The neurotoxicity induced by engineered nanomaterials

Figures & data

Table 1 Mechanisms of ENM-induced neurotoxicity in vivo

Exposure	NP type	NP properties	Model	Mechanisms	Results	Reference
IV	Iron oxide	10 nm	Adult male wild-type SD rats	Oxidative stress	Brain vasculature damage; a significant decrease in striatal dopamine and its metabolites	^Citation113
IV	Single-walled CNTs	Diameter: around 1.0 nm; length: around 1.38 µm	Male Kunming mice	Oxidative stress; oxidative stress-induced inflammation; NF-κB accumulation; enhanced release of pro-inflammatory mediators TNF-α and IL-1β; mitochondrial perturbation; apoptosis	Cognitive deficits and decreased locomotor activity; functional and pathological lesions in the mouse brains	^Citation114
Oral	Silver	Small-sized Ag NPs (22, 42, and 71 nm) and large-sized Ag NPs (323 nm)	ICR mice, male and female	Inflammation; small-sized Ag NPs induced increased B cell distribution and TGF-β levels in serum; IL-1, IL-6, IL-4, IL-10, IL-12, and TGF-β levels were increased in a dose-dependent manner	Size-dependent uptake of Ag NPs (NPs were distributed to the organs including brain, lung, liver, kidneys, and testes)	^Citation115
Oral	Titanium dioxide	5 nm	SD rats	Significant oxidative damage to nucleic acids and lipids in the offspring's brain	Induced depressive-like behaviors in adulthood	^Citation116
Oral	Titanium dioxide	Anatase structure; hydrodynamic diameter: 208–330 nm; positive potential	ICR female mice	Increased expression of TLR2 and TLR4; inflammation; necrosis; shrinkage of cell volume; nuclear irregularity and cellular degeneration; over-proliferation of all glial cells	Significant reductions in body weight; accumulation of titanium in the hippocampus; necrosis and abscission of perikaryon; impaired spatial recognition memory	^Citation62
IN	Silica	Average particle size: 80 nm; not uniform; near spherical	Young male rats of Wistar strain	Oxidative stress; activated p53 signal transduction pathway; morphological changes in mitochondria and ER; apoptotic neuronal cell death	Neuromuscular coordination and spontaneous locomotor activity altered; changes in biochemical, neurochemical, and ultrastructural profiles in CS region of rat brain	^Citation96
IN	Silica	15 nm (primary size); 156 nm in physiological saline; 92 nm in DMEM cell culture medium	SD adult rats	Oxidative stress in striatum; high TNF-α and IL-1β levels and significant reduction of DA activity in the striatum	Deposition in the striatum. No disorders in general behavior after 1 and 7 days' instillation	^Citation27
IN	Silver	Spherical; 22.8–25.9 nm in culture medium; negative zeta potential	Neonatal SD rats	Apoptosis	Obvious alterations in the morphology of granular layer; dose-related elevation of silver levels in cerebellum	^Citation51
IN	Titanium dioxide	Rutile-phase; needle-like or short rod-like;	CD-1 mice, female	Rutile TiO2 NPs caused morphological changes to the neurons and disturbed monoamine neurotransmitter levels in the sub-brain regions	Accumulated TiO2 NPs in the brain. No mortality or obvious health disturbances in mice	^Citation26
IP	Silica	Spherical, 20±6.34 nm	SD rats	Opened BBB paracellular spaces; oxidative stress and astrocyte activation in the brain	BBB permeability elevated; systemic inflammation	^Citation30
IP	Aluminum oxide	Oval shape; various sizes ranging from 30–60 nm	ICR female mice	Oxidative stress; production and aggregation of Aβ; disturbance of brain energy metabolism (reduction of AMPK)	Aluminum accumulation in brain; impairment of hippocampus-dependent memory; AD neuropathology; impaired spatial learning and memory deficit	^Citation80
IP	Titanium dioxide	<100 nm; average crystallite size: 44 nm	Male Swiss Webster mice	Oxidative stress; oxidative DNA damage and chromosomal damage; mutations in p53	Nano-TiO2 accumulation selectively; dose-dependent toxicity	^Citation82
	Titanium dioxide	Primary particle sizes: 33.4±1.9 nm; hydrodynamic size in water: 149.4±1.3 nm	Larval zebra fish	Loss of DA; increased gene expression related to Lewy bodies	Cell death in hypothalamus; no significant increases in mortality; induced PD-like symptoms; decreased hatching time of zebra fish; disturbed locomotive activity; increased malformation rate	^Citation117
	GO	With a sheet thickness of 1.02±0.15 nm; lateral lengths: ranged from approximately 0.5 μm to several microns	Larval zebra fish	Oxidative stress; structural and morphological damage to the mitochondria; loss of DA neurons; CASP8-associated apoptosis; β-galactosidase-associated senescence; metabolic disturbance; the promotion of Lewy bodies (α-synuclein and ubiquitin)	Tail flexure and spinal curvature; PD-like symptoms; disturbance of locomotive activity	^Citation79
	Zinc oxide	Spherical or short-rod shaped; average size of the aggregates: 30–60 nm	Zebra fish embryos	Oxidative stress; upregulation of p53; reduction in the Bcl-2/Bax ratio; reduction in MMP; release of cytochrome C; activation of CASP9 and 3; apoptosis; DNA oxidative damage	Reduced rate of embryo hatching; significantly higher heart rates when the dose was 120 mg/L	^Citation92
	Iron oxide	Coated with cross-linked aminated dextran	Zebra fish	Apoptosis; enhanced mRNA levels of CASP8, 9, and jun genes	Decreased AChE activity; reduction in the exploratory performance; significantly higher level of ferric iron in the brain	^Citation118
	Fullerenes	Uncoated; 99.5% pure; stable 30–100 nm aggregates	Largemouth bass	Significant lipid peroxidation in the brain; oxidative stress	Toxicity was not obvious	^Citation119

