Toxic effects of metal oxide nanoparticles and their underlying mechanisms

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  • ReceivedNov 15, 2016
  • AcceptedJan 3, 2017
  • PublishedJan 17, 2017


Nanomaterials have attracted considerable interest owing to their unique physicochemical properties. The wide application of nanomaterials has raised many concerns about their potential risks to human health and the environment. Metal oxide nanoparticles (MONPs), one of the main members of nanomaterials, have been applied in various fields, such as food, medicine, cosmetics, and sensors. This review highlights the bio-toxic effects of widely applied MONPs and their underlying mechanisms. Two main underlying toxicity mechanisms, reactive oxygen species (ROS)- and non-ROS-mediated toxicities, of MONPs have been widely accepted. ROS activates oxidative stress, which leads to lipid peroxidation and cell membrane damage. In addition, ROS can trigger the apoptotic pathway by activating caspase-9 and -3. Non-ROS-mediated toxicity mechanism includes the effect of released ions, excessive accumulation of NPs on the cell surface, and combination of NPs with specific death receptors. Furthermore, the combined toxicity evaluation of some MONPs is also discussed. Toxicity may dramatically change when nanomaterials are used in a combined system because the characteristics of NPs that play a key role in their toxicity such as size, surface properties, and chemical nature in the complex system are different from the pristine NPs.

Funded by

National Basic Research Program of China(2011CB933402)

National Natural Science Foundation of China(21371115,11025526,40830744,41073073,21101104)

Innovation Program of Shanghai Municipal Education Commission(14YZ025)

Program for Innovative Research Team in University(IRT13078)


This work was supported by the National Natural Science Foundation of China (21371115, 11025526, 40830744, 41073073, and 21101104), the National Basic Research Program of China (2011CB933402), the Innovation Program of Shanghai Municipal Education Commission (14YZ025), and the Program for Innovative Research Team in University (IRT13078).

Interest statement

The authors declare that they have no conflict of interest.

Contributions statement

Wang Y, Wu M and Ding L organized the references and wrote the paper. Ding L, Yao C, Li C, Xing X, Huang Y and Gu T finished the literature investigation. Ding L took the leadership of the literature investigation and organized the figures. All authors discussed the idea of the paper.

Author information

Yanli Wang is now working at the Institute of Nanochemistry and Nanobiology of Shanghai University as an associate professor since 2012. She obtained her PhD degree in environmental engineering from Shanghai University in 2010. Her research interests include bio-effects and safety evaluation of nanomaterials and their application in bio-imaging and cancer therapy.

Minghong Wu obtained her PhD degree from Shanghai Institute of Applied Physics of Chinese Academy of Sciences in 1999. She is the National outstanding youth and Yangtze River scholar of China. Based on her scientific contribution, she was selected as the Russian Academy of foreign academicians of Russian Academy of Engineering in 2008 and Russian Academy of Science in 2015. Her research interests mainly focus on bio-effects and safety evaluation of nanomaterials and environmental pollution analysis and control.


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  • Figure 1

    (a–h) Microtubule dynamics following exposure to TiO2 NPs using immunofluorescence staining: (a–d) fluorescence images of 4T1 cells examined under a laser scanning confocal microscope and (e–h) phase contrast images of 4T1 cells. (a, e) Control group (treated in the absence of TiO2 NPs); (b, f) groups treated with 200 mg L−1 TiO2 NPs for 24 h; (c, g) 50 mg L−1 TiO2 NPs for 48 h, and (d, h) 200 mg L−1 TiO2 NPs for 48 h. (i–p) Representative histological photomicrographs of the liver in young and adult rats after gastrointestinal exposure to TiO2 NPs for 30 days. Circles: liver edema in young rats. Arrows: inflammatory cell infiltration in adult rat liver Y0–Y3: young rats, A0−A3: adult rats, Y0 & A0: control group (0 mg kg−1), Y1 & A1: low-dose exposure group (10 mg kg−1), Y2 & A2: middle-dose exposure group (50 mg kg−1), Y3 & A3: high-dose exposure group (200 mg kg−1). Reprinted with permission from: (a–h) Ref. [31], Copyright 2015, Royal Society of Chemistry; (i–p) Ref. [49], Copyright 2013, WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  • Figure 2

    ROS levels in HUVECs after exposure to NPs. (a–l) Fluorescence microscope images of intracellular ROS induced by NPs. HUVECs were treated with ZnO NPs/CeO2 NPs (240 µmol L−1) for 8 h; then the endoplasmatic reticulum (ER) and ROS were stained. (m) Image from ZnO NPs-treatment group shows the segmentation process of high-content analysis (HCA) method. (n) Quantitative analyses of ROS levels by HCA after HUVECs were treated with NPs for 8 h. Data is expressed as mean ± SD, (# p< 0.01 compared with that in blank, n = 6. Bars: 10 µm). The white arrows show bright and aggregated ER in ZnO NPs-treated cells. Reprinted with permission from Ref. [62], Copyright 2014, American Chemical Society.

