环境内分泌干扰物二噁英的细胞毒性作用机制研究
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摘要
环境内分泌干扰物(EEDs)是我国广泛存在、危害效应十分严重的环境与食品污染物。目前,EEDs已成为全世界广泛关注的安全卫生问题之一。二嗯英(Dioxin)和多氯联苯类(PCBs)化合物是目前国际社会极为关注的持久性有机污染物(POPs)与EEDs。由于它们广泛分布并共存于环境中,具有可生物蓄积、难以降解、远距离迁移及高毒等特性,已成为环境毒理学研究的热点。2,3,7,8-四氯二苯并二嗯英(TCDD)是二噁英类物质中毒性最大、毒作用最为典型、研究中最具有代表性的物质,被公认为世界最强的致癌物。它主要来源于垃圾焚烧,农药、化肥、除草剂等含氯化合物的生产和使用。TCDD化学性质非常稳定,在环境中普遍存在,近年来相继发生了数起有关二噁英污染事件,世界各国都极为关注二噁英对人类健康和环境安全的潜在威胁。因此,对TCDD的研究已成为一个热点,对其作用机制有了初步的认识,但对细胞的毒性作用机制尚不完全清楚,对其毒性作用的拮抗研究也报道较少,致使临床上还未有有效的诊治措施。本研究从体内和体外两个方面研究了TCDD的毒性作用及其机制,并就锌对TCDD产生毒性效应的保护作用进行了初步探讨,旨在为进一步探索临床防治措施提供一定的理论和实验依据。本研究包括二部分：
第一部分TCDD与PCBs联合作用对大鼠外周血淋巴细胞DNA的影响
本部分实验应用TCDD和Aroclor 1254单独及联合染毒大鼠,采用碱性单细胞凝胶电泳技术检测TCDD和Aroclor 1254对大鼠外周血淋巴细胞DNA完整性的影响,并利用析因设计方差分析判定二者对所检测的毒理学终点是否存在联合作用,初步探讨了TCDD和Aroclor 1254单独及联合毒性作用及其作用模式,以期为进一步研究二嗯英与PCBs的联合毒性作用提供一定的毒理学依据。采用2×2析因设计将20只SD大鼠按体重随机分为4组,即对照组(给予等体积橄榄油)、Aroclor 1254单独染毒组(10mg/kg)、TCDD单独染毒组(10μg/kg)、联合染毒组(Aroclor 1254 10 mg/kg+TCDD 10μg/kg),每天灌胃染毒一次,连续灌胃6 d。末次染毒24 h后,取外周血,分离淋巴细胞。采用碱性单细胞凝胶电泳技术(彗星试验)检测外周血淋巴细胞DNA损伤情况,并采用CASP软件分析各组彗星的尾部DNA百分含量(TailDNA%)、尾长(Tail Length)、尾矩(Tail Moment),并利用析因方差分析判定TCDD与Aroclor1254联合暴露的联合毒性效应的作用模式。结果表明,Aroclor 1254单独染毒组Tail DNA%、Tail Length、Tail Moment与对照组比较差异无统计学意义(p>0.05); TCDD单独染毒组和联合染毒组Tail DNA%、Tail Length、Tail Moment与对照组比较差异显著(p<0.01)。析因分析结果表明,在本实验条件下,TCDD与Aroclor 1254联合作用对大鼠外周血淋巴细胞DNA损伤的影响为协同作用。
第二部分环境内分泌干扰物二噁英的细胞毒性作用
本部分研究采用TCDD和氯化锌同时作用于HepG2细胞,通过检测细胞内活性痒(ROS)、抗氧化物质的含量和抗氧化酶的活性、一些蛋白表达的变化及细胞凋亡情况,探讨氧化损伤在TCDD所致的HepG2细胞毒性效应中的作用,并初步探讨了锌对TCDD所致毒性效应的保护作用,为进一步探索临床防治措施提供理论基础。分别以不同浓度的TCDD和ZnCl2染毒HepG2细胞,细胞培养24 h后。采用MTT法检测细胞活力；荧光探针DCFH-DA法检测ROS；采用TBA法测定细胞中脂质过氧化产物丙二醛(MDA)含量、采用Beutler改良法测定细胞中谷胱甘肽(GSH)含量、采用试剂盒测定细胞中超氧化物歧化酶(SOD)活性；Hoechst荧光探针检测细胞凋亡情况；单细胞凝胶电泳实验检测细胞DNA完整性；Western Blot检测细胞细胞色素P4501A1 (CYP1A1)、SODⅠ、SODⅡ和热休克蛋白70(HSP70)蛋白表达水平。结果表明,TCDD可引起明显的细胞毒性效应,并呈明显的剂量-效应关系,表现为：HepG2细胞活力受到明显抑制；各染毒组细胞内ROS的生成量明显高于对照组(p<0.01)、细胞MDA含量随TCDD浓度的提高而明显升高(p<0.05)、细胞内GSH含量明显减少(p<0.05)、细胞内SOD活性显著降低(p<0.01); TCDD能够引起HepG2细胞的DNA损伤,尾部DNA百分含量(Tail DNA%)、尾长(Tail length)、尾矩(Tail moment)随TCDD染毒浓度提高而增加(p<0.01); TCDD可诱导HepG2细胞发生凋亡；TCDD可诱导细胞中CYP1A1和HSP70蛋白表达量明显高于对照组(P<0.01),并使细胞中SODⅠ和SODⅡ蛋白表达明显低于对照组(P<0.05). ZnCl2对TCDD所致的细胞毒性效应具有明显的保护作用,表现为：ZnCl2能明显增加HepG2细胞活力；细胞内ROS的生成量明显低于对照组(p<0.01)、细胞MDA含量明显降低(p<0.05)、细胞内GSH含量和SOD活性显著升高(p<0.01)；能明显减轻TCDD所引起HepG2细胞的DNA损伤,使Tail DNA%、Tail length、Tail moment减少(p<0.01)；抑制细胞的凋亡发生；使细胞中CYP1A1和HSP70蛋白表达量明显低于对照组(P<0.01),并使细胞中SODⅠ和SODⅡ蛋白表达明显高于对照组(P<0.05)。
综合本研究结果,在本实验条件下,可以得到如下结论：①TCDD可引起大鼠外周血淋巴细胞DNA的损伤,TCDD和Aroclor 1254联合染毒对大鼠外周血淋巴细胞DNA的损伤更为严重。②TCDD能引起HepG2细胞内ROS过量产生,同时降低了细胞抗氧化防御系统的能力,诱导CYP1A1和HSP70蛋白表达升高,使SODⅠ和SODⅡ蛋白表达降低,并最终导致细胞内脂质、DNA发生氧化损伤及细胞凋亡。表明氧化应激是TCDD引起细胞损伤的重要机制之一。③锌作为自由基清除剂,对TCDD所引起的抗氧化防御系统的破坏及其引起的氧化应激反应、细胞凋亡具有一定的保护作用。表明锌是可以作为TCDD引起氧化应激的有效抗氧化剂。本实验首次研究了锌对TCDD所致细胞毒性效应的保护作用。
