环境激素壬基酚对小鼠神经毒性作用及其分子生物学机制研究
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摘要
壬基酚(nonylphenol, NP)是一种非常典型的烷基酚类化合物,被广泛应用于工农业和一些日用品的生产中,并被排放到自然界,造成环境污染。作为一种环境激素,壬基酚暴露对动物的生殖系统、免疫系统都有一定的干扰作用。然而,目前对于壬基酚的神经毒性作用的研究还很少。本论文首次通过体内实验从ROS介导的细胞凋亡以及炎症反应信号通路角度,探讨了NP的神经毒性作用及其相应的分子机制,为后续的深入研究以及防治烷基酚类环境激素神经毒性作用提供理论基础,并为制定相关环境污染标准提供理论依据。
本实验采用灌胃法建立NP暴露的亚慢性毒性实验模型。将雄性小鼠随机分为4组,每组9只。处理组分别灌喂50, 100, 200 mg/kg/d的壬基酚(nonylphenol, NP)(玉米油溶解),对照组灌喂玉米油。连续处理90天之后,开始进行各种检测。
利用生化实验方法,对实验小鼠中枢神经系统中的抗氧化系统进行检测,发现NP可以显著抑制抗氧化酶过氧化物歧化酶和过氧化氢酶的活性,激活单胺氧化酶的活性,而抑制小鼠脑组织的总抗氧化能力和抑制羟自由基能力,引起自由基在脑组织中的积累,引起氧化应激,造成脂质过氧化。
利用基因克隆以及体外转录的方法合成探针进行原位杂交,并结合RT-PCR、免疫组化和Western Blot等分子生物学方法,对细胞凋亡信号通路上关键基因表达进行检测,最后应用TUNEL法检测细胞凋亡水平。实验发现,NP能够显著抑制脑组织中皮质和海马区域抗凋亡基因bcl-2的转录,活化Caspase-3蛋白,诱导脑组织中神经细胞凋亡。但是NP对于细胞凋亡内在通路中的促凋亡蛋白bax mRNA以及外在通路中的关键蛋白Fas和Fas-L的表达都没有影响。这提示NP诱导的中枢神经系统细胞凋亡是通过抑制bcl-2的转录并激活Caspase-3蛋白实现的。
利用Western Blot和免疫组化的方法,分别对炎症反应中的关键蛋白的表达进行定量和定位检测。结果发现NP可以促进转录因子NF-κB的活化,诱导其下游炎症反应酶iNOS和COX-2在海马和皮质中的表达。同时,通过生化实验还发现总NOS活性和NO水平在NP处理组也有显著提高,提示NP具有潜在的诱导脑组织慢性炎症反应以及神经毒性的作用。
通过开场行为学实验、避暗试验以及Morris水迷宫实验,检测NP对小鼠学习记忆能力以及对新异环境的兴奋性、适应性、探究和紧张程度等行为的影响,发现高剂量的NP对小鼠的空间学习记忆能力有明显的削弱作用,并使其在新异环境中适应性减弱,更容易紧张以及探究行为减少。从整体行为学角度进一步说明了NP对小鼠的中枢神经系统有一定的损伤作用。
通过以上一系列的研究发现,NP对于雄性小鼠中枢神经系统有一定的毒害作用,大剂量长期接触NP对中枢神经系统会造成一定的损伤。NP诱导的神经毒性很有可能是通过促进神经细胞内ROS生成,激活线粒体依赖的细胞凋亡途径以及NF-κB介导的炎症信号通路,从而影响细胞凋亡因子以及炎症因子的表达,引起神经细胞的炎症反应促进细胞凋亡,从而对中枢神经系统起到毒性作用。
Nonylphenol (NP) is an organic compound of the broad family of alkylphenols. It is widely used in industrial and agricultural production and the production of consumer goods, and was released into the natural world, causing environmental pollution. As an endocrine disruptor, the exposure of NP could disturb the function of reproductive systems and immune system. However, few in vivo studies have assessed whether chronically administering of NP produces neurotoxic effects. The present study was performed to investigate the molecular mechanism of the neurotoxicity of NP on the view of ROS related apoptosis and inflammatory pathway for the first time, which laid the theoretical foundation for the following in-depth study and control of the alkylphenols neurotoxicity. And these results provide a theoretical basis for the development of relevant environmental standards.
