量子点与Cu~（2+）对L02细胞与细菌的联合毒性及机理研究
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摘要
环境中往往是多种污染物同时存在并共同进入体内,彼此之间的相互作用有时表现为协同作用,协同作用所会放大污染物的毒性从而带来更多的污染物共同暴露风险,由协同作用扩大的毒性以及其可能的机理值得研究。
木马技术当前被广泛用于药物的体内运送,大部分药物因为其溶解性较低以及不能有效地跨过细胞膜屏障或者脑血屏障等而导致利用率较低,不能有效到达病灶部位而使得该部位蓄积的药物浓度不足从而减弱疗效。一种新型的木马技术被用来提高药物的运送效率,简单的说就是将运送的药物分子连接在能够跨过细胞膜的木马蛋白上,通过受体介导的胞吞作用等进入细胞,到达病灶部位,并成功释放携带的药物,这样即使在较低的药物浓度条件下也可以获得较高的细胞内浓度,从而提高疗效。
量子点也被开发作为药物运送的工具。从另一个层面来说,量子点作为小尺度的纳米粒子,其表面的巯基类官能团及较大的比表面积赋予其强大的结合或吸附其他小分子物质的能力。虽然其没有在合成过程包裹Cu2+,但由于量子点可以吸附Cu2+并且两者都可能在肝脏内或者环境中蓄积,所以二者结合并由量子点执行木马功能携带Cu2+进入细胞,导致更高的细胞毒性并进而导致肝脏疾患。类似的由于纳米材料的木马功能可能带来的环境复合污染的问题值得关注,同时这也可能解释不同的环境污染物的协同作用的联合毒性效应。
本论文着重验证MPA-CdTe量子点(以下在本论文中被简称为量子点)的木马角色,从而为纳米材料的潜在风险进行阐述。首先在量子点和Cu2+共存的溶液中对两者的结合进行确认。这种结合为MPA-CdTe量子点充当木马携带Cu2+提供了可能。MPA-CdTe量子点的木马角色是通过比较MPA-CdTe量子点加入前后细胞铜浓度的变化来确定的,细胞内增加的镉浓度也证明了量子点进入细胞,单独的Cu2+处理的细胞铜浓度显著低于加入量子点后细胞铜浓度,说明了MPA-CdTe量子点在这个过程中可能充当了木马携带铜进入细胞,使得铜在细胞膜或者细胞质释放蓄积。
为了进一步证明这种由于木马效应带来的细胞铜蓄积的增加是否带来细胞毒性的增加,本论文进一步通过细胞存活率的测定和细胞形态变化来确定细胞毒性的变化。MPA-CdTe量子点本身只能引起细胞存活率10%的下降,而在加入Cu2+处理的细胞样品中,却造成原本Cu2+诱导的细胞存活率最高(10%-40%)下降6倍。并伴随细胞形态的明显变化。
因为活性氧自由基(ROS)诱导的氧化损伤是量子点和Cu2+诱导的细胞毒性的共同机理,所以本论文在确定木马效应的同时,研究了是否ROS介导的氧化损伤是两种样品的共同作用的联合毒性机理,相对于单独的Cu2+处理的细胞样品来说,量子点的加入使得细胞内的ROS水平最高增加了4倍,而MPA-CdTe量子点本身只能获得相对与对照来说30%左右的ROS水平的提高。同时线粒体作为ROS的主要来源,其膜电位的下降也进行了调查,但是该膜电位的下降没有与ROS的增加呈现一致对应。
一般环境污染物作用与细胞产生毒性,都通过一些分子路径来实现,了解这样的路径对于防护其毒性具有重要意义,可以从上游进行分子水平调控从而有效地控制毒性。对于量子点和Cu2+联合毒性确定为氧化损伤相关后,为了进一步确定其分子水平的机制,对一般环境污染物的共同的氧化损伤的路径Nrf2/ARE (Nrf2:NF-E2 Related Factor2核转移因子2；ARE：抗氧化反应元件Antioxidative Response Elements)路径进行了研究。调查了量子点加入前后的细胞内谷胱甘肽转移酶(GST)和Nrf2水平的变化,量子点的加入引起了细胞内GST水平的增加同时Nrf2的细胞核转录水平也增加。
复合污染在环境污染中具有重要的意义,尤其是关联新型的纳米污染物的联合毒性。在确定上述MPA-CdTe量子点和Cu2+对人胚肝细胞(L02细胞)的木马效应机理和氧化损伤的毒性后,为了调查这种复合污染对于土壤生态的潜在风险,对MPA-CdTe量子点和Cu2+对土壤代表微生物的大肠杆菌和枯草芽孢杆菌的毒性进行了调查。关注其对土壤微生物的生长和正常的酶代谢等毒性。首先,调查了量子点和Cu2+对大肠杆菌的生长周期的影响。同时也验证了木马效应和氧化损伤机制。量子点的加入使得Cu2+存在下的大肠杆菌的生长停滞期增加,细胞死亡率提高四倍,同时细胞内ROS水平提高了400%,细胞积聚的铜也呈现了与存活率下降的一致趋势。
然后调查了MPA-CdTe量子点和Cu2+枯草芽孢杆菌生长和产酶量以及相关的木马效应和氧化损伤机理。MPA-CdTe量子点的加入使得Cu2+诱导的细胞存活率显著下降,但是对产酶量没有显著影响。为了考虑木马效应在其他纳米材料上的体现,对纳米Ti02与Cu2+对枯草芽孢杆菌联合毒性进行了调查,纳米TiO2加入提高了Cu2+诱导的细胞存活率的减少,对细胞生长周期没有显著影响,同时提高了α-蛋白酶的合成。
Variou pollutants co-exist in environment and possible enter human body, some related antagonistic and additive as well as independent functions between these pollutants become possible. The current toxin evaluation normally focus on individual chemicals, which make the combined toxicity blind to people sometime, therefore the improved toxicity resulting from the synergistic function between individual toxins is worth noting.