Endocrine disruptors (EDs) are widely dispersed environmental and food contaminants in our country that poses a great risk to the public health.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) compounds are persistent organic pollutants (POPs) and the typical environmental endocrine disruptors (EEDs), which the present international society pays attention extremely. At present, they are one of the hot spots in the field of environmental toxicology because of their extensive disposition and coexistence in the environment, persistence, bioaccumulation, migration and high toxicity. It mainly comes from waste incineration, the use and manufacture of pesticide, fertilizer, herbicides and other production with chlorine compounds. The prototype chemical for toxicity study is TCDD, which is recognized as the world's strongest carcinogens and the most toxic congener of dioxins. It is a ubiquitous environmental pollutant. In recent years, several dioxin contamination incidents have taken place, so many countries in the world pay great concern about dioxin on human health and environmental safety of the potential threat. Thus, TCDD is one of the hot spots in the field of environmental toxicology. Although preliminary achievements of the mechanism have been gained on the research of TCDD, the cytotoxic mechanism of TCDD is still not entirely clear. In this study, the toxic mechanism of TCDD has been researched both in vivo and in vitro. In addition, in order to provide a theoretical and experimental basis,we have studied the protective effect of zinc to TCDD. This study can be divided into two parts.
1.The effect of individual and combined exposure to TCDD and PCBs in peripheral blood lymphocyte of rats
The Sprague-Dawley rats were exposured to TCDD and Aroclor 1254 individual and combined, and detect the integrity of DNA by single cell gel electrophoresis(SCGE). Factorial design analysis of variance was used for determining the joint action of toxicological endpoints in TCDD and Aroclor 1254. The goal of this experiment is to further study the combined effects of TCDD and PCBs and the possible modes and mechanisms of and combined effects were investigated. In the present study, Twenty Sprague-Dawley rats were subjected to 2×2 factorial experimental design and randomly divided into four groups, and were treated intragastrically with vehicle(olive oil), Aroclor 1254(Aroclor 1254 10 mg/kg), TCDD(TCDD 10μg/kg), and the combination (Aroclor1254 10 mg/kg + TCDD 10μg/kg)once a day for six consecutive days, respectively. After 6 d exposure, peripheral blood lymphocytes were obtained and detected for DNA damage by single cell gel electrophoresis(SCGE). Tail Length, Tail DNA% and Tail Moment were analyzed by SCGE image analysis software(CASP). The possible interactions between the two compounds and the involvement of different mechanisms are discussed. The consequence suggested that The Tail Length, Tail DNA% and Tail Moment in both TCDD group and combined group were higher than those in the control(p<0.01). However, no obvious DNA damage was observed in Aroclor 1254 group. The result of the two-way analysis of variance revealed that the combined effects of TCDD and PCBs were synergistic under the present experimental condition.
