The neurotoxicity induced by engineered nanomaterials
Received 30 January 2019
Accepted for publication 9 April 2019
Published 6 June 2019 Volume 2019:14 Pages 4167—4186
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Linlin Sun
Dan Ge,1,2,* Qiqi Du,1,2,* Bingqing Ran,1,2 Xingyu Liu,1,2 Xin Wang,1,2 Xuehu Ma,1 Fang Cheng,1,3 Bingbing Sun1,2
1State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, People’s Republic of China; 2Department of Chemical Engineering, Dalian University of Technology, Dalian 116024, People’s Republic of China; 3Department of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, People’s Republic of China
*These authors contributed equally to this work
Abstract: Engineered nanomaterials (ENMs) have been widely used in various fields due to their novel physicochemical properties. However, the use of ENMs has led to an increased exposure in humans, and the safety of ENMs has attracted much attention. It is universally acknowledged that ENMs could enter the human body via different routes, eg, inhalation, skin contact, and intravenous injection. Studies have proven that ENMs can cross or bypass the blood–brain barrier and then access the central nervous system and cause neurotoxicity. Until now, diverse in vivo and in vitro models have been developed to evaluate the neurotoxicity of ENMs, and oxidative stress, inflammation, DNA damage, and cell death have been identified as being involved. However, due to various physicochemical properties of ENMs and diverse study models in existing studies, it remains challenging to establish the structure-activity relationship of nanomaterials in neurotoxicity. In this paper, we aimed to review current studies on ENM-induced neurotoxicity, with an emphasis on the molecular and cellular mechanisms involved. We hope to provide a rational material design strategy for ENMs when they are applied in biomedical or other engineering applications.
Keywords: engineered nanomaterials, neurotoxicity, oxidative stress, inflammation, DNA damage, cell death
Engineered nanomaterials (ENMs) exhibit extraordinary chemical, biological, optical, mechanical, and magnetic properties due to their small size and large surface-to-volume ratio. Until now, ENMs have been successfully applied not only in traditional manufacturing, eg, catalysis, energy, electronics, and personal care products, but also in emerging biomedical fields, eg, imaging, diagnosis, drug delivery, and cancer immunology.1 With the extensive application of ENMs, their safety has raised wide public attention. In the process of ENM production, processing, transportation, usage, and disposal, people are obviously exposed to ENMs via several different routes including skin contact, inhalation, ingestion, and systemic administration.2,3 After exposure, ENMs can be distributed to various organs, eg, heart, liver, spleen, lungs, and kidneys.4–7 More importantly, more and more studies have demonstrated that ENMs could cross the blood–brain barrier (BBB) and further access the central nervous system (CNS), where ENMs could cause neurotoxicity.5,8–13
The BBB is a dynamic barrier separating blood and the CNS with the function of restricting the material exchanges between the blood and brain, and helping to maintain the homeostasis of the brain.14,15 With special physicochemical properties, ENMs could pass through BBB via different routes, eg, receptor-mediated transcytosis, adsorptive-mediated transcytosis, transcellular diffusion, paracellular diffusion, and cell-mediated transcytosis after incidental exposure or systemic administration.10,16,17 After crossing BBB, ENMs can interact with glial cells and neurons, which could potentially induce a series of disrupted outcomes in the neurological system.12 Current studies have demonstrated that the physicochemical properties of ENMs, eg, chemical composition,18 size,19 shape,20 surface coating,21 charge,22,23 and aggregation state,24 can affect their neurotoxicity in several in vivo study models, eg, zebra fish, rats, and mice (Table 1) and in various cell types, eg, microvascular endothelial cells, glial cells, and neurons (Table 2).12,25 However, ENM-induced neurotoxicity is not well understood owing to the diverse physicochemical properties of ENMs, and the complicated regulating signaling pathways in organisms.
Table 1 Mechanisms of ENM-induced neurotoxicity in vivo
Table 2 Mechanisms of ENM-induced neurotoxicity in vitro
Table 3 Assays for DNA damage and corresponding results
In this paper, we aimed to review the neurotoxicity of ENMs in different study models. We focused on potential mechanisms of ENM-induced toxicity in different neurological systems. With these information, we hope to provide more knowledge for the establishment of structure-activity relationships (SARs) and safer design of ENMs.