The Trojan horse technology has been developed recently to enhance some therapeutic drug uptake by smaller basic peptides.As we all know, many drug leads fail to make it into clinical trials due to the additional delivery obstacles arising from the less bioavailability and, the cellular membrane barrier even the blood-brain barrier (BBB). To deliver functional drug molecular into cells, normally methods of linking them to some receptor-specific Trojan-horse peptides, which, mediates the transcytosis of the "package" across the blood-brain barrier (BBB) and endocytosis across the plasma membrane. Such Trojan horse peptides can not only penetrate cells and tissues, but even release the carried drug in the cytoplasm and enhance the uptake of the cargos at nontoxic concentrations.
Quantum dots (QDs) are luminescent nanoparticles with unique optical properties that have been exploited for molecular imaging and drug delivery. Their characteristic size-dependent variable fluorescence wavelength and surface properties are reasons for the wide applications. The surface-coating of functional groups and/or biomolecules on QDs may promote their interactions with other toxicants and present a potential risk to human body. The interaction of Cu2+with MSA-CdTe QDs has been exploited for trace Cu2+analysis. The nanoparticles might play the Trojan horse role by allowing more transition metals accumulate into living cells followed by the subsequent release of the metals leading to the higher toxicity.
In this study, we focus on "Trojan horse" role of QDs. QDs (quantum dots) nanoparticles thus possible carry Cu2+causing much more cellular accumulation of Cu2+. the carrier role of MPA-CdTe QDs for Cu2+uptake was confirmed according to the following procedure using human hepatic L02 cells:Firstly, the 10 nm red shifts of QDs luminescence emission with addition of Cu2+implied the possible redox reaction between of QDs and Cu2+, and the emerged Cu element in the X-ray energy dispersive spectroscopy (EDS) data confirm the interaction of the two species. Then a small amount of MSA-CdTe QDs (2μg/ml) in a Cu2+ solution (2.5-20μg/ml) resulted in a higher cellular [Cu2+].
The presence of a small amount of MPA-CdTe QDs in a Cu2+solutionresulted in a higher toxicity with up to 6-fold cell viability decrease, which was accompanied by cell morphology changes.A major mechanism of QDs enhanced toxicity of Cu2+was thus proposed as the adsorption of Cu2+ions on the negatively charged QDs surface; QDs served the role of a Trojan horse carrying Cu2+when it migrated into the cells.
Considering Quantum dots (QDs) and Cu2+are known ROS (Reactive oxygen species) inducer, we investigated the combined oxidative stress and corresponding protective strategy using human hepatic L02 cells. The combined toxicity was then confirmed as ROS associated oxidative stress with up to 4-fold increase of the intracellular ROS level. NAC (N-acetylcysteine) also provided almost complete protection against the induced toxicity. Therefore the ROS associated oxidant injury are responsible for the QDs-Cu2+/Cu2+induced toxicity.