Abbreviations: ENM, engineered nanomaterial; IV, intravenous; IP, intraperitoneal; IN, intranasal; CNTs, carbon nanotubes; NP, nanoparticle; ER, endoplasmic reticulum; BBB, blood–brain barrier; SD, Spraguee Dawley; CS, corpus striatum; PD, Parkinson’s disease; AD, Alzheimer’s disease; DA, dopaminergic; AChE, acetylcholine esterase. AMPK, adenosine 5'-monophosphate activated protein kinase; ICR, institute of cancer research; DA, dopamine; GO, graphene oxide; Aβ, amyloid beta; MMP, mitochondrial membrane potential.

Table 2 Mechanisms of ENM-induced neurotoxicity in vitro

Model	NP type	NP properties	Cell type	Mechanisms	Results	Reference
BBB	Copper oxide	40 and 60 nm; strong aggregation	rBMECs	Increased levels of pro-inflammatory cytokines like PGE2, TNF-α, and IL-1β were associated with rBMEC permeability	Induced proliferation at low concentration but cytotoxitity at high concentration; enhanced barrier permeability	^Citation71
	Iron oxide	8 nm core; uncoated and oleic acid-coated	HCECs	For oleic acid-coated USPIO, poor internalization, a significantly decreased DNA synthesis and increased ROS was found. For uncoated USPIO, rapid deposition on the cell surface and a significant decrease in thiol levels. Significant DNA damage. Autophagy and lysosomal activation	Oleic acid-coated USPIO had higher cytotoxicity than the uncoated	^Citation99
	Silica	25 and 50 nm; fluorescent	HCECs	A significant decrease in DNA synthesis and a slight increase in ROS was found; 50 nm silica induced autophagy	50 nm silica had higher cytotoxicity	^Citation99
	Silica	Spherical, 20±6.34 nm	hBMEC/astrocytes	Oxidative stress and Rho/ROCK mediated pathway; microtubule destabilization; inflammation	BBB disruption	^Citation30
	Silver	25, 40, and 80 nm	rBMECs	Secretion of pro-inflammatory mediators(TNF-α, IL-1β, and PGE2)	Cytotoxicity and morphological changes of monolayer perforations; Increased rBMEC permeability; 25 nm has the biggest effect among 25, 40, and 80 nm nano-silver	^Citation19
	Silver	8 nm	bEnd.3 and ALT cells	Different toxic potency of Ag ions and Ag NPs. Ag NPs induced production of ROS	Damage of BBB integrity	^Citation70
	Titanium dioxide	21 nm core	HCECs	Increased ROS; a slight decrease in DNA synthesis and significant DNA damage	Significant cytotoxicity was induced	^Citation99
	Titanium dioxide	25.2 nm	Rat primary BECs+glial cells	Intense inflammatory response; a modulation of BBB functioning and repercussions on ABC transporter activities of glial cells	Accumulation of TiO2 NPs and dysfunction of BBB	^Citation74
	Titanium dioxide	6 nm, 35 nm	bEnd.3 and ALT cells	Production of cytokine secretion (IL-4, IL-12, IL-13, IFN-γ, and TNF-α)	Damage of BBB integrity	^Citation70
Glial cells	Copper oxide	Diameter: 5 nm; dimercaptosuccinate-coated	Primary brain astrocytes	Intracellular liberation of copper ions from CuO-NPs; oxidative stress	Time-, concentration- and temperature-dependent accumulation of NPs; decreased cell viability	^Citation120
	Silica	150–200 nm; sphercal; different mass/volume	Primary rat microglial cells	Increased intracellular ROS and RNS; decreased TNF-α gene expression and increased pro-inflammatory genes' expression; detectable level of IL-1β.	Alteration of microglia functions	^Citation69
	Silver	3–5 nm; negative potential	ALT cells; BV-2 cells	Significant IL-1β secretion was induced in BV-2; induced gene expression of CXCL13 and GSS for inflammatory response and oxidative stress	Decreased cell proliferation of ALT but not BV-2	^Citation121
	Titanium dioxide	A mixture of the anatase (70%) and rutile (30%) forms; ~330 nm in media; positive surface charge	BV-2 cells	Oxidative stress, apoptosis, mitochondrial dysfunction, and inflammation (NF-κB) were induced	Time- and dose-dependent cytotoxicity was found	^Citation49