The NP exposed sub-chronic toxicological experimental model was established by oral gavages. Young male mice were randomly divided into four groups, and nine mice per group. After acclimatization to the laboratory conditions for one week, the treated groups were given NP (dissolved in corn oil) daily by oral gavages at 50, 100, 200 mg/kg per day, respectively. Mice in the control group were given the vehicle (corn oil) alone. After treating for 90 days, the mice were sacrificed for analysis. To detect the antioxidant defense system in central nervous system (CNS) by biochemical studies, we found that NP could induce lipid peroxidation and oxidative stress by refraining Superoxide Dismutase (SOD) activity, catalase (CAT) activity, total antioxidative capacity, and the scavenging activity on hydroxyl free radical.
The expressions of the key genes on the apoptosis pathway were detected by in situ hybridization, RT-PCR, immunohistochemistry and immunoblotting assays, and the apoptosis in the brain was examine by TUNEL assay. The probes for in situ hybridization were generated by gene clone and in vitro transcription. In our present study, NP could significantly down-regulate the transcription of the anti-apoptosis gene bcl-2 and up-regulation of active caspase-3 in hippocampus and cortex, which is in accord with the results of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) (p<0.05). However the expression of pro-apoptosis gene, bax mRNA, in the intrinsic apoptotic pathway and the expression of the key protein, Fas and Fas-L, in the extrinsic pathway were not affected in NP treated mice. These results indicated that NP induced apoptosis in the mice brain via suppression the transcription of the anti-apoptosis gene bcl-2 and up-regulation of active caspase-3.
Western Blot and immunohistochemistry assays were used to detect the quantity and distribution of the key protein on the inflammatory signaling pathways. NP could up-regulate the nuclear transcription factor-κB (NF-κB) activation, and induce the expression of its downstream inflammatory mediators iNOS and COX-2 in hippocampus and cortex. The results of biochemical studies also suggested that nitric oxide synthase (NOS) activity and nitric oxide (NO) level were significantly higher in NP treated mice brain. These findings demonstrated that NP may have the potential to induce the chronic inflammatory and cause neurotoxicity in the mouse brain.
Open-field test, step-through test and Morris-maze test were used to detect the effect of NP on the behaviors (learning and memory, excitability, adaptability, exploration and tensity) in the new environment. High dose of NP could significantly impair spatial learning and memory. NP could also make the mice easier to tension, weaken the adaptability, and reduce the exploration in the new environment. These results give more evidences that NP could induce neurotoxicity in CNS on the view of learning and memory behavior.
All of these findings indicated that chronic exposure to NP could induce neurotoxicity and damage in the CNS of male mice. The neurotoxicity of NP was probably via activation of mitochondrial apoptosis pathway and NF-κB mediated inflammatory signaling pathway, which influence the expression of apoptosis genes and inflammatory mediators.
本实验采用灌胃法建立NP暴露的亚慢性毒性实验模型。将雄性小鼠随机分为4组,每组9只。处理组分别灌喂50, 100, 200 mg/kg/d的壬基酚(nonylphenol, NP)(玉米油溶解),对照组灌喂玉米油。连续处理90天之后,开始进行各种检测。
利用生化实验方法,对实验小鼠中枢神经系统中的抗氧化系统进行检测,发现NP可以显著抑制抗氧化酶过氧化物歧化酶和过氧化氢酶的活性,激活单胺氧化酶的活性,而抑制小鼠脑组织的总抗氧化能力和抑制羟自由基能力,引起自由基在脑组织中的积累,引起氧化应激,造成脂质过氧化。
利用基因克隆以及体外转录的方法合成探针进行原位杂交,并结合RT-PCR、免疫组化和Western Blot等分子生物学方法,对细胞凋亡信号通路上关键基因表达进行检测,最后应用TUNEL法检测细胞凋亡水平。实验发现,NP能够显著抑制脑组织中皮质和海马区域抗凋亡基因bcl-2的转录,活化Caspase-3蛋白,诱导脑组织中神经细胞凋亡。但是NP对于细胞凋亡内在通路中的促凋亡蛋白bax mRNA以及外在通路中的关键蛋白Fas和Fas-L的表达都没有影响。这提示NP诱导的中枢神经系统细胞凋亡是通过抑制bcl-2的转录并激活Caspase-3蛋白实现的。
利用Western Blot和免疫组化的方法,分别对炎症反应中的关键蛋白的表达进行定量和定位检测。结果发现NP可以促进转录因子NF-κB的活化,诱导其下游炎症反应酶iNOS和COX-2在海马和皮质中的表达。同时,通过生化实验还发现总NOS活性和NO水平在NP处理组也有显著提高,提示NP具有潜在的诱导脑组织慢性炎症反应以及神经毒性的作用。
通过开场行为学实验、避暗试验以及Morris水迷宫实验,检测NP对小鼠学习记忆能力以及对新异环境的兴奋性、适应性、探究和紧张程度等行为的影响,发现高剂量的NP对小鼠的空间学习记忆能力有明显的削弱作用,并使其在新异环境中适应性减弱,更容易紧张以及探究行为减少。从整体行为学角度进一步说明了NP对小鼠的中枢神经系统有一定的损伤作用。
通过以上一系列的研究发现,NP对于雄性小鼠中枢神经系统有一定的毒害作用,大剂量长期接触NP对中枢神经系统会造成一定的损伤。NP诱导的神经毒性很有可能是通过促进神经细胞内ROS生成,激活线粒体依赖的细胞凋亡途径以及NF-κB介导的炎症信号通路,从而影响细胞凋亡因子以及炎症因子的表达,引起神经细胞的炎症反应促进细胞凋亡,从而对中枢神经系统起到毒性作用。
