Molecular mechanism of nanomaterials induced liver injury: A review

Table 6 Effects and molecular mechanisms underlying TiO₂NPs induced hepatonanotoxicity

NPs	Size	Tested model	Dose & route of administration	Effects & mechanism	Ref.
TiO2NPs (Anatase)	7 nm (XRD)	80 CD-1 (ICR) mice	5, 10, 50 mg/kg b.w. every other day for 60 d (i.g.)	SOD, CAT, GSH-Px, MT, HSP70, GST (downregulation); CYP1A (upregulation)	[117]
				Oxidative stress, apoptosis
TiO2NPs (Anatase)	5 nm (XRD)	CD-1 (ICR) mice	5, 10, 50, 100, 150 mg/kg b.w. daily for 14 d (abdominal injection)	Accumulated in liver DNA; Inserted in DNA base pairs; Binds to DNA nucleotides; Alter DNA secondary structure; Liver DNA cleavage at higher dose	[119]
				Genotoxicity
TiO2NPs	< 25 nm anatase; < 100 nm rutile (SEM)	HepG2 cell	1, 10, 100 and 250 mg/mL incubated for 4, 24, 48 h	p21, mdm2, p53, gadd45α (increased expression); DNA strand break; DNA damage; ROS production	[120]
				Genotoxicity
TiO2NPs (Anatase)	5 nm (XRD)	80 CD-1 (ICR) mice	5, 10, 50 mg/kg b.w. for 60 d (i.g.)	TLR2, TLR4, IKK1, IKK2, NF-kB, NF-kBP52, NF-kBP65, TNF-α, NIK (upregulation); IkB, IL-2 (downregulation); ALT, AST, ALP, LDH, PCh, LAP (upregulation)	[116]
				Inflammation, apoptosis
TiO2NPs (Anatase & rutile)	Anatase –561.63 ± 26.26 nm; Rutile – 206.22 ± 2.18 nm (TEM)	HepG2 cell	5-320 μg/mL for 24 h	ERK1/2, p38 (increased phosphorylation); TNFα (upregulated); A20 (downregulated); Activation of MAPK & NF-kB pathway	[115]
				Inflammation
TiO2NPs; Rutile anatase; P25 