	Titanium dioxide	50 nm	C6 cells; U373 cells	Oxidative stress; morphological changes and damage of mitochondria; reduction in MMP	Cytotoxicity	^Citation122
	Titanium dioxide	P25, 3:1 mixture of anatase and rutile, 21 n; anatase, spherical, 50 nm; rutile, rod-like, 50 nm	Primary rat cortical astrocytes	Increased ROS generation and decrease in MMP	Mitochondrial damage and morphology changes; dose-dependent cytotoxicity; anatase crystalline phase was more toxic than rutile	^Citation123
	Titanium dioxide	Anatase (96%) and rutile (4%), 40–200 nm	C6 cells; U373 cells	Inhibitation of cell proliferation; induction of apoptotic death; depolymerization of Factin	Dose-related cytotoxicity; morphological changes	^Citation88
	Titanium dioxide	Anatase isoform; 15 nm	D384 cells; SHSY5Y cells	Alterations of the mitochondrial function; cell membrane damage	Dose- and time-dependent alterations of the mitochondrial function; SHSY5Y was more sensitive compared to D384	^Citation124
	Zinc oxide	45 nm, rod-shaped with smooth surfaces	Primary rat astrocytes	JNK pathway was involved in ROS-induced apoptosis in primary astrocytes; mitochondrial dysfuction was found	Significant cytotoxcity; cellular morphological modification	^Citation90
	Zinc oxide	38.52 nm	N9 cells	Altered intracellular calcium level, mitochondrial ROS, MAP kinases, cytochrome C, as well as CASP9 and 3; ATP depletion played a major role	Dose-and time-dependent toxicity	^Citation50
	Zinc oxide	Hexagonal prism-shaped; 50 nm	BV-2 cells	Oxidative stress; autophagy; PINK1/parkin-mediated mitophagy	Decreased cell viability	^Citation102
Neuron	Aluminum oxide	Oval shape; 30–60 nm	SHSY5Y cells; HT22 cells	Oxidative stress; DNA damage; activation of CASP3/7	Decreased cell viability; efficient internalization	^Citation80
	Copper	15–30 nm; weight fraction of Cu, CuO, and Cu2O: 85.93%, 8.99%, and 5.08%	PC12 cells	Increased ROS; significant apoptosis	Concentration- and time- dependent cytotoxicity	^Citation125
	Graphene and SWCNTs	Graphene diameter: 100–110 nm; thickness: 3–5 nm. SWCNTs: diameter: 0.8–1.2 nm	PC12 cells	Concentration- and time-dependent ROS generation; apoptosis; increased LDH release; changed cell morphology	Concentration- and shape-dependent cytotoxicity; LDH levels were significantly higher for SWCNT than graphene	^Citation126
	GO	GO layer: thickness 0.6 nm, with sags and crests on the surface; rGO layer: thickness 0.9 nm, more fluent surface than GO	PC12 cells	Apoptosis and cell cycle arrest maybe due to ERK pathway regulation	Dose- and time-dependent cytotoxicity; GO was more toxic than rGO	^Citation85
	Iron oxide	A core size of 10 and 30 nm with a diameter of 8–10 nm surface coating; spherical	SHSY5Y cells	Activation of c-Abl (a pro-death compound), a molecular switch induced by oxidative stress; increased expression of neuronal α-synuclein (protein dysfunction); oxidative stress; mitochondrial integrity was affected; apoptosis	10 nm NPs had higher cytotoxicity than 30 nm ones	^Citation113
	Manganese	40 nm	PC12 cells	Oxidative stress	Nanoscale manganese can deplete DA, DOPAC, and HVA in a dose-dependent manner	^Citation127
	PAMAM dendrimers	5–6 nm; positive potential in water and negtive potential in media	PC12 cells; SHSY5Y cells	Increased ROS and autophagy flux	Cytotoxicity	^Citation106
	Silica	25±4 nm by TEM; 95.8±9.7 nm in suspended DMEM containing 10% FBS	PC12 cells	Aggregation of α-synuclein; impairment of UPS; autophagy	Cytotoxicity	^Citation100
	Silica	12.1 nm	SK-N-SH cells; N2a cells	Apoptosis and ROS release; morphological changes	Concentration-dependent cytotoxicity	^Citation128