How could ENMs access the CNS?
ENMs could access the blood or lymph nodes, and then translocate to different organs including lungs, liver, kidneys, heart, and even the brain which is well-protected by the BBB. It has been found that ENMs could be deposited in different regions of the brain, including olfactory bulb, hippocampus, cerebral cortex, and striatum.26,27
It was found that ENMs with specific characteristics could pass through the BBB via several different ways (Figure 1). 1) Transcellular diffusion. Solid lipid nanoparticles (NPs) with low molecular weight could pass through the BBB in this way.28 2) Paracellular diffusion. Silica NPs and reduced graphene oxide (rGO) could open paracellular spaces and access the CNS.29,30 3) Receptor-mediated transcytosis. ENMs with ligands such as transferrin, insulin, ANG, and ApoE, could be recognized by corresponding receptors on endothelial cells' surface and then cross the BBB through transcytosis. ANG conjugated carbon nanotubes could pass through BBB efficiently, probably with the help of LRP1 which is located on the brain capillary endothelium.31 4) Adsorptive-mediated transcytosis. Cationic albumin-conjugated pegylated NPs could deliver hTRAIL-encoding plasmid (pORF-hTRAIL) into the CNS through adsorptive transcytosis after intravenous administration.32 Lactoferrin-modified cationic dendrimer-based NPs could be promoted to cross BBB through both receptor- and adsorptive-mediated transcytosis.33 5) Cell-mediated transcytosis. Macrophages could phagocytize ENMs in the blood, pass through BBB, and then release ENMs into the CNS.
In addition to transpassing the BBB directly through blood circulation, studies have indicated that ENMs could translocate to the olfactory bulb of the brain through the olfactory nerve or into the CNS via the trigeminal nerve when they are inhaled or intranasally instilled.34–37 Neurons could also transport ENMs by retrograde and anterograde movement in axons and dendrites as well as perineural translocation.36 Additionally, particles can be found in the brain of offspring when animals are exposed to ENMs. For example, both 70 nm silica (SiO2) and 35 nm titanium dioxide (TiO2) particles were found in the placenta, brain, and liver of offspring when the particles were injected into pregnant mice intravenously, suggesting ENMs could cross the placenta barrier in pregnant mice and further cause damage to offspring.38
Additionally, ENMs that have been applied in medical devices could have opportunities to interact directly with glial cells or neurons and cause neurotoxicity. For example, carbon nanofibers were considered to be a potential material in neuronal implants.39 Gold (Au) NPs and silica-poly (ε-caprolactone) (Si-PCL/ICG) NPs were proposed to be used for laser-assisted tissue soldering in the brain, eg, cerebral bypass surgery.40 Nano-electromechanical systems in the brain, eg, implantable silicon-based micro-electrodes, are used in supervising and diagnoses.41–43 Once these implants that are coated with ENMs are worn, potential toxicity may be inevitable.
Mechanisms of neurotoxicity induced by ENMs
Oxidative stress is commonly caused by over-production of ROS with disturbance of redox homeostasis.44 The brain is especially vulnerable to oxidative stress due to the large amount of oxygen consumption, abundance of lipids and proteins, and low antioxidant defense activity.45 ROS are usually produced at an early stage when cells interact with ENMs and oxidative stress is regarded as one of the main mechanisms of neurotoxicity induced by ENMs.46–48 Thus far, ROS production through different sources have been documented (Figure 2).