Nonylphenol (NP) is an organic compound of the broad family of alkylphenols. It is widely used in industrial and agricultural production and the production of consumer goods, and was released into the natural world, causing environmental pollution. As an endocrine disruptor, the exposure of NP could disturb the function of reproductive systems and immune system. However, few in vivo studies have assessed whether chronically administering of NP produces neurotoxic effects. The present study was performed to investigate the molecular mechanism of the neurotoxicity of NP on the view of ROS related apoptosis and inflammatory pathway for the first time, which laid the theoretical foundation for the following in-depth study and control of the alkylphenols neurotoxicity. And these results provide a theoretical basis for the development of relevant environmental standards.
The NP exposed sub-chronic toxicological experimental model was established by oral gavages. Young male mice were randomly divided into four groups, and nine mice per group. After acclimatization to the laboratory conditions for one week, the treated groups were given NP (dissolved in corn oil) daily by oral gavages at 50, 100, 200 mg/kg per day, respectively. Mice in the control group were given the vehicle (corn oil) alone. After treating for 90 days, the mice were sacrificed for analysis. To detect the antioxidant defense system in central nervous system (CNS) by biochemical studies, we found that NP could induce lipid peroxidation and oxidative stress by refraining Superoxide Dismutase (SOD) activity, catalase (CAT) activity, total antioxidative capacity, and the scavenging activity on hydroxyl free radical.
The expressions of the key genes on the apoptosis pathway were detected by in situ hybridization, RT-PCR, immunohistochemistry and immunoblotting assays, and the apoptosis in the brain was examine by TUNEL assay. The probes for in situ hybridization were generated by gene clone and in vitro transcription. In our present study, NP could significantly down-regulate the transcription of the anti-apoptosis gene bcl-2 and up-regulation of active caspase-3 in hippocampus and cortex, which is in accord with the results of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) (p<0.05). However the expression of pro-apoptosis gene, bax mRNA, in the intrinsic apoptotic pathway and the expression of the key protein, Fas and Fas-L, in the extrinsic pathway were not affected in NP treated mice. These results indicated that NP induced apoptosis in the mice brain via suppression the transcription of the anti-apoptosis gene bcl-2 and up-regulation of active caspase-3.
Western Blot and immunohistochemistry assays were used to detect the quantity and distribution of the key protein on the inflammatory signaling pathways. NP could up-regulate the nuclear transcription factor-κB (NF-κB) activation, and induce the expression of its downstream inflammatory mediators iNOS and COX-2 in hippocampus and cortex. The results of biochemical studies also suggested that nitric oxide synthase (NOS) activity and nitric oxide (NO) level were significantly higher in NP treated mice brain. These findings demonstrated that NP may have the potential to induce the chronic inflammatory and cause neurotoxicity in the mouse brain.
Open-field test, step-through test and Morris-maze test were used to detect the effect of NP on the behaviors (learning and memory, excitability, adaptability, exploration and tensity) in the new environment. High dose of NP could significantly impair spatial learning and memory. NP could also make the mice easier to tension, weaken the adaptability, and reduce the exploration in the new environment. These results give more evidences that NP could induce neurotoxicity in CNS on the view of learning and memory behavior.
All of these findings indicated that chronic exposure to NP could induce neurotoxicity and damage in the CNS of male mice. The neurotoxicity of NP was probably via activation of mitochondrial apoptosis pathway and NF-κB mediated inflammatory signaling pathway, which influence the expression of apoptosis genes and inflammatory mediators.
引文
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