2. The cytotoxic effect of TCDD
This part we studied the oxidative stress and the protective effect of zinc on cytotoxicity induced by TCDD. The ROS production, DNA damage, Content of antioxidants, activity of antioxidant enzymes, expression of protein and Apoptosis were measured to investigate the role of toxic effects of TCDD-induced oxidative damage in HepG2 cells. HepG2 cells were cultured and treated with TCDD 1 nM.10 nM、100 nM、TCDD 100 nM+ZnCl265μM、TCDD 100 nM+ZnCl2 100μM for 24 h. Cell viability was assayed by MTT method; DCFH-DA was used for detecting the production of ROS in cells; GSH and MDA content, activity of SOD in cells were measured by colorimetry method; Apoptosis was measured with Hoechst 33258; The integrity of DNA was detected by SCGE; The express levels of CYP1A1、SODⅠ、SODⅡand HSP70 were measured by western blot. The results of this partial study suggest that TCDD decreased the cell viability in a well dose-response way; Formation of intracellular ROS and MDA content induced by TCDD increased in a dose-response way, and achieved the highest level in TCDD 100 nM(p<0.01). The GSH content and activity of SOD in cells decreased exposed by TCDD for 24 h(p<0.05); Obvious DNA damage and apoptosis was induced by TCDD(p<0.05). Compared with the control group, the expression of CYP1A1 and HSP70 increased induced by TCDD(P<0.05); But the expression of SODⅠand SODⅡdecreased by TCDD-induced(p<0.01). TCDD-induced cytotoxicity could be inhibited by Zinc
Based on the results of this study, the following conclusions could be made under the present experimental condition:①TCDD can significantly induced DNA damage in peripheral blood lymphocytes, and the effect was significant in the combined group.②TCDD induced oxidative stresses in HepG2 cells significantly:Formation of intracellular ROS increased, and the antioxidant defense system reduced by TCDD-induced. The expression of CYP1A1 and HSP70 increased, but the expression of SODⅠand SODⅡdecreased by TCDD-induced. The cellular lipid, DNA oxidative damage and apoptosis occurred at last.③Zinc as a radical scavenger, play protective effects on cytotoxicity induced by TCDD. In another word, zinc could be the antioxidant for TCDD-induced oxidative stress. It is the first time that Zinc was used in the inhibition for TCDD-induced oxidative stress in this study.
第一部分TCDD与PCBs联合作用对大鼠外周血淋巴细胞DNA的影响
本部分实验应用TCDD和Aroclor 1254单独及联合染毒大鼠,采用碱性单细胞凝胶电泳技术检测TCDD和Aroclor 1254对大鼠外周血淋巴细胞DNA完整性的影响,并利用析因设计方差分析判定二者对所检测的毒理学终点是否存在联合作用,初步探讨了TCDD和Aroclor 1254单独及联合毒性作用及其作用模式,以期为进一步研究二嗯英与PCBs的联合毒性作用提供一定的毒理学依据。采用2×2析因设计将20只SD大鼠按体重随机分为4组,即对照组(给予等体积橄榄油)、Aroclor 1254单独染毒组(10mg/kg)、TCDD单独染毒组(10μg/kg)、联合染毒组(Aroclor 1254 10 mg/kg+TCDD 10μg/kg),每天灌胃染毒一次,连续灌胃6 d。末次染毒24 h后,取外周血,分离淋巴细胞。采用碱性单细胞凝胶电泳技术(彗星试验)检测外周血淋巴细胞DNA损伤情况,并采用CASP软件分析各组彗星的尾部DNA百分含量(TailDNA%)、尾长(Tail Length)、尾矩(Tail Moment),并利用析因方差分析判定TCDD与Aroclor1254联合暴露的联合毒性效应的作用模式。结果表明,Aroclor 1254单独染毒组Tail DNA%、Tail Length、Tail Moment与对照组比较差异无统计学意义(p>0.05); TCDD单独染毒组和联合染毒组Tail DNA%、Tail Length、Tail Moment与对照组比较差异显著(p<0.01)。析因分析结果表明,在本实验条件下,TCDD与Aroclor 1254联合作用对大鼠外周血淋巴细胞DNA损伤的影响为协同作用。