The combined oxidative damage and corresponding toxicity mechanisms are keys to evaluate ecological hazards via co-exposure of QDs plus original contaminants. GST enzyme activity and Nrf2 expression in individual Cu2+ and QDs-Cu2+ treated L02 cells were investigated. Addition of QDs improved Cu2+-induced GST synthesis and Nrf2 transcription with maximum increase by 35%and 86%respectively. The increased toxicity could also be consisit with cell morphology changes, indicating QDs and/or Cu2+induced cytoprotective antioxidant enzyme GST via the Nrf2/ARE pathway.
Quantum dots (QDs) represent a new kind of environmental pollutants. The combined toxicity of QDs with Cu2+is also concerned due to the increasing release of these two chemicals. E.coli, a common environmental model microbial, used to evaluated the possible synergistic toxicity and the regarding mechanism. It was observed that addition of MS A-CdTe QDs (5μg/mL) in a Cu2+solution (9-72μg/mL) resulted in a higher toxicity with up to 8-fold cell viability decrease and the elongated lag phase. The intracellular ROS levels were also improved by up to 400%. Meanwhile, accumulation of copper in the E.coli were correlated with the decreased cell viability, suggesting that a primary cause of QDs enhanced copper toxicity is through the production of superoxide anions and improved accumulation of copper in the cytoplasm.
Also, the combined toxicity of QDs with Cu2+to B.subtilis, a known soil model bacterial, was investigated. It was observed that addition of MPA-CdSe QDs in a Cu2+solution resulted in a higher toxicity with up to 2-fold of cell viability decrease. The intracellular ROS levels were also improved by up to 500%compared that of Cu2+, which was consistent with induction of Antioxidant enzymes SOD and copper accumulation at higher concentrations (14 and 28μg/mL of Cu2+) in the case QDs-Cu2+. Implying the potential of QDs enhanced copper toxicity is possibly through the production of superoxide anions and improved copper cellular accumulation.
TiO2 nanoparticles (NPs) possess the potential to co-exist with Cu2+in soil. The individual and combined toxicity of these two chemicals was evaluated here using Bacillus subtilis, a known soil model bacterial. Cu+(6.25～50μg/mL) alone exhibited toxicity to bacterial with cell viability andα-Amylase production decrease up to 51%and 85%, respectively. Addition of TiO2 (50 mg/mL) decreased Cu2+induced cell viability with up to 25%,while increased enzyme biosynthesis by 28 compared that of Cu+, and the growth rate and lag period didn't exhibit significant change. A primary cause of TiO2 increasing Cu2+ toxicity is assumed as·OH formation and the increased enzyme activity are considered arise from Cu2+ facilitating TiO2 degradation ability.
木马技术当前被广泛用于药物的体内运送,大部分药物因为其溶解性较低以及不能有效地跨过细胞膜屏障或者脑血屏障等而导致利用率较低,不能有效到达病灶部位而使得该部位蓄积的药物浓度不足从而减弱疗效。一种新型的木马技术被用来提高药物的运送效率,简单的说就是将运送的药物分子连接在能够跨过细胞膜的木马蛋白上,通过受体介导的胞吞作用等进入细胞,到达病灶部位,并成功释放携带的药物,这样即使在较低的药物浓度条件下也可以获得较高的细胞内浓度,从而提高疗效。
量子点也被开发作为药物运送的工具。从另一个层面来说,量子点作为小尺度的纳米粒子,其表面的巯基类官能团及较大的比表面积赋予其强大的结合或吸附其他小分子物质的能力。虽然其没有在合成过程包裹Cu2+,但由于量子点可以吸附Cu2+并且两者都可能在肝脏内或者环境中蓄积,所以二者结合并由量子点执行木马功能携带Cu2+进入细胞,导致更高的细胞毒性并进而导致肝脏疾患。类似的由于纳米材料的木马功能可能带来的环境复合污染的问题值得关注,同时这也可能解释不同的环境污染物的协同作用的联合毒性效应。