	Silver	14 nm, spherical	PC12 cells	Apoptosis	Dose-dependent cytotoxicity. AgAc had higher cytotoxicity than nano-Ag, and there were silimar neurotoxic effects between two forms of silver	^Citation93
	Silver	10 nm or 75 nm, PVP or citrate coated	N27 cells	PVP-Ag increased intra-neuronal nitrite, activated ARE/NRF2, and CASP3/7; 75-nm PVP-Ag caused mitochondrial dysfunction, while 10 nm PVP-Ag affected NRF2	PVP-coated nano-Ag had higher cytotoxicity than citrate-coated ones	^Citation129
	Silver	3–5 nm; negative potential	N2a cells	Aβ deposition	Decreased cell proliferation	^Citation121
	Silver	85±5 nm; spherical	Human neurons (from dental pulp mesenchymal stem cells)	Apoptosis; damage of neuronal connections; changes of the gene expression involved in heavy metals' metabolism and cellular growth during oxidative stress conditions; impairment of mitochondrial function	Concentration-dependent cytotoxicity; changes of cell morphology and neurite outgrowth	^Citation130
	Silver	Spherical; 22.8–25.9 nm in culture medium and 21.7 nm 24.4 nm in aqueous solution; negative zeta potential	Rat CGCs	CASP3 mediated apoptosis; oxidative stress; increase of intracellular calcium	Significant dose-dependent cytotoxicity without cell membrane damage; Cell body shrinkage	^Citation51
	Single-walled CNTs	SWCNTs: diameter 0.7–1.6 nm, length 0.2–3 μm; SWCNT-PEG: diameter 2.5–4.5 nm, length 0.1–1 μm	PC12 cells	Concentration- and surface coating-dependent ROSproduction; genes involved in oxidoreductases and antioxidant activity, nucleic acid or lipid metabolism, and mitochondrial dysfunction were highly represented	Concentration-dependent and surface coating-dependent cytotoxicity; SWCNT-PEGs were less cytotoxic than uncoated SWCNTs	^Citation131
	Titanium dioxide	TiO2-S: 25 nm, 100% anatase; TiO2-D: 25 nm, 80% anatase and 20% rutile	SHSY5Y cells	Induced dose-dependent cell cycle alterations; genotoxicity	No effects on viability; effective internalization; higher uptake for TiO2-S NPs than for TiO2-D NPs; TiO2-S NPs induced more cytotoxicity	^Citation86
	Titanium dioxide	Primary sizes: 33.4±1.9 nm;	PC12 cells	ROS generation; mitochondrial dysfunction	Dose-dependent cytotoxicity; reduced DA levels	^Citation132
	Titanium dioxide	Anatase TiO2-NPs: 20 nm; rutile TiO2-NPs: 20 nm	PC12 cells	Increased levels of LDH; increased ROS and apoptosis; activation of JNK- and p53-mediated signaling pathway; cell cycle arrest in G2/M phase	Concentration, size, and crystal structure-dependent cytotoxicity and membrane damage; anatase TiO2 NPs were more toxic than rutile	^Citation91
	Titanium dioxide	A mixture of the anatase (70%) and rutile (30%) forms; ~330 nm in media; positive surface charge	N27 cells; primary cultures of embryonic rat striatum	For primary cultures of embryonic rat striatum, apoptosis was induced	For N27, no significant cytotoxicity; for primary cultures of embryonic rat striatum, neuronal loss occurred	^Citation49
	Titanium dioxide	21 nm	PC12	Apoptosis; enhanced intracellular ROS generation	Dose-dependent and time-dependent cytotoxicity	^Citation133
	Zinc oxide	A: rod-shaped, smooth surfaces, average size 47.1 nm, width 27.9 nm; B: NPs: rod-shaped, average size 18.5 nm, width 6.8 nm	SHSY5Y cells	Oxidative stress; apoptosis and cytoskeleton changes	Size-dependent cytotoxicity; cell morphology changes	^Citation134
	Zinc oxide	100 nm	SHSY5Y cells	Apoptosis and cell cycle alterations; DNA damage	Concentration- and time-dependent cytotoxicity	^Citation81
	Zinc oxide	Spherical, 35 nm; microsphere, 45 nm; hexahedral, prism-like, 2.5–6.0 µm in diameter and 18.0–60.0 µm in length; flower-like, 500–600 nm in diameter and several microns in length	RCS96	Apoptosis induction and G2/M phase cell cycle arrest; significant release of Zn-ions	Shape- and time-dependent neurotoxicity	^Citation20

