纳米材料量子点神经毒性及机制
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摘要
量子点是一种有着特殊光学电学特性的生物纳米材料,已被广泛的应用于生物医学领域。由于纳米材料的应用日益增多,对环境和生物体的安全性及是否具有潜在的危害性,一直是人们密切关注的问题。本文以原代培养的海马神经元和Wistar大鼠的海马DG区作为模型,应用单细胞膜片钳,钙成像,免疫化学,免疫沉淀,树突(树突棘)形态学和在位场电位记录等技术,研究了离体和活体水平上量子点的神经毒性及作用机制。
实验结果:
(1)量子点对原代培养海马神经元细胞内钙稳态的影响
我们发现,量子点能够浓度依赖的长时程提高细胞内钙水平。浓度在10nM以上未经包被的CdSe量子点能升高胞内钙水平长达15分钟以上。若用胞外无钙的胞外液和细胞内钙耗尽药物thapsigargin预处理细胞时,均不能完全阻断量子点引起的内钙浓度升高。这说明在量子点的暴露下,细胞内钙的升高既有细胞外钙的流入,也有细胞内钙库的钙释放。我们进一步用膜通道阻断剂验证,发现胞外钙的流入主要是通过N型钙通道和电压门控钠通道流入胞内的。而胞内的原因则更复杂一些。通过电压门控钠通道流入的同时还有一部分钠离子,它们可以激活线粒体上的MNCX,使一部分钙离子从线粒体里交换出来,这一部分钙离子和细胞外流入的钙离子可以进一步激活内质网上的ryanodine受体,使大量的钙离子从内质网里释放出来。这一过程可能就是熟知的钙诱导钙释放的过程。这些结果表明,量子点的应用可能会干扰到细胞的钙稳态,并带来相应的危害,同时,用量子点来标记蛋白受体时,也应考虑到其对内钙的影响。
(2)量子点对电压门控钠通道电生理特性的影响
既然在量子点引起的内钙升高当中,电压门控钠通道扮演了一个很重要的角色,于是,我们就用单细胞膜片钳技术检测了量子点对钠通道电生理特性的影响。当用不同浓度的量子点孵育细胞24小时后,我们观察了钠通道的激活,失活,复活等特性的变化。结果表明,10nM以上的未经包被的CdSe量子点能够使钠通道的激活曲线向去极化的方向移动,但延长了钠通道的激活时程;同时它使钠通道的失活曲线向超极化的方向移动,并减慢了钠通道的复活,减少了可被利用的钠通道的数目。这些看似矛盾的结果提示了量子点毒性的复杂性和广泛性。
(3)量子点对麻醉Wistar大鼠海马DG区突触传递和突触可塑性的影响
由于细胞内钙和电压门控钠通道都跟突触传递和突触可塑性密切相关,我们继而在麻醉的wistar大鼠上,用在位场电位记录的方法,比较了两种不同类型的量子点(分别为未经包被的裸核CdSe量子点和包被良好的strep-CdSe/ZnS量子点)的急性暴露对海马DG区突触传递和突触可塑性的影响。结果发现,这两种量子点都能提高基本的突触传递,例如能提高基线的fEPSP的斜率和PS的幅度,增强输入/输出功能,但同时他们却能损伤短时程和长时程的突触可塑性,比如压抑双脉冲反应和长时程增强。并且这两种量子点在对突触传递和可塑性上的影响并无显著性差异。这些结果提示,如果考虑将量子点应用到生物研究或临床上时,必须考虑量子点的的毒性问题。
As a class of nanomaterials with unique optical and electrical properties,quantum dots(QDs) are now being widely applied in biology and medicine.However,the prevalence of these man-made nanomaterials increases the likelihood of exposure to environment and organism,which brings the potential following risks.In this paper, in a rat primary hippocampal culture model and the hippocampal DG area of Wistar rats,we explored the biocompatibility and biosafety of QDs and the underlying mechanisms using whole-cell patch clamp,calcium imaging,immunohistochemistry, western blotting,dendrite(spine) morphology and in vivo field potential recordings techniques.
