途径的毒性研究，尤其在哺乳动物中的报道还不多。此外，生活在蓝藻水体爆发水体中生物，并非处于单一毒素的暴露之中，水华释放到水体中的众多有害成分对它们有着复杂的毒性作用。基于此，本研究对MC家族中的重要成员MC-RR以及蓝藻水华粗提物经口途径暴露的毒性作用及致毒机制进行了探讨。
本研究中，MC-RR和蓝藻水华粗提物分别以4.6，23，46，93，186μg／kg和4.6，23，46，93μg／kg·MC(RR+LR)的剂量经灌胃方式连续7天染毒小鼠，第八天处死小鼠后摘取肝脏对MC-RR和蓝藻水华粗提物对肝脏的毒性作用及其凋亡机制进行研究：采用TUNEL法测定MC-RR诱导肝组织细胞的凋亡率，通过检测各种凋亡相关(蛋白因子)在染毒小鼠肝脏中的表达或活性变化来探究它们在细胞凋亡过程中的作用，包括用普通显微镜直接观察MC-RR染毒后小鼠肝组织HE染色的结构变化，通过ROS底物DCFH-DA测定染毒后小鼠肝脏ROS的改变，通过测定MDA的含量来检测毒素暴露小鼠脂质过氧化程度，用calpain和PP2A活性检测试剂盒测定MC-RR染毒小鼠肝组织calpain和PP2A酶活性的变化，用免疫印迹法(western blot)检测PP2A-A和C亚基、Bax、Bcl-2、p53、HSP70以及与内质网应激相关蛋白GRP78和CHOP的表达变化。
实验结果如下：
1．MC-RR染毒小鼠后，小鼠肝组织切片的TUNEL检测结果表明，从46μg／kg染毒组开始，小鼠肝脏细胞的凋亡率出现显著升高并与剂量相关。
2．MC-RR染毒小鼠后，在93μg／kg染毒组小鼠肝脏出现ROS显著升高，但所有染毒组未见MDA的明显改变。
3．MC-RR染毒小鼠后，所有染毒组均未发现小鼠肝组织PP2A活性和其A、C亚基表达的明显改变。
4．MC-RR染毒小鼠后，与对照相比，染毒小鼠肝组织中Bcl-2表达出现下降，并从23μg／kg染毒组开始下降具有显著性；Bax表达在46μg／kg和93μg／kg染毒组出现显著上升；同时Bax／Bcl-2比值从23μg／kg染毒组开始也显著性升高；此外，p53蛋白表达在93μg／kg染毒组出现显著上升。
5．MC-RR染毒小鼠后，与对照组相比，小鼠肝组织GRP78和HSP70均在93μg／染毒组表达显著升高，但在所有染毒组CHOP的表达未见明显变化。
6．MC-RR染毒小鼠后，所有染毒组小鼠肝组织的calpain活性与对照组相比未见明显改变。
7．蓝藻水华粗提物染毒小鼠后，与对照相比，染毒组小鼠肝组织PP2A A亚基表达从23μg／kg染毒组开始出现剂量依赖性显著升高，同时Bax表达呈现明显上升趋势，从23μg／kg染毒组开始表达显著上升；相反，所有染毒组Bcl-2表达改变不明显，但Bax／Bcl-2比值出现显著上升。
8．蓝藻水华粗提物染毒小鼠后，与对照组相比，所有染毒组小鼠肝组织均未发现ROS和MDA的显著变化。
9．蓝藻水华粗提物染毒小鼠后，与对照组相比，小鼠肝组织GRP78和HSP70均在93μg／kg染毒组表达显著升高，但在所有染毒组CHOP的表达未见明显变化。
结论：
MC-RR经口染毒7天未发现明显的氧化损伤及PP2A活性的抑制表明它们可能不是MC-RR对小鼠肝组织产生的主要毒性效应；毒素可诱导小鼠肝组织发生细胞凋亡，诱导效应与染毒剂量相关，而与之同时发生的p53水平升高、促凋亡蛋白Bax的升高、抗凋亡蛋白Bcl-2的下降表明毒素诱导凋亡的机理与线粒体途径密切相关；毒素引起了轻度的内质网应激但内质网凋亡信号通路尚未启动。
蓝藻水华粗提物经口染毒7天可引起小鼠肝组织发生轻度内质网应激并引起Bax、HSP70表达的显著改变；对PP2A A亚基蛋白水平的明显影响表明其毒性作用可能与干扰了PP2A介导的众多细胞信号通路的调节有关。
无论是纯毒素RR还是蓝藻水华粗提物，即使是低剂量经口染毒都可以对小鼠产生影响，预示经口摄入的毒素对动物的毒性是不容忽视的；而蓝藻水华粗提物对同类指标产生的影响与纯毒素相比有类似也有不同，提示对于天然水体水华产生的潜在危害需要进一步全面评价。
The frequent occurrences of the toxic cyanobacterial (specifically Microcystisaeruginosa) bloom are becoming a global environmental issue. Microcystin produced bycyanobacteria in diverse water systems is a potent specific hepatotoxin and has beendocumented to induce hepatotoxicity and tumor promotion. There are more than eightyreported microcystins and microcystin-RR (MC-RR) is one of the most widelydistributed variants among the MC family. One of the mechanisms of toxicity of thesetoxins is their inhibition on protein phosphatases 1 and 2A, leading to increased proteinphosphorylation, which is directly related to their cytotoxicity and tumor-promotingactivity. Acute microcystin poisoning in mammals is characterized by disruption ofhepatic architecture due to phosphorylation of cytoskeletal proteins leading to massiveintrahepatic haemorrhage and death in few hours and chronic uptake of microcystinsresults in generalized hepatocyte degeneration with necrosis, progressive fibrosis andmononuclear leukocyte infiltration. At present, the exact mechanisms by which MCinduce hepatotoxicity have not been fully elucidated. Several pieces of evidencesstrongly suggest that apoptosis induced by MC may play a significant role in thepathogenesis of MCs-induced toxicity in mammals, but its detailed mechanism is notclarified so far. It has been documented that oxidative stress and mitochondrial injure are the main elements involved in MC-triggered apoptosis, which means mitochondrialpathway may play a key role in the apoptosis induced by MCs. Nowadays anotherapoptotic pathway, which is iniated by the extress ER stress exceeding the homeostasisof ER, has been proposed by some researchers, however there is little knowledge aboutthe role of ER pathway in the MC- induced apoptosis.
