Evaluation of immunoresponses and cytotoxicity from skin exposure to metallic nanoparticles

Figures & data

Table 1 Skin absorption of metallic NPs

	Species	Study duration	Analysis method	Observation	Reference
ZnO NPs	Human	2, 4 hours	ZnO NPs and NAD(P)H signals quantified by TCSPC-FLIM	No ZnO-NP penetration detected in human skin after 2 and 4 hours’ treatment; free NAD(P)H signal significantly increased in tape-stripped viable epidermis treated for 4 hours with ZnO-NP compared to vehicle control	^Citation19
TiO2 NPs	Hairless rat	2, 4, and 8 weeks	Histopathological, TEM, EDS	Particles located only in stratum corneum layer of epidermis and follicular epithelium histopathologically; TEM and EDS analysis failed to show TiO2 NPs in viable skin areas	^Citation20
TiO2 NPs	Porcine back skin	8, 24, 48 hours	PIXE, RBS, STIM, SEI	TiO2 NPs penetrated SC into SG but not SS within 8 hours; NPs not detected in hair follicles	^Citation21
TiO2 NPs and ZnO NPs	Human	2, 48 hours	Nuclear microscopy, PIXE	NPs observed only in the 70%–90% depth of SC and openings of follicles	^Citation22
AuNPs	Human	2 hours	Multiphoton microscopy	AuNPs detected up to 14 µm deep in human skin, whereas a wide range of detectable depths (20–100 µm) observed in reconstructed skin	^Citation23
AgNPs	Porcine ear skin	24 hours	TPT-FLIM, CRM, SERS	TPT-FLIM, CRM, SERS showed depths of 12–14, 11.1±2.1, and 15.6±8.3 µm, respectively	^Citation24
AgNPs	Human	4–6 days	Histopathological, SEM, XRD	A limited number of NPs noted histopathologically; metallic particles seen within the dermis by SEM; XRD confirmed these were AgNPs	^Citation25
AuNPs	Human	0.5, 2, 6, and 24 hours	Franz method, multiphoton microscopy	AuNPs penetrated SC into deeper skin layers after 24 hours’ skin exposure	^Citation26
CoNPs	Human intact and abraded skin	2, 4, 8, 16, and 24 hours	Franz method, ICP-AES	NPs able to penetrate human skin in an in vitro cell-diffusion system; cobalt concentration in damaged skin significantly greater than in intact skin	^Citation27
NiNPs	Human intact and needle-abraded human skin	4, 8, 16, and 24 hours	Franz method, ICP-AES	NiNPs caused increase in nickel content into skin and significant permeation flux through skin in vitro, higher when damaged-skin protocol used	^Citation28

Abbreviations: TCSPC, time-correlated single-photon counting; FLIM, fluorescence-lifetime imaging microscopy; TEM, transmission electron microscopy; EDS, energy-dispersive X-ray spectroscopy; SG, stratum granulosum; SS, stratum spinosum; PIXE, particle-induced X-ray emission; RBS, Rutherford back-scattering; STIM, scanning transmission ion microscopy; SEI, secondary electron imaging; TPT, two-photon tomography; CRM, confocal Raman microscopy; SERS, surface-enhanced Raman scattering; XRD, X-ray diffusion; ICP-AES, inductively coupled plasma–atomic-emission spectroscopy; NPs, nanoparticles.

Figure 1 Skin penetration of metal NPs.

Notes: Three main possible skin-penetration pathways are illustrated: the intracellular pathway, intercellular pathway, and follicular pathway. Metal NPs may penetrate the stratum corneum in healthy skin. In damaged skin, more NPs may penetrate the epidermis and dermis. They may move to the lymph modes and be engulfed by macrophages. During penetration, metal NPs release metal ions, which induce metal ion-specific CD4⁺ T-cell and IL17-mediated immunoreactions.

Abbreviation: NPs, nanoparticles.