Notes: hCMEC/D3, immortalized human brain capillary endothelial cells; bEnd.3, mouse endothelial cells; ALT, mouse brain astrocyte-like cell line; N9, mouse microglial cells; BV-2, mouse microglial cells; C6, rat brain glial tumor cells; U373, human glial cells; D384, human glial cells; N27, rat dopaminergic neurons; RSC96, rat Schwann cells; HT22, mouse hippocampal neuronal cells; SK-N-SH, human neuroblastoma Cell Line; N2a, mouse neuroblastoma cells.

Abbreviations: ENM, engineered nanomaterial; BBB, blood–brain barrier; PAMAM, polyamidoamine; CNTs, carbon nanotubes; NP, nanoparticle; GO, graphene oxide; rGO, reduced graphene oxide; SWCNT, single-walled carbon nanotube; SWCNT-PEG, SWCNTs functionalized with polyethylene glycol; CGCs, cerebellum granule cells; USPIO, ultra-small superparamagnetic iron oxide; GSS, glutathione synthetase; DA, dopamine; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid; PVP, polyvinylpyrrolidone; UPS, ubiquitin-proteasome system; MMP, mitochondrial membrane potential; TEM, transmission electron microscope; rBMECs, rat brain microvessel endothelial cells; hBMEC, human brain microvessel endothelial cells; HCECs, human cerebral endothelial cells; BECs,brain endothelial cells; c-Abl, Abelson murine leukemia viral homolog 1; ARE, antioxidant response element; NRF2, nulear erythroid 2-related factor 2.