Among the study on MC variants, the toxic effects of MC-RR have not beenstudied extensively, especially in mammals and via oral exposure. Though the toxicityof MC-RR is less than MC-LR, but its toxic effect should be paid attention to sinceaccumulated evidences have shown that MC-RR is the dominant toxin produced bycyanobacterial bloom in some water bodies, especially in China.
Until now, there are varieties of researches related to the toxicity of purifiedmicrocystins, but little is reported on the toxic effects of cyanobacteria crude extract,whose components are most similar to the natural environment water bodies (wherecyanobacteria bloom occurred), but all the organisms are living in a complexcircumstance where multiple effect factors exist. To study the complicated toxic effectof cyanobacteria is very important for us to evaluate the risk of human and animalsexposed to these toxins.
In this work, an in vivo approach was applied to administrate MC-RR andcyanobacterial bloom extract orally to mice and multiple indicators were measured. Theaim of this work is to investigate the toxic effect of MC-RR and cyanobacteria bloomextract on mice liver. In current work, the two kinds of preparation of microcystinhave been administered orally to ICR mice for 7 days with different dosages. In MC-RRtreated mice, apoptotie cell death in liver was detected by TUNEL assay, and theexpression levels of Bcl-2, Bax and p53, GRP 78 and CHOP which have been reportedto be related to apoptosis and ER stress were determined via western-blot. The activityof PP2A was measured using the serine-threonine phosphatase assay system, and PP2AA subunit and C subunit expression is measured by western blot, the oxidative stress isdetermined by ROS and MDA assay, and the calpain activity is investigated todetermine its role in MC-RR induced apoptosis. In cyanobacteria bloom extract-treatedmice, the expression levels of Bcl-2, Bax, GRP 78 and CHOP, HSP 70, PP2A-A subunit were determined via western-blot ; the oxidative stress is determined by ROS and MDAassay.
The results were showed as below:
1. MC-RR exposure has induced significant apoptosis in mice liver.
2. MC-RR exposure has no significant effect on ROS lever in mice liver, except for93μg/kg treated group. There is no distinct change on MDA content in anyMC-RR treated group.
3. MC-RR exposure has no distinct effect on PP2A activity or its A/C subunitexpression level in mice livers.
4. MC-RR exposure significantly increased the expression level of p53 and Bax anddecreased the level of Bcl-2 in mice livers. The ratio of Bax/Bcl-2 was increaseddistinctly.
5. MC-RR exposure significantly increased the expression level of liSP70 and GRP78,and the level of CHOP had not changed obviously..
6. MC-RR exposure has no distinct effect on calpain activity in mice livers.
7. Cyanobacteria bloom extract exposure significantly increased the expression levelof Bax and PP2A A subunit in a dose-dependent manner, but there was no distincteffect on Bcl-2 level in mice liver. However, the ratio of Bax/Bcl-2 was increasedobviously.
8. Cyanobacteria bloom extract exposure has no obviously effect on oxidative stresssystem in mice livers, based on ROS level and MDA content in mice liver.
9. Cyanobacteria bloom extract exposure obviously increased the expression level ofHSP70 and GRP78, but there was no distinct effect on CHOP expression level inmice livers.
Conclusions:
There is no significant change in PP2A activity or subunit expression level after themice were orally exposed to MC-RR for 7 days. In this study, the inhibition of PP2Aand the induced oxidative stress is not a major mechanism of the MC-RR toxic effect.The apoptosis in MC-RR treated mouse livers is proportional to MC-RR dosage, andaccompanied with increased expression level of p53 and Bax and decreased level ofBcl-2. This suggests that the apoptosis is closely related to the mitochondrial pathway.MC-RR exposure can induced moderate ER stress and the ER apoptotic pathway hasnot initiated.
Cyanobacteria bloom extract can induce moderate ER stress and increase theexpression level of Bax, and HSP70. The obvious change of PP2A A subunit indicatedthat the toxic effects exerted by cyanobacteria bloom may be related with its interferingon signal pathways regulated by PP2A.
This study concludes that both pure MC and cyanobacteria bloom have negativerole on mice, even at a low dosage. The toxicity of oral exposure to MC can not benegligible. The toxic effect of cyanobacteria bloom is not exactly the same with puretoxin. A comprehensive assessment of its toxicity is necessary and will be our futurework.
引文
周伦，鱼达，于海等．2000．饮用水源中的微囊藻毒素与大肠癌发病的关系．中华预防医学杂志，34(4)：37-39
吴和岩，郑力行，苏瑾，等．2005，上海市供水系统微囊藻毒素LR含量调查．卫生研究．34(2)：152-15
傅文宇，陈加平，徐立红．2004a．Caspase-3在微囊藻毒素诱导的细胞凋亡中的作用．中国环境科学．24(1)：6-8
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