Cytotoxicity of Metal-Based Nanoparticles: From Mechanisms and Methods of Evaluation to Pathological Manifestations

Abstract

Metal-based nanoparticles (NPs) are particularly important tools in tissue engineering-, drug carrier-, interventional therapy-, and biobased technologies. However, their complex and varied migration and transformation pathways, as well as their continuous accumulation in closed biological systems, cause various unpredictable toxic effects that threaten human and ecosystem health. Considerable experimental and theoretical efforts have been made toward understanding these cytotoxic effects, though more research on metal-based NPs integrated with clinical medicine is required. This review summarizes the mechanisms and evaluation methods of cytotoxicity and provides an in-depth analysis of the typical effects generated in the nervous, immune, reproductive, and genetic systems. In addition, the challenges and opportunities are discussed to enhance future investigations on safer metal-based NPs for practical commercial adoption.

Keywords: cytotoxic effect; cytotoxicity; evaluation method; metal-based nanoparticle; toxic mechanism.

Figure 1

The cytotoxicity induced by metal‐based NPs with regards to mechanisms (light brown), evaluation methods (blue), and pathological manifestations (green).

Figure 2

Typical mechanism of cytotoxicity induced by metal‐based NPs.

Figure 3

STEM images of a neuron in a rat olfactory bulb after 3 months of inhalation exposure to NiO NPs at a concentration of 0.23 mg m^‐3. a) NiO NPs retention. b) Ultrastructural autolysis. Reproduced with permission.^{[ 87 ]} Copyright 2019, Molecular Diversity Preservation International (MDPI).

Figure 4

a) Cell viability comparison and b) corresponding XTT images of mouse embryonic fibroblasts NIH3T3 after incubating with 32.5 ng mL^‐1 of SPIONs for different durations. Reproduced with permission.^{[ 102 ]} Copyright 2016, Molecular Diversity Preservation International (MDPI). c) Cell viability of the HepG2 cell line after exposure to TiO₂ NPs assessed by the AB viability assay in serum‐free and complete media. Reproduced with permission.^{[ 104 ]} Copyright 2016, Elsevier.

Figure 5

a–c) The Th2 (IL‐4, IL‐5, and IL‐13) cytokines results revealed the significant differences induced by TiO₂ NPs in cytokine levels among the research groups. Reproduced with permission.^{[ 136 ]} Copyright 2020, Springer Nature. d) Comet pictures illustrating the effects of TiO₂ NPs (150 mg kg^‐1 body weight) on the extent of DNA damage: I) Control group, II) NPs group. Reproduced with permission.^{[ 138 ]} Copyright 2021, Springer Nature. e) The mutagenic effect of CdO NPs on fish: I) Control group. II) MN in erythrocytes of Oreochromis mossambicus at sublethal II (1/4 of LC50–10 µg mL^‐1) for 21 d. III)MN in erythrocytes of O. mossambicus at sublethal III (1/2 of LC50–20 µg mL^‐1) for 21 d. Reproduced with permission.^{[ 139 ]} Copyright 2020, Hindawi.

Figure 6

Pathway for the translocation of NPs (ZnO and TiO₂) to the brain by tongue instillation. Reproduced with permission.^{[ 172 ]} Copyright 2017, Future Medicine Ltd.

Figure 7

Histological images of mice brain of a) the control group and tissue after treating with b) ZnO NPs. Reproduced with permission.^{[ 176 ]} Copyright 2020, Elsevier. c–f) Ultrastructure of hippocampal cell of mice caused by nasal administration of TiO₂ NPs for 90 consecutive days. c) Control group. d) 2.5 mg kg^‐1 body weight TiO₂ NPs. e) 5 mg kg^‐1 body weight TiO₂ NPs. f) 10 mg kg^‐1 body weight TiO₂ NPs. Green arrows indicate irregularity of nuclear membrane, significant shrinkage of the nucleus. Red arrows suggest chromatin marginalization. Yellow arrows exhibit mitochondria swelling. Reproduced with permission.^{[ 177 ]} Copyright 2014, Wiley‐VCH.

Figure 8

Optical images of a) untreated and b) TiO₂ NP‐treated (80 µg cm^‐2) 16HBE cell monolayers. TiO₂ exposure can cause a marked and widespread perturbation of the distribution of claudin‐7 (red in the online version) and ZO‐1 (green in the online version). Reproduced with permission.^{[ 191 ]} Copyright 2020, Taylor & Francis Group. c) SPADE (spanning‐tree progression analysis of density‐normalized events) trees for control and Ag NP‐treated samples. The SPADE trees show that the cell‐associated Ag NPs were not evenly distributed for all cell types. d) The t‐SNE (t‐distributed stochastic neighbor embedding) results support the findings in SPADE trees, namely, cellular Ag NP association is high in monocytes and B cells, but medium in T cells and NK cells. In t‐SNE plots, the color gradient representing the cell‐associated Ag amount and positions of each cell type are displayed in the right‐most figure. Reproduced with permission.^{[ 193 ]} Copyright 2020, Wiley‐VCH.

Figure 9

Chromosome aberrations induced by Ag NPs and Ag ions in rat bone marrow cells. a) Vehicle control. Structure aberrations include gap, breakage, and exchange can be observed in both (b,c) Ag ion and Ag NPs treated groups (d–f) as indicated in each panel, and a phenomenon with increase of chromosome count in single cell was observed in the latter. Reproduced with permission.^{[ 216 ]} Copyright 2017, PLOS.

Figure 10

a) Morphological changes of spermatozoa induced by NiO NPs. (I) normal morphology. (II–IX) Perms of NiO NP‐treated rats show an amorphous, knobbed, hooked, or detached head. while some of the tails of few sperms exhibit a spiral, bifurcated or broken tail. Reproduced with permission.^{[ 226 ]} Copyright 2021, Springer Nature. b) Histopathological examination of mice ovary following gavage administration of TiO₂ NPs for 30 d. (I) unexposed mice present normal development of primary follicles (black arrow) and secondary follicles (yellow arrow). (II) 2.5 mg kg^‐1 TiO₂ NPs exposed group shows atrophic secondary follicle (yellow arrow), primary follicle atresia (green arrow), and apoptosis of granule cells (blue arrow). (III) 5 mg kg^‐1 TiO₂ NPs exposed group shows large primary follicle atresia (green arrow) and granule cell apoptosis (blue arrow). (IV) 10 mg kg^‐1 TiO₂ NPs exposed group shows severe inflammatory cell infiltration (green circle), congestion (yellow circle), significant primary follicle atresia (green arrow) and disposed disorder or apoptosis of granule cells (blue arrow). Reproduced with permission.^{[ 232 ]} Copyright 2018, National Center for Biotechnology Information, U.S. National Library of Medicine. c,d) Representative micrographs of TiO₂ and ZnO NP effects on cytoskeletal organization in theca cells after culture with or without Trolox. Reproduced with permission.^{[ 233 ]} Copyright 2020, Elsevier.