Oxidative burst in microglia
It usually happens when microglia are activated by foreign stimuli. During this process, a large amount of superoxide anion (O2.−) is released through NADPH-oxidase mediated molecular oxygen (O2) catalysis. O2.− could be further transformed to other forms of ROS, eg, hydrogen peroxide (H2O2), hydroxyl radicals (OH.), and peroxynitrites. Phenrat et al48 found that when microglia were exposed to TiO2 NPs (Degussa P25), there was immediate (<5 minutes) concentration-dependent intracellular H2O2 production through oxidative burst. The particle size, aggregation state, surface coating, and sedimentation could influence the interaction between ENMs and cells that further affect oxidative burst-mediated ROS production. A study has demonstrated that large zero-valent iron (ZVI) NPs could agglomerate into micron-size particles and induce oxidative burst in BV-2 cells.24
Mitochondria are a main source of ROS as a result of the electron transport chain (ETC) through which adenosine triphosphate (ATP) is generated. Mitochondrial disruption will lead to significant increase of ROS. Long et al48,49 showed the existence of O2.- in mitochondria of BV-2 cells after TiO2 (Degussa P25) exposure. Sharma et al50 showed that ZnO NPs possibly induced mitochondrial ROS, which led to mitochondrial dysfunction, eg, decreased MMP and release of cytochrome C, and further induced microglial death. In addition, Yin et al51 demonstrated that after exposure to silver (Ag) NPs, elevated calcium ions (Ca2+) influx could cause oxidative stress by promoting mitochondrial depolarization in rat cerebellar granule cells.
Transition metals, eg, iron, copper, chromium, and cobalt, could mediate the formation of ROS, eg, highly reactive hydroxyl radical (OH.), through Fenton reaction. Phenrat et al showed that ZVI NPs could act as electron donors and produce ROS through Fenton reaction in microglia. They also showed that iron oxide NPs (IONPs) could induce Fenton reaction by oxidizing ferrous iron to ferric iron, which contributed to the oxidative stress in astrocytes.24,52
Enzyme-like activities of ENMs
It was demonstrated that when human glioma U251 cells were exposed to dimercaptosuccinic acid-coated Fe3O4 and γ-Fe2O3 together with H2O2, both two types of NPs could localize in lysosomes and behave as peroxidase and catalyze H2O2 into OH., which could further induce cytotoxicity.53 On the contrary, GO quantum dots (QDs) showed catalase-like activity and decreased MPP+-induced ROS generation in PC12 cells.54
Lysosome membrane permeabilization (LMP)
LMP is a known form of lysosome dysfunction and suggested as an indirect source of ROS. Firstly, LMP could produce ROS through lysosomal ferrous iron. Secondly, LMP could lead to mitochondrial membrane permeabilization and production of mitochondrial ROS by releasing proteases, eg, cathepsin B/D inside lysosomes.55 Yang et al56 found that when RAW264.7 macrophages were exposed to carbon nanohorn, LMP could be induced, which further led to the production of mitochondrial ROS.
However, it still remains unclear that how ENMs with different physicochemical properties could affect ROS generation via the previously mentioned mechanisms. Thus, more detailed studies are needed.
With the induction of oxidative stress, the subsequent consequences have been investigated. Firstly, oxidative stress is prone to enhancing the permeability of the BBB. Liu et al showed that, when brain microvessel endothelial cells (BMECs) were exposed to silica NPs, ROS were induced and considered as the mediators in increasing BBB permeability by down-regulating the tight junction proteins, eg, CLDN5 and OCLN, and further causing microtubule destabilization and triggering inflammatory response. By using N-acetyl cysteine, an antioxidant agent, ROS-induced BBB permeability was significantly inhibited.30 Furthermore, ENM-induced ROS in microglia may damage surrounding neurons.27,49,57,58 The study by Hsiao et al showed that BV-2 could produce large amounts of H2O2 after nano TiO2 exposure. Co-culture of N2a neuroblastoma cells and BV-2 cells showed that N2a cells were significantly damaged when BV-2 cells were in direct contact with nano TiO2. In contrast, direct exposure to nano-TiO2 did not reduce the viability of N2a cells.57 Another study by Long et al found that Degussa P25 induced the release of ROS and apoptosis in BV-2 microglia, but did not affect the cell viability of isolated rat dopaminergic neurons (N27). However, P25 caused neuronal loss of embryonic rat striatum containing both microglia and dopaminergic neurons, indicating the influence of microglia-generated ROS on neurons.49
Inflammation is a protective response in the body with the function of eliminating xenobiotic stimuli and repairing damaged tissue.59 Neuroinflammation can be induced directly after ENMs get into the brain. It mainly occurs in microglia, the resident macrophages in the brain (Figure 3). Microglia are immune-competent cells, which usually remain quiescent and will respond to the destruction of brain homeostasis and entry of environmental toxins.11 Upon ENM exposure, microglia could be activated and change their morphology from ramified to rounded macrophage-like ones and further produce pro-inflammatory cytokines, eg, interleukins, tumour necrosis factor protein families, and chemokines.60,61 Knudsen et al found that cationic PEGylated micelles and cationic liposomes could induce the focal filtration of phagocytes and activate microglia and astrocytes in the brain after an intracerebroventricular particle injection.22
ENMs, as a kind of stimuli, can provoke TLRs, eg, TLR2 and TLR4, of microglia that reside on the cell membrane. It was reported that nano-TiO2 could induce TLR2 and TLR4 activation in the hippocampus after oral administration. The response of TLRs could further induce the activation of NF-κB through negatively regulating nucleic inhibitor of NF-κB (IκB) kinase and caused subsequent hippocampal inflammation in mice.62 Hutter et al63 showed that poly(ethylene glycol)-coated urchin/rod but not sphere Au NPs could upregulate TLR2 expression of microglia, suggesting effects of geometries on the activation of TLRs. However, detailed mechanistic studies are needed to elucidate the exact role of TLRs in neuroinflammation after ENM exposure.