本论文着重验证MPA-CdTe量子点(以下在本论文中被简称为量子点)的木马角色,从而为纳米材料的潜在风险进行阐述。首先在量子点和Cu2+共存的溶液中对两者的结合进行确认。这种结合为MPA-CdTe量子点充当木马携带Cu2+提供了可能。MPA-CdTe量子点的木马角色是通过比较MPA-CdTe量子点加入前后细胞铜浓度的变化来确定的,细胞内增加的镉浓度也证明了量子点进入细胞,单独的Cu2+处理的细胞铜浓度显著低于加入量子点后细胞铜浓度,说明了MPA-CdTe量子点在这个过程中可能充当了木马携带铜进入细胞,使得铜在细胞膜或者细胞质释放蓄积。
为了进一步证明这种由于木马效应带来的细胞铜蓄积的增加是否带来细胞毒性的增加,本论文进一步通过细胞存活率的测定和细胞形态变化来确定细胞毒性的变化。MPA-CdTe量子点本身只能引起细胞存活率10%的下降,而在加入Cu2+处理的细胞样品中,却造成原本Cu2+诱导的细胞存活率最高(10%-40%)下降6倍。并伴随细胞形态的明显变化。
因为活性氧自由基(ROS)诱导的氧化损伤是量子点和Cu2+诱导的细胞毒性的共同机理,所以本论文在确定木马效应的同时,研究了是否ROS介导的氧化损伤是两种样品的共同作用的联合毒性机理,相对于单独的Cu2+处理的细胞样品来说,量子点的加入使得细胞内的ROS水平最高增加了4倍,而MPA-CdTe量子点本身只能获得相对与对照来说30%左右的ROS水平的提高。同时线粒体作为ROS的主要来源,其膜电位的下降也进行了调查,但是该膜电位的下降没有与ROS的增加呈现一致对应。
一般环境污染物作用与细胞产生毒性,都通过一些分子路径来实现,了解这样的路径对于防护其毒性具有重要意义,可以从上游进行分子水平调控从而有效地控制毒性。对于量子点和Cu2+联合毒性确定为氧化损伤相关后,为了进一步确定其分子水平的机制,对一般环境污染物的共同的氧化损伤的路径Nrf2/ARE (Nrf2:NF-E2 Related Factor2核转移因子2；ARE：抗氧化反应元件Antioxidative Response Elements)路径进行了研究。调查了量子点加入前后的细胞内谷胱甘肽转移酶(GST)和Nrf2水平的变化,量子点的加入引起了细胞内GST水平的增加同时Nrf2的细胞核转录水平也增加。
复合污染在环境污染中具有重要的意义,尤其是关联新型的纳米污染物的联合毒性。在确定上述MPA-CdTe量子点和Cu2+对人胚肝细胞(L02细胞)的木马效应机理和氧化损伤的毒性后,为了调查这种复合污染对于土壤生态的潜在风险,对MPA-CdTe量子点和Cu2+对土壤代表微生物的大肠杆菌和枯草芽孢杆菌的毒性进行了调查。关注其对土壤微生物的生长和正常的酶代谢等毒性。首先,调查了量子点和Cu2+对大肠杆菌的生长周期的影响。同时也验证了木马效应和氧化损伤机制。量子点的加入使得Cu2+存在下的大肠杆菌的生长停滞期增加,细胞死亡率提高四倍,同时细胞内ROS水平提高了400%,细胞积聚的铜也呈现了与存活率下降的一致趋势。
然后调查了MPA-CdTe量子点和Cu2+枯草芽孢杆菌生长和产酶量以及相关的木马效应和氧化损伤机理。MPA-CdTe量子点的加入使得Cu2+诱导的细胞存活率显著下降,但是对产酶量没有显著影响。为了考虑木马效应在其他纳米材料上的体现,对纳米Ti02与Cu2+对枯草芽孢杆菌联合毒性进行了调查,纳米TiO2加入提高了Cu2+诱导的细胞存活率的减少,对细胞生长周期没有显著影响,同时提高了α-蛋白酶的合成。
Variou pollutants co-exist in environment and possible enter human body, some related antagonistic and additive as well as independent functions between these pollutants become possible. The current toxin evaluation normally focus on individual chemicals, which make the combined toxicity blind to people sometime, therefore the improved toxicity resulting from the synergistic function between individual toxins is worth noting.
The Trojan horse technology has been developed recently to enhance some therapeutic drug uptake by smaller basic peptides.As we all know, many drug leads fail to make it into clinical trials due to the additional delivery obstacles arising from the less bioavailability and, the cellular membrane barrier even the blood-brain barrier (BBB). To deliver functional drug molecular into cells, normally methods of linking them to some receptor-specific Trojan-horse peptides, which, mediates the transcytosis of the "package" across the blood-brain barrier (BBB) and endocytosis across the plasma membrane. Such Trojan horse peptides can not only penetrate cells and tissues, but even release the carried drug in the cytoplasm and enhance the uptake of the cargos at nontoxic concentrations.
Quantum dots (QDs) are luminescent nanoparticles with unique optical properties that have been exploited for molecular imaging and drug delivery. Their characteristic size-dependent variable fluorescence wavelength and surface properties are reasons for the wide applications. The surface-coating of functional groups and/or biomolecules on QDs may promote their interactions with other toxicants and present a potential risk to human body. The interaction of Cu2+with MSA-CdTe QDs has been exploited for trace Cu2+analysis. The nanoparticles might play the Trojan horse role by allowing more transition metals accumulate into living cells followed by the subsequent release of the metals leading to the higher toxicity.