Results:
(1) Effects of QDs on intracellular calcium homeostasis in primary cultured hippocampal neurons
We found that QDs could elevate internal calcium levels([Ca~(2+)]_i) for long in a dose-dependent manner.10 nM and above unmodified CdSe QDs could induce [Ca~(2+)]_i rise for at least 15 minutes.[Ca~(2+)]_i rise couldn't be totally blocked when calcium-free external solutions or pre-incubation of thapsigargin(used for depletion of calcium in calcium stores) were used.These indicate that external calcium could influx into the cell and internal calcium could be released from calcium stores under QD exposure.Furthermore,the external calcium was found to influx mainly through N-type calcium channels and voltage-gated sodium channels.Meantime,the internal source was more complex.Sodium ions influx through voltage-gated sodium channels could trigger mitochondrial sodium-calcium exchangers(MNCX),then,some calcium ions could be pumped out from the mitochondrion.These calcium ions and those from external further activated ryanodine receptors in endoplasmic reticulum(ER) followed by much more calcium release from ER,which might be the process known as calcium induced calcium release.Our results showed that QD might interfere with internal calcium homeostasis and the following risks should be noticed,otherwise, these effects should be considered when tracking receptors or proteins with QDs.
(2) Effects of QDs on voltage-gated sodium channels(VGSCs)
Given that VGSCs play a central role in QD-induced[Ca~(2+)]_i rise,we examined the effects of QDs on VGSCs employing the conventional whole-cell patch clamp.We explored the changes of the functional properties of activation,inactivation and recovery of sodium currents under QD insult for 24 hours.The results showed that 10 nM and above unmodified CdSe QDs could cause the curve of activation to a depolarized way,while they prolonged the activation course.Meantime,they shifted the curve of inactivation to a hyperpolarized direction,slowed the recovery of sodium channels and reduced the fraction of available sodium channels.These ambivalent results imply the diversity and complexity of QD toxicology.
(3) QDs enhance synaptie transmission but impair synaptic plasticity in the hippocampal dentate gyrus area of anethetized rats in vivo
Considering that both[Ca~(2+)]_i and VGSCs could interfere with synaptic transmission and plasticity,we then used in vivo field potential recordings to explore the effects of QDs(unmodified CdSe QDs and well modified strep-CdSe/ZnS QDs) on synaptic transmission and plasticity in the hippocampal DG area of anethetized rats.These results show that both of the two kinds of QDs could enhance the basal synaptic transmission,boosting the basal fEPSP slope and PS amplitude and the IO functions, while they could impair the short- and long-term potentiation,suppressing the paired-pulses reactions and Ion.g-term potentiation.And these two kinds of QDs showed comparative impairment on the synaptic transmission and plasticity.These results imply that we must eliminate or reduce QD in vivo toxicity before any further clinical use.
实验结果:
(1)量子点对原代培养海马神经元细胞内钙稳态的影响
我们发现,量子点能够浓度依赖的长时程提高细胞内钙水平。浓度在10nM以上未经包被的CdSe量子点能升高胞内钙水平长达15分钟以上。若用胞外无钙的胞外液和细胞内钙耗尽药物thapsigargin预处理细胞时,均不能完全阻断量子点引起的内钙浓度升高。这说明在量子点的暴露下,细胞内钙的升高既有细胞外钙的流入,也有细胞内钙库的钙释放。我们进一步用膜通道阻断剂验证,发现胞外钙的流入主要是通过N型钙通道和电压门控钠通道流入胞内的。而胞内的原因则更复杂一些。通过电压门控钠通道流入的同时还有一部分钠离子,它们可以激活线粒体上的MNCX,使一部分钙离子从线粒体里交换出来,这一部分钙离子和细胞外流入的钙离子可以进一步激活内质网上的ryanodine受体,使大量的钙离子从内质网里释放出来。这一过程可能就是熟知的钙诱导钙释放的过程。这些结果表明,量子点的应用可能会干扰到细胞的钙稳态,并带来相应的危害,同时,用量子点来标记蛋白受体时,也应考虑到其对内钙的影响。
(2)量子点对电压门控钠通道电生理特性的影响
既然在量子点引起的内钙升高当中,电压门控钠通道扮演了一个很重要的角色,于是,我们就用单细胞膜片钳技术检测了量子点对钠通道电生理特性的影响。当用不同浓度的量子点孵育细胞24小时后,我们观察了钠通道的激活,失活,复活等特性的变化。结果表明,10nM以上的未经包被的CdSe量子点能够使钠通道的激活曲线向去极化的方向移动,但延长了钠通道的激活时程;同时它使钠通道的失活曲线向超极化的方向移动,并减慢了钠通道的复活,减少了可被利用的钠通道的数目。这些看似矛盾的结果提示了量子点毒性的复杂性和广泛性。
(3)量子点对麻醉Wistar大鼠海马DG区突触传递和突触可塑性的影响