  • Figure 3

    In vivo accumulation, degradation, and clearance of IONPs in mice. (a) Iron distributed in the liver, spleen, lung, kidney and brain after intravenous injection (5 mg Fe kg−1) of PEG-phospholipid-coated IO nanocrystals for 24 h, prepared via the organometallic route (sizes of ∼5, ∼15, and ∼30 nm), and Feridex (is a dextran-coated cluster of IONPs approved as a contrast agent for hepatic imaging). (b, c) Percent of IONPs (percent superparamagnetic/ferrimagnetic content) remaining in liver (b) and spleen (c). Reprinted with permission from Ref. [91], Copyright 2012, American Chemical Society.

  • Figure 4.

    Schematic diagram of MONP toxicity and mechanism. In vitro toxicity of MONPs is mainly caused by the damage of mitochondrial/DNA/protein and phospholipid bilayer, leading to cell toxicity. In vivo toxicity is caused by penetration of MONPs into the blood circulation through inhalation, oral, and dermal routes, and these MONPs finally reach the main organs of the body causing organ damage. Some nanomaterials also cause phototoxicity on the skin. MONP toxicity is induced mainly by four ways: the generation of ROS, effect of released ions, excessive accumulation of NPs on the cell surface, and combination of NPs with specific death receptors.

  • Figure 5

    Cytotoxicity evaluation of ZnO NPs (15 mg L−1), Vc (300 mg L−1), and ZnO NPs plus Vc treatment for 24 h (a, b). Cell viability of gastric epithelial cell line (GES-1) (a), and neural stem cell line (NSCs) (b) after 24 h co-incubation with ZnO NPs, Vc, and ZnO NPs plus Vc treatment. *p< 0.05 compared with cells exposed to ZnO NPs. Cell viability after treatment of various concentrations of ZnO NPs (c), various concentrations of CPP (d); (e) the effect of CPP (500 mg L−1) at various concentrations of ZnO NPs; (f) cell counts after treatment with 20 mg L−1 ZnO NPs, 500 mg L−1 CPP, 20 mg L−1 ZnO NPs & 500 mg L−1 CPP, respectively; (g) the effects of various concentrations of CPP and ZnO NPs (20 mg L−1); (h) the effects on LDH release at various concentrations of CPP with ZnO NPs (20 mg L−1). #p< 0.05 compared with control group; *p< 0.05 compared with cells exposed to ZnO NPs. Reprinted with permission from: (a, b) Ref. [58], Copyright 2014, Royal Society of Chemistry; (c–h) Ref. [135], Copyright 2014, Royal Society of Chemistry.

  • Table 2   Toxicities of IONPs with different surface coatings

    Coating material

    Cell types

    Size (nm)


    Incubation time



    Macrophages (human)


    0.1 mg mL−1

    7 days

    20% cell viability after 7 days [82]

    Primary peritoneal macrophages (rats and mice)

    20, 60

    0.2–20 µmol L−1

    15 min–2 days

    Increased anti-inflammatory cytokines, reduced pro-inflammatory cytokines [83]

    Poly (vinyl alcohol)

    L929 (mouse fibroblasts)


    0.2–20 mmol L−1

    2 days

    Toxicity depends on nanoparticles shape and size [84]


    HepG2 (human liver cancer cell)


    0.03–3000 µg mL−1

    5 days

    High positive charge causes severe cytotoxicity [85]


    macrophages J774 (mouse)


    25–500 µg mL−1

    1–6 h

    Dose- and time-dependent damage [86]


    A549 (human lung cancer cell)


    10 µg mL−1

    2 days

    Dose- and size-dependent damage [87]


    A549 (human lung cancer cell)


    Up to 80 µg mL−1

    18 h

    No or low toxicity [88]


    BRL 3A (rat liver derived cell)

    30, 47

    Up to 250 µg mL−1

    1 days

    No toxicity up to 100 µg mL−1, significant toxic effects at 250 µg mL−1 [89]

  • Table 1   Biochemistry assay of serum in rats after gastrointestinal exposure to TiO NPs for 30 days (mean ± SD, = 7)





    [mmol L−1]


    [mmol L−1]


    [mmol L−1]


    [mmol L−1]


    [mmol L−1]


    [g L−1]


    [g L−1]


    [g L−1]