Table 3 Assays for DNA damage and corresponding results

Test method	Results
SSCP	Mutation
Ames test	Mutation
HPRT forward mutation assay	Mutation
Chromosome aberration test	Chromosomal alterations
Comet assay	DNA single and double strand breaks
Cytokinesis-blocked micronucleus assay	Chromosomal damage
γ-H2AX staining	DNA double strand breaks
8-OHdG DNA adducts	DNA oxidative damage

Abbreviations: SSCP, single strand conformation polymorphism; HRPT, hypoxanthine–guanine phosphoribosyltransferase; H2AX, H2A histone family member X; 8-OHdG, 8-hydroxydeoxyguanosine.

Figure 1 Possible ways in which engineered nanomaterials (ENMs) cross the blood–brain barrier (BBB) and the potential risks. ENMs with specific physicochemical properties could pass through the BBB by way of several different strategies.Notes: 1) Transcellular diffusion. ENMs with low molecular weight, eg, solid lipid nanoparticles, can pass through the BBB in this way. 2) Paracellular diffusion. Some ENMs, eg, silica nanoparticles and reduced graphene oxide, can open paracellular spaces, and then get into the central nervous system (CNS). 3) Receptor-mediated transcytosis. ENMs with ligands like transferrin, insulin, ApoE, etc can be identified by corresponding receptors on the endothelial cells. 4) Adsorptive mediated transcytosis. ENMs with positive charges can be attracted by microvascular endothelial cells that are negatively charged. 5) Cell-mediated transcytosis. Macrophages with phagocytized ENMs in the blood could pass through the BBB, and release ENMs into the CNS.

Figure 2 Mechanisms of ROS production induced by engineered nanomaterials (ENMs). ROS have different sources.Notes: 1) Oxidative burst. ENM-activated microglia can produce ROS with the catalyzation of NADPH-oxidase. 2) Mitochondrial ROS. Disruption of electron transport chain will lead to significant increase of ROS. 3) Fenton or Fenton-like reaction. The transition metals, eg, iron, copper, chromium, and cobalt can mediate the formation of ROS like highly reactive hydroxyl radical (OH^.) through Fenton reaction. 4) Enzyme-like activities of ENMs. For example, the INOPs could behave like peroxidase. (5) Lysosome membrane permeabilization (LMP). LMP could produce ROS through lysosomal iron or by causing mitochondrial membrane permeabilization and producing mitochondrial ROS.

Abbreviation: IONPs, iron oxide nanoparticles.

Figure 3 Possible mechanisms of releasing pro-inflammatory cytokines in microglia. Engineered nanomaterials (ENMs) can provoke TLRs like TLR2 and TLR4. TLR4 can further activate NF-κB pathway, which results in the release of inflammatory cytokines. ENMs can also activate ERK1/2 by inhibiting MKPs (MAPK phosphatases), and then cause the release of inflammatory cytokines.

Figure 4 Mechanisms of engineered nanomaterials (ENMs)-induced DNA damage. ENMs could cause different types of DNA damage including DNA crosslinks, single/double strand breaks, and DNA adducts. DNA damage could lead to cell cycle arrest to provide enough time for DNA repair and inefficient DNA repair could induce apoptosis, senescence, and cancer.

Figure 5 Mechanisms of engineered nanomaterials (ENMs)-induced cell death in neurotoxicity. Apoptosis is a caspase-dependent cell death, which has three main pathways including death receptor pathway, mitochondrial pathway, and endoplasmic reticulum stress pathway. Autophagy could be negatively mediated by PI3K-Akt-mTOR pathway. For necrosis, RIP3 responding to TNF family of cytokines binds to the kinase RIP1 and is crucial in the programmed necrosis pathway.

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