Table 2 Risk evaluation of metal NPs in skin cells

	Size (nm)	Concentration	Cellular model/organism	Impact	Reference
AgNPs	20	1, 10 ng/mL	Murine fibroblasts	No significant cytotoxicity on cell viability	^Citation59
AuNPs	15	25, 500 µg/mL	Human dermal fibroblasts	No morphological changes observed	^Citation60
TiO2 NPs	10–60	5%	Hairless mouse skin	Changed production of MDA and reduced HYP expression in skin samples	^Citation61
SiNPs	20	500, 1,000, 2,000 mg/kg	Mouse skin	No systemic toxicity	^Citation62
AgNPs	75–90	1–100 µg/mL	HaCaT keratinocytes	Reduced cell viability; toxicity influenced by NP shape and concentration	^Citation63
TiO2 NPs	10±4	1%	Human dermal fibroblasts	Initiated oxidative stress	^Citation64
TiO2 NPs	50	20, 40, 80, 160 µg/mL	Mouse fibroblasts	Initiated collagen deformation, inflammation, and protein structural deformations	^Citation65
TiO2 NPs, ZnO NPs	21.5±0.6, 18.2±0.4	25%	Hairless mouse skin	No histological changes seen in skin; elevated Ti detected in mouse livers	^Citation66
AgNPs	15, 30, 55	20, 30, 40, 50 µg/mL	Human neonatal skin stromal cells	Caused apoptosis or necrosis	^Citation67
AgNPs	10, 30, 60	1.0 mg/mL	HaCaT keratinocytes	Impact on cell viability and metabolism; downregulated glycolysis and disrupted energy production common to AgNPs; ROS mediated impact on metabolic pathways, such as GSH synthesis, glutaminolysis, and the Krebs cycle	^Citation68
AgNPs	4.7, 42	0.1–1.6 µg/mL for 4.7 nm; 0.1–6.7 µg/mL for 42 nm	Human dermal fibroblasts	Induced DNA-strand breaks in dose- and size-dependent manner	^Citation69
SiO2 NPs	15	2.5, 5, 10 µg/mL	HaCaT keratinocytes	Decreased DNMT1, DNMT3A, and MBD2 levels at mRNA and protein levels, implying global epigenomic response	^Citation70
ZnO NPs	15.38±1.47	10 µg/mL	Mouse epidermal skin	Led to cell death through autophagic vacuole accumulation and mitochondrial damage via ROS induction	^Citation71
Fe3O4 NPs	25	25, 50, 100 µg/mL	Human skin epithelial A431 cells	Depleted glutathione and induced ROS and lipid peroxidation; significantly upregulated caspase 3 expression	^Citation72
ZnO NPs	30	1 mg/day applied on murine skin	Murine facial hair follicle stem cells	Caused obvious DNA damage and induced apoptosis; perturbed genes associated with cell communication and differentiation	^Citation15
PtNPs	4.8±11.7	25, 50, 100, 200, 400 µg/mL	Human foreskin fibroblasts	Inhibited DNA replication and affected secondary structure of DNA; genotoxic stress activated p53 and subsequently induced activation of p21, leading to proliferating cell nuclear antigen-mediated growth arrest in S phase and apoptosis	^Citation73
TiO2 NPs	20–30	0–1,000 µg/mL	Human fibroblast skin cells	Promoted cytotoxicity and oxidative damage; fatty-acid composites could reduce toxicity	^Citation74
AgNPs and AuNPs		0.1, 1, and 10 µg/mL	Human fibroblast skin cells	Decreased collagen, laminin production, and percentage of cells expressing collagen receptor; may influence fibroblast function by negatively modulating ECM deposition and altering ECM-receptor expression, cytoskeletal reorganization, and cell migration	^Citation75

Abbreviations: NPs, nanoparticles; ROS, reactive oxygen species.

Figure 2 Possible toxic mechanisms of metal NPs in HaCaT cells.

Notes: Metal NPs induce ROS explosion intracellularly, and the accumulation of NPs might result in the following effects: cell-cycle arrest, which is associated with DNA damage and chromatin structure remodeling caused by oxidative stress (G₂/M cell-cycle arrest prevents DNA-damaged cells from entering mitosis to repair DNA and induce apoptosis); expression of epigenetic related genes, resulting in modifications of chromatin structure and alterations in gene expression; and mitochondrial damage and alteration of apoptosis and autophagy-related genes, which lead to autophagy and mitochondrial apoptosis.

Abbreviations: NPs, nanoparticles; ROS, reactive oxygen species.

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