第二部分环境内分泌干扰物二噁英的细胞毒性作用
本部分研究采用TCDD和氯化锌同时作用于HepG2细胞,通过检测细胞内活性痒(ROS)、抗氧化物质的含量和抗氧化酶的活性、一些蛋白表达的变化及细胞凋亡情况,探讨氧化损伤在TCDD所致的HepG2细胞毒性效应中的作用,并初步探讨了锌对TCDD所致毒性效应的保护作用,为进一步探索临床防治措施提供理论基础。分别以不同浓度的TCDD和ZnCl2染毒HepG2细胞,细胞培养24 h后。采用MTT法检测细胞活力；荧光探针DCFH-DA法检测ROS；采用TBA法测定细胞中脂质过氧化产物丙二醛(MDA)含量、采用Beutler改良法测定细胞中谷胱甘肽(GSH)含量、采用试剂盒测定细胞中超氧化物歧化酶(SOD)活性；Hoechst荧光探针检测细胞凋亡情况；单细胞凝胶电泳实验检测细胞DNA完整性；Western Blot检测细胞细胞色素P4501A1 (CYP1A1)、SODⅠ、SODⅡ和热休克蛋白70(HSP70)蛋白表达水平。结果表明,TCDD可引起明显的细胞毒性效应,并呈明显的剂量-效应关系,表现为：HepG2细胞活力受到明显抑制；各染毒组细胞内ROS的生成量明显高于对照组(p<0.01)、细胞MDA含量随TCDD浓度的提高而明显升高(p<0.05)、细胞内GSH含量明显减少(p<0.05)、细胞内SOD活性显著降低(p<0.01); TCDD能够引起HepG2细胞的DNA损伤,尾部DNA百分含量(Tail DNA%)、尾长(Tail length)、尾矩(Tail moment)随TCDD染毒浓度提高而增加(p<0.01); TCDD可诱导HepG2细胞发生凋亡；TCDD可诱导细胞中CYP1A1和HSP70蛋白表达量明显高于对照组(P<0.01),并使细胞中SODⅠ和SODⅡ蛋白表达明显低于对照组(P<0.05). ZnCl2对TCDD所致的细胞毒性效应具有明显的保护作用,表现为：ZnCl2能明显增加HepG2细胞活力；细胞内ROS的生成量明显低于对照组(p<0.01)、细胞MDA含量明显降低(p<0.05)、细胞内GSH含量和SOD活性显著升高(p<0.01)；能明显减轻TCDD所引起HepG2细胞的DNA损伤,使Tail DNA%、Tail length、Tail moment减少(p<0.01)；抑制细胞的凋亡发生；使细胞中CYP1A1和HSP70蛋白表达量明显低于对照组(P<0.01),并使细胞中SODⅠ和SODⅡ蛋白表达明显高于对照组(P<0.05)。
综合本研究结果,在本实验条件下,可以得到如下结论：①TCDD可引起大鼠外周血淋巴细胞DNA的损伤,TCDD和Aroclor 1254联合染毒对大鼠外周血淋巴细胞DNA的损伤更为严重。②TCDD能引起HepG2细胞内ROS过量产生,同时降低了细胞抗氧化防御系统的能力,诱导CYP1A1和HSP70蛋白表达升高,使SODⅠ和SODⅡ蛋白表达降低,并最终导致细胞内脂质、DNA发生氧化损伤及细胞凋亡。表明氧化应激是TCDD引起细胞损伤的重要机制之一。③锌作为自由基清除剂,对TCDD所引起的抗氧化防御系统的破坏及其引起的氧化应激反应、细胞凋亡具有一定的保护作用。表明锌是可以作为TCDD引起氧化应激的有效抗氧化剂。本实验首次研究了锌对TCDD所致细胞毒性效应的保护作用。
Endocrine disruptors (EDs) are widely dispersed environmental and food contaminants in our country that poses a great risk to the public health.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) compounds are persistent organic pollutants (POPs) and the typical environmental endocrine disruptors (EEDs), which the present international society pays attention extremely. At present, they are one of the hot spots in the field of environmental toxicology because of their extensive disposition and coexistence in the environment, persistence, bioaccumulation, migration and high toxicity. It mainly comes from waste incineration, the use and manufacture of pesticide, fertilizer, herbicides and other production with chlorine compounds. The prototype chemical for toxicity study is TCDD, which is recognized as the world's strongest carcinogens and the most toxic congener of dioxins. It is a ubiquitous environmental pollutant. In recent years, several dioxin contamination incidents have taken place, so many countries in the world pay great concern about dioxin on human health and environmental safety of the potential threat. Thus, TCDD is one of the hot spots in the field of environmental toxicology. Although preliminary achievements of the mechanism have been gained on the research of TCDD, the cytotoxic mechanism of TCDD is still not entirely clear. In this study, the toxic mechanism of TCDD has been researched both in vivo and in vitro. In addition, in order to provide a theoretical and experimental basis,we have studied the protective effect of zinc to TCDD. This study can be divided into two parts.