由于细胞内钙和电压门控钠通道都跟突触传递和突触可塑性密切相关,我们继而在麻醉的wistar大鼠上,用在位场电位记录的方法,比较了两种不同类型的量子点(分别为未经包被的裸核CdSe量子点和包被良好的strep-CdSe/ZnS量子点)的急性暴露对海马DG区突触传递和突触可塑性的影响。结果发现,这两种量子点都能提高基本的突触传递,例如能提高基线的fEPSP的斜率和PS的幅度,增强输入/输出功能,但同时他们却能损伤短时程和长时程的突触可塑性,比如压抑双脉冲反应和长时程增强。并且这两种量子点在对突触传递和可塑性上的影响并无显著性差异。这些结果提示,如果考虑将量子点应用到生物研究或临床上时,必须考虑量子点的的毒性问题。
As a class of nanomaterials with unique optical and electrical properties,quantum dots(QDs) are now being widely applied in biology and medicine.However,the prevalence of these man-made nanomaterials increases the likelihood of exposure to environment and organism,which brings the potential following risks.In this paper, in a rat primary hippocampal culture model and the hippocampal DG area of Wistar rats,we explored the biocompatibility and biosafety of QDs and the underlying mechanisms using whole-cell patch clamp,calcium imaging,immunohistochemistry, western blotting,dendrite(spine) morphology and in vivo field potential recordings techniques.
Results:
(1) Effects of QDs on intracellular calcium homeostasis in primary cultured hippocampal neurons
We found that QDs could elevate internal calcium levels([Ca~(2+)]_i) for long in a dose-dependent manner.10 nM and above unmodified CdSe QDs could induce [Ca~(2+)]_i rise for at least 15 minutes.[Ca~(2+)]_i rise couldn't be totally blocked when calcium-free external solutions or pre-incubation of thapsigargin(used for depletion of calcium in calcium stores) were used.These indicate that external calcium could influx into the cell and internal calcium could be released from calcium stores under QD exposure.Furthermore,the external calcium was found to influx mainly through N-type calcium channels and voltage-gated sodium channels.Meantime,the internal source was more complex.Sodium ions influx through voltage-gated sodium channels could trigger mitochondrial sodium-calcium exchangers(MNCX),then,some calcium ions could be pumped out from the mitochondrion.These calcium ions and those from external further activated ryanodine receptors in endoplasmic reticulum(ER) followed by much more calcium release from ER,which might be the process known as calcium induced calcium release.Our results showed that QD might interfere with internal calcium homeostasis and the following risks should be noticed,otherwise, these effects should be considered when tracking receptors or proteins with QDs.
(2) Effects of QDs on voltage-gated sodium channels(VGSCs)
Given that VGSCs play a central role in QD-induced[Ca~(2+)]_i rise,we examined the effects of QDs on VGSCs employing the conventional whole-cell patch clamp.We explored the changes of the functional properties of activation,inactivation and recovery of sodium currents under QD insult for 24 hours.The results showed that 10 nM and above unmodified CdSe QDs could cause the curve of activation to a depolarized way,while they prolonged the activation course.Meantime,they shifted the curve of inactivation to a hyperpolarized direction,slowed the recovery of sodium channels and reduced the fraction of available sodium channels.These ambivalent results imply the diversity and complexity of QD toxicology.
(3) QDs enhance synaptie transmission but impair synaptic plasticity in the hippocampal dentate gyrus area of anethetized rats in vivo
Considering that both[Ca~(2+)]_i and VGSCs could interfere with synaptic transmission and plasticity,we then used in vivo field potential recordings to explore the effects of QDs(unmodified CdSe QDs and well modified strep-CdSe/ZnS QDs) on synaptic transmission and plasticity in the hippocampal DG area of anethetized rats.These results show that both of the two kinds of QDs could enhance the basal synaptic transmission,boosting the basal fEPSP slope and PS amplitude and the IO functions, while they could impair the short- and long-term potentiation,suppressing the paired-pulses reactions and Ion.g-term potentiation.And these two kinds of QDs showed comparative impairment on the synaptic transmission and plasticity.These results imply that we must eliminate or reduce QD in vivo toxicity before any further clinical use.
引文
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