    0 mg kg−1 BW

    5.04 ± 0.98

    1.59 ± 0.22

    0.82 ± 0.29

    0.60 ± 0.07

    0.23 ± 0.03

    70.86 ± 2.85

    36.51 ± 1.29

    34.34 ± 1.74

    1.06 ± 0.04


    10 mg kg−1 BW

    5.20 ± 1.18

    1.76 ± 0.27

    1.04 ± 0.37

    0.61 ± 0.07

    0.29 ± 0.04

    70.43 ± 1.40

    35.60 ± 1.14

    34.83 ± 0.39

    1.02 ± 0.03


    50 mg kg−1 BW

    6.61 ± 0.73**

    1.91 ± 0.30

    0.59 ± 0.13

    0.60 ± 0.07

    0.43 ± 0.09**

    1.57 ± 1.62

    36.54 ± 0.98

    35.03 ± 1.38

    1.04 ± 0.05


    200 mg kg−1 BW

    6.44 ± 0.36**

    1.69 ± 0.36

    0.63 ± 0.13

    0.58 ± 0.08

    0.36 ± 0.05**

    69.86 ± 2.79

    35.99 ± 1.27

    33.87 ± 1.75

    1.06 ± 0.04



    0 mg kg−1 BW

    5.73 ± 1.57

    1.65 ± 0.35

    0.84 ± 0.30

    0.62 ± 0.10

    0.26 ± 0.06

    70.43 ± 2.70

    35.66 ± 1.35

    34.77 ± 1.71

    1.03 ± 0.04


    10 mg kg−1 BW

    5.13 ± 1.09

    1.72 ± 0.25

    0.72 ± 0.20

    0.67 ± 0.06

    0.27 ± 0.06

    70.71 ± 3.64

    35.34 ± 1.67

    35.37 ± 2.23

    1.00 ± 0.04


    50 mg kg−1 BW

    4.88 ± 0.88

    1.83 ± 0.37

    0.52 ± 0.11

    0.64 ± 0.07

    0.29 ± 0.05

    72.17 ± 2.23

    35.67 ± 1.03

    36.50 ± 2.35

    0.98 ± 0.08


    200 mg kg−1 BW

    5.06 ± 0.36

    1.61 ± 0.28

    0.82 ± 0.37

    0.59 ± 0.07

    0.24 ± 0.05

    68.86 ± 2.54

    34.54 ± 1.58

    34.31 ± 1.60

    1.01 ± 0.06




    ALT [U L−1]


    [U L−1]



    [µmol L−1]


    [U L−1]


    [U L−1]


    [U L−1]


    [mmol L−1]


    [µmol L−1]



    0 mg kg−1 BW

    47.57 ± 4.83

    209.14 ± 31.91

    0.23 ± 0.04

    1.27 ± 0.21

    1852.86 ±467.30

    890.43 ±344.28

    2792.00 ±294.97

    6.93 ± 1.08

    52.57 ± 5.32


    10 mg kg−1 BW

    44.43 ± 7.68

    179.71 ± 36.59

    0.25 ± 0.06

    1.23 ± 0.19

    1731.29 ±306.55

    770.71 ±206.29

    2083.29 ±622.24

    7.13 ± 1.26

    52.29 ± 3.73


    50 mg kg−1 BW

    54.43 ± 7.09

    152.14 ± 28.20**

    0.37 ± 0.07**

    1.47 ± 0.18

    1313.86 ±346.95

    510.86 ±168.34**

    2154.43 ±914.55

    6.49 ± 1.10

    52.86 ± 3.07


    200 mg kg−1 BW

    48.86 ± 6.39

    157.57 ± 31.83**

    0.32 ± 0.06*

    2.11 ± 0.30**

    1499.43 ±383.68

    617.28 ±222.54*

    1658.00 ±685.07*

    6.44 ± 1.11

    49.71 ± 2.75



    0 mg kg−1 BW

    52.43 ± 6.16

    170.43 ± 38.31

    0.32 ± 0.07

    1.81 ± 0.13

    1548.86 ±393.39

    692.86 ±328.89

    2045.86 ±520.32

    5.60 ± 0.91

    53.43 ± 3.10


    10 mg kg−1 BW

    47.43 ± 5.65

    178.57 ± 54.36

    0.28 ± 0.05

    2.09 ± 0.41

    1753.71 ±545.80

    835.71 ±439.23

    2176.86 ±777.33

    6.43 ± 0.94

    53.00 ± 8.74


    50 mg kg−1 BW

    46.00 ± 5.66

    167.83 ± 31.24

    0.29 ± 0.08

    1.90 ± 0.29

    1560.33 ±336.45

    690.83 ±232.51

    1789.17 ±459.89

    8.42 ± 1.96++

    54.33 ± 5.96


    200 mg kg−1 BW

    51.57 ± 9.05

    177.00 ± 19.21

    0.29 ± 0.03

    1.37 ± 0.50+

    1647.29 ±44.32

    709.29 ±27.40

    2041.86 ±337.52

    7.26 ± 0.61+

    50.29 ± 4.57

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