In this study, we focus on "Trojan horse" role of QDs. QDs (quantum dots) nanoparticles thus possible carry Cu2+causing much more cellular accumulation of Cu2+. the carrier role of MPA-CdTe QDs for Cu2+uptake was confirmed according to the following procedure using human hepatic L02 cells:Firstly, the 10 nm red shifts of QDs luminescence emission with addition of Cu2+implied the possible redox reaction between of QDs and Cu2+, and the emerged Cu element in the X-ray energy dispersive spectroscopy (EDS) data confirm the interaction of the two species. Then a small amount of MSA-CdTe QDs (2μg/ml) in a Cu2+ solution (2.5-20μg/ml) resulted in a higher cellular [Cu2+].
The presence of a small amount of MPA-CdTe QDs in a Cu2+solutionresulted in a higher toxicity with up to 6-fold cell viability decrease, which was accompanied by cell morphology changes.A major mechanism of QDs enhanced toxicity of Cu2+was thus proposed as the adsorption of Cu2+ions on the negatively charged QDs surface; QDs served the role of a Trojan horse carrying Cu2+when it migrated into the cells.
Considering Quantum dots (QDs) and Cu2+are known ROS (Reactive oxygen species) inducer, we investigated the combined oxidative stress and corresponding protective strategy using human hepatic L02 cells. The combined toxicity was then confirmed as ROS associated oxidative stress with up to 4-fold increase of the intracellular ROS level. NAC (N-acetylcysteine) also provided almost complete protection against the induced toxicity. Therefore the ROS associated oxidant injury are responsible for the QDs-Cu2+/Cu2+induced toxicity.
The combined oxidative damage and corresponding toxicity mechanisms are keys to evaluate ecological hazards via co-exposure of QDs plus original contaminants. GST enzyme activity and Nrf2 expression in individual Cu2+ and QDs-Cu2+ treated L02 cells were investigated. Addition of QDs improved Cu2+-induced GST synthesis and Nrf2 transcription with maximum increase by 35%and 86%respectively. The increased toxicity could also be consisit with cell morphology changes, indicating QDs and/or Cu2+induced cytoprotective antioxidant enzyme GST via the Nrf2/ARE pathway.
Quantum dots (QDs) represent a new kind of environmental pollutants. The combined toxicity of QDs with Cu2+is also concerned due to the increasing release of these two chemicals. E.coli, a common environmental model microbial, used to evaluated the possible synergistic toxicity and the regarding mechanism. It was observed that addition of MS A-CdTe QDs (5μg/mL) in a Cu2+solution (9-72μg/mL) resulted in a higher toxicity with up to 8-fold cell viability decrease and the elongated lag phase. The intracellular ROS levels were also improved by up to 400%. Meanwhile, accumulation of copper in the E.coli were correlated with the decreased cell viability, suggesting that a primary cause of QDs enhanced copper toxicity is through the production of superoxide anions and improved accumulation of copper in the cytoplasm.
Also, the combined toxicity of QDs with Cu2+to B.subtilis, a known soil model bacterial, was investigated. It was observed that addition of MPA-CdSe QDs in a Cu2+solution resulted in a higher toxicity with up to 2-fold of cell viability decrease. The intracellular ROS levels were also improved by up to 500%compared that of Cu2+, which was consistent with induction of Antioxidant enzymes SOD and copper accumulation at higher concentrations (14 and 28μg/mL of Cu2+) in the case QDs-Cu2+. Implying the potential of QDs enhanced copper toxicity is possibly through the production of superoxide anions and improved copper cellular accumulation.
TiO2 nanoparticles (NPs) possess the potential to co-exist with Cu2+in soil. The individual and combined toxicity of these two chemicals was evaluated here using Bacillus subtilis, a known soil model bacterial. Cu+(6.25～50μg/mL) alone exhibited toxicity to bacterial with cell viability andα-Amylase production decrease up to 51%and 85%, respectively. Addition of TiO2 (50 mg/mL) decreased Cu2+induced cell viability with up to 25%,while increased enzyme biosynthesis by 28 compared that of Cu+, and the growth rate and lag period didn't exhibit significant change. A primary cause of TiO2 increasing Cu2+ toxicity is assumed as·OH formation and the increased enzyme activity are considered arise from Cu2+ facilitating TiO2 degradation ability.
引文
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