NLRP3 inflammasome belongs to the NLR family, and is a multiprotein complex that could respond to exogenous stimuli. NLRP3 inflammasome could be directly activated by ENMs, and modulate the release of pro-inflammatory cytokines, eg, IL-1β.64 Moquin et al65 showed that lipopolysaccharides-QDs (LPS-QDs) could potentially induce mitochondrial ROS and lead to lysosome rupture, followed by NLRP3 inflammasome activation and cleavage of IL-1β in microglia. In addition, the uptake of large LPS-QDs contributed to the rupture of lysosomes. As many studies have already shown, ENMs could be taken up by microglia through macropinocytosis, phagocytosis, and clathrin-mediated endocytosis, and then translocate to lysosomes through endo-lysosome pathway for the activation of NLRP3 inflammasome.57,66,67
Neuroinflammation occurs not only in immune cells,64 eg, microglia68,69 in the brain, but also in microvascular endothelial cells,19,70,71 astrocytes,57 and neurons.57 When encountering ENMs, common in vitro BBB models, BMECs or co-culture of BMECs and astrocytes/pericytes could produce pro-inflammatory cytokines. Trickler et al71-73 found that CuO NPs and Ag NPs induced an increase of pro-inflammatory mediators IL-1β, TNF-α, and PGE2 in rat BMECs and porcine BMECs, which affected the integrity of the BBB. ENM-induced pro-inflammatory cytokines and chemokines in BMECs could recruit immune cells in the blood and also promote the expression of CAMs, eg, E-selectin and ICAM-1, to facilitate the adhesion and transmigration of leukocytes through the BBB.30,74 In addition, there was an immuno-regulatory loop between BMECs and astrocytes after exposure of ENMs.74 In short, astrocytes could integrate the paracrine inflammatory signals from BMECs, amplify them, and then return them to BMECs, thereby contributing to the destruction of the BBB.30,75
ENM exposure could induce DNA damage that could potentially lead to carcinogenesis or even impact offspring (Figure 4).76 Thus far, different types of DNA damage have been identified, including DNA cross-links, single/double strand breaks, and DNA adducts (Table 3).77
Studies have found that ENMs could induce DNA damage in two different ways, ie, primary DNA damage and secondary DNA damage. The former refers to the fact that ENMs could enter the cells and subsequently the nuclei, and further directly interact with DNA or DNA-related proteins.78 For example, Ren et al79 showed that GO sheet could translocate into cell nuclei of diencephalon in zebra fish larvae brain from water. Even if ENMs could not penetrate the nucleus, there still remains the opportunity that they could affect DNA in the process of mitosis. As to secondary DNA damage, it usually refers to the impact induced by ROS and inflammation. Shah et al80 showed that nano-alumina could induce oxidative DNA damage in both in vitro models, ie, mouse hippocampal HT22 cells and human neuroblastoma SHSY5Y cells, and in vivo model, ie, brain of mouse models. Valdiglesias et al81 showed that ZnO NPs could induce oxidative DNA damage and H2AX phosphorylation representing DNA double strand breaks in human SHSY5Y cells. El-Ghor et al82 found that nano-TiO2 induced both chromosomal damage and DNA damage in brain tissue due to ROS. In addition, Hawkins et al83 found that cobalt and chromium (CoCr) NPs triggered release of IL-6 in a placental barrier model, and IL-6 led to DNA double strand breaks in differentiating neural progenitor cells.