1.The effect of individual and combined exposure to TCDD and PCBs in peripheral blood lymphocyte of rats
The Sprague-Dawley rats were exposured to TCDD and Aroclor 1254 individual and combined, and detect the integrity of DNA by single cell gel electrophoresis(SCGE). Factorial design analysis of variance was used for determining the joint action of toxicological endpoints in TCDD and Aroclor 1254. The goal of this experiment is to further study the combined effects of TCDD and PCBs and the possible modes and mechanisms of and combined effects were investigated. In the present study, Twenty Sprague-Dawley rats were subjected to 2×2 factorial experimental design and randomly divided into four groups, and were treated intragastrically with vehicle(olive oil), Aroclor 1254(Aroclor 1254 10 mg/kg), TCDD(TCDD 10μg/kg), and the combination (Aroclor1254 10 mg/kg + TCDD 10μg/kg)once a day for six consecutive days, respectively. After 6 d exposure, peripheral blood lymphocytes were obtained and detected for DNA damage by single cell gel electrophoresis(SCGE). Tail Length, Tail DNA% and Tail Moment were analyzed by SCGE image analysis software(CASP). The possible interactions between the two compounds and the involvement of different mechanisms are discussed. The consequence suggested that The Tail Length, Tail DNA% and Tail Moment in both TCDD group and combined group were higher than those in the control(p<0.01). However, no obvious DNA damage was observed in Aroclor 1254 group. The result of the two-way analysis of variance revealed that the combined effects of TCDD and PCBs were synergistic under the present experimental condition.
2. The cytotoxic effect of TCDD
This part we studied the oxidative stress and the protective effect of zinc on cytotoxicity induced by TCDD. The ROS production, DNA damage, Content of antioxidants, activity of antioxidant enzymes, expression of protein and Apoptosis were measured to investigate the role of toxic effects of TCDD-induced oxidative damage in HepG2 cells. HepG2 cells were cultured and treated with TCDD 1 nM.10 nM、100 nM、TCDD 100 nM+ZnCl265μM、TCDD 100 nM+ZnCl2 100μM for 24 h. Cell viability was assayed by MTT method; DCFH-DA was used for detecting the production of ROS in cells; GSH and MDA content, activity of SOD in cells were measured by colorimetry method; Apoptosis was measured with Hoechst 33258; The integrity of DNA was detected by SCGE; The express levels of CYP1A1、SODⅠ、SODⅡand HSP70 were measured by western blot. The results of this partial study suggest that TCDD decreased the cell viability in a well dose-response way; Formation of intracellular ROS and MDA content induced by TCDD increased in a dose-response way, and achieved the highest level in TCDD 100 nM(p<0.01). The GSH content and activity of SOD in cells decreased exposed by TCDD for 24 h(p<0.05); Obvious DNA damage and apoptosis was induced by TCDD(p<0.05). Compared with the control group, the expression of CYP1A1 and HSP70 increased induced by TCDD(P<0.05); But the expression of SODⅠand SODⅡdecreased by TCDD-induced(p<0.01). TCDD-induced cytotoxicity could be inhibited by Zinc
Based on the results of this study, the following conclusions could be made under the present experimental condition:①TCDD can significantly induced DNA damage in peripheral blood lymphocytes, and the effect was significant in the combined group.②TCDD induced oxidative stresses in HepG2 cells significantly:Formation of intracellular ROS increased, and the antioxidant defense system reduced by TCDD-induced. The expression of CYP1A1 and HSP70 increased, but the expression of SODⅠand SODⅡdecreased by TCDD-induced. The cellular lipid, DNA oxidative damage and apoptosis occurred at last.③Zinc as a radical scavenger, play protective effects on cytotoxicity induced by TCDD. In another word, zinc could be the antioxidant for TCDD-induced oxidative stress. It is the first time that Zinc was used in the inhibition for TCDD-induced oxidative stress in this study.
引文
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