In addition, studies have demonstrated that DNA damage could lead to cell cycle arrest to provide enough time for DNA repair, while inefficient DNA repair could induce apoptosis.84 Kang et al85 found that GO and rGO exposure could lead to two or more nuclei in PC12 cells and G0/G1 cell cycle arrest, further leading to apoptosis. Valdiglesias et al86 found that TiO2 NPs induced micronuclei together with DNA strand breaks in SHSY5Y cells, and further, apoptosis was induced.
ENM induces differential cell death
Studies have suggested that different types of cell death are involved in the neurotoxicity of ENMs, such as apoptosis, necrosis, and autophagy (Figure 5).
Apoptosis and necrosis
Apoptosis is programmed cell death with the function of eliminating damaged cells and further maintaining the organism's homeostasis. It is the most common cell death found in ENM-induced neurotoxicity with the characteristics of cell shrinkage, nuclear condensation, and fragments.87,88 In general, apoptosis can be induced by mitochondrial dysfunction (intrinsic pathway), death receptor (extrinsic pathway), and endoplasmic reticulum (ER) stress. Different caspases, eg, CASP8, 9, 3, are the primary molecular signals of apoptosis.
The underlying mechanisms of ENM-induced intrinsic apoptosis have been widely studied. MAPK molecules including p38 MAPK, JNK, and ERK are usually associated with intrinsic apoptosis.89 In addition, P53 can be activated by ROS and DNA damage which may lead to apoptosis by inducing the transcription of pro-apoptotic genes like Bax. Xu et al72 found that Ag NPs induced apoptosis through activating MAPK pathway, reducing anti-apoptotic Bcl-2 expression, and altering activity of mTOR in primary astrocytes. Wang et al90 showed that ZnO NPs induced phosphorylation of JNK, ERK, and p38 MAPK in astrocytes, and that JNK played the major role in apoptosis. Wu et al91 discovered that P53 promoted apoptosis together with JNK pathway in PC12 cells while they were treated with TiO2 NPs. Zhao et al92 found that ZnO NPs could lead to apoptosis in zebra fish embryos characterized by reduction in the Bcl-2/Bax ratio, decrease of MMP, release of cytochrome C, and activation of CASP9 and 3. In addition, Hadrup et al93 showed that Ag NPs could induce both extrinsic and intrinsic apoptosis in PC12 cells based on the activation of CASP8 and 9. Another study also found that ZnO NPs induced the phosphorylation of ERK and p38, which further activated CASP9 and 8 respectively, and then apoptosis was induced.50
The ER is responsible for the synthesis, processing, and trafficking of protein, and the regulation of Ca2+. ER stress could be induced by the change of Ca2+ homeostasis and misfolded proteins.94 Ducray et al95 found that two types of silica NPs, ICG/polycaprolactone (PCL)-rhodamine-doped NPs and Si-ICG/polycaprolactone-polylactic acid-rhodamine-doped NPs could be taken up by microglia and translocate in the ER when they were exposed to hippocampal slice cultures. This could cause a potential risk of inducing protein misfolding. Parveen et al96 demonstrated that silica NPs could induce ER stress in the corpus striatum of young male Wistar rats. They showed significantly increased ER stress markers including CHOP, also known as GADD153, and CASP12, and further, Bax/Bcl-2 homeostasis was disrupted and apoptosis was induced.
In contrast, necrosis is caspase-independent with the characteristics of cytoplasmic swelling, expansion of organelles, and rupture of cell membrane. It further causes the outflow of intracellular content and induces inflammatory response.97 Zhang et al98 found that both necrosis and apoptosis were induced in the hippocampal cells in ICR mice when nano-alumina NPs were intranasally injected. More necrotic than apoptotic cell death was observed in hippocampal cells, and necrosis was further considered as a type of primary cell death contributing to the neurobehavioral defects in ICR mice.
Current studies have demonstrated that necrosis is not as common as apoptosis in the neurotoxicity induced by ENMs, however, more studies are needed to clarify the effects of necrosis induced by ENMs and the underlying mechanisms.
Autophagy is an intracellular mechanism for the degradation and reuse of cellular components, elimination of aberrant materials, and maintaining cellular homeostasis.55 Autophagy occurs when ENMs get into endosomes in cells and form double-membrane autophagosomes, which fuse with lysosomes to produce autolysosomes for the degradation of ENMs.
Xue et al99 demonstrated that TiO2 NPs and oleic acid-coated IONPs could induce autophagy in human cerebral endothelial cells, which may involve oxidative stress and aggregations of ENMs. Xie et al100 found that SiO2 NPs induced autophagy in PC12 cells with elevated LC3-II and BECN1 levels. Further more, a mechanistic study showed that the autophagy was induced by inhibiting PI3K-protein kinase-B (Akt)-mTOR pathway. In addition, Wang et al101 showed that cationic polyamidoamine (PAMAM) dendrimers could induce autophagy via Akt-mTOR pathway in human gloma cell lines.
Studies have demonstrated that autophagy plays both protective and detrimental roles in ENM-induced cytotoxicity. Wei et al102 showed that ZnO NPs induced mitophagy, a form of autophagy which degrades dysfunctional mitochondria in BV-2 cells. They proved that mitophagy played a protective role in ENM-induced cytotoxicity. Hu et al103 suggested that when zebra fish were exposed to GO, autophagy in the offspring played an important role in clearing α-synuclein and damaged ER. However, ENM-induced autophagy could also lead to toxicity.104 Zhou et al105 found that TiO2 NPs could induce excessive autophagy in offspring of mice after prenatal exposure, based on the findings that there were significant increases of PI3K3C, BECN1, c-Jun, p-JNK, and microtubule-associated protein 1A/1B-light chain 3 (LC3), which led to the inhibition of dendritic outgrowth of hippocampal neurons. Wang et al101 found that cationic PAMAM dendrimers induced autophagic flux in human gloma cell lines, which was suggested as the main source of their cytotoxicity. In addition, Li et al106 also showed that the inhibition of PAMAM dendrimers-induced autophagy could improve the viability of SHSY-5Y cells.
We have comprehensively reviewed ENM-induced oxidative stress, inflammation, DNA damage, and cell death, all of which are considered as potential mechanisms of neurotoxicity. These mechanisms may work independently or they could interact with each other. For example, oxidative stress, as one of the most common mechanisms, is considered to trigger inflammation, DNA damage, apoptosis, and autophagy in some cases. DNA damage could also result in apoptosis. In addition, different types of cell death may share the same characteristics. For example, ATP depletion, ROS increase, and MMP decrease are associated with both apoptosis and necrosis. However, the specific roles of these mechanisms and their relationship with ENM-induced neurotoxicity remain elusive. Deeper exploration of the underlying mechanisms requires more efforts, and effective methodologies are required to establish a complete neurotoxicity evaluation system. More importantly, it is critical to establish SARs between ENMs and their biological effects. However, we still face the dilemma of lack of enough experimental data and sufficient knowledge about the interaction of nanomaterials and the biological system.107–109 In addition, the neurotoxicity evaluations are mostly focused on inorganic nanomaterials, eg, metallic nanomaterials and carbon-based nanomaterials, and the studies on organic nanomaterials, eg, polymeric NPs and liposomes are limited.110–112 Thus, more detailed studies are warranted for a better understanding of the interaction of ENMs with neurological systems for safer and effective applications of ENMs.
This work was supported by the National Natural Science Foundation of China (31870919, 31300809, and 21773022), Natural Science Foundation of Liaoning Province (20180550597), LiaoNing Revitalization Talents Program (XLYC1807113) and Fundamental Research Funds for the Central Universities (DUT17RC(3)021). Bingbing Sun would also like to thank the Recruitment Program of Global Youth Experts for support.
The authors report no conflicts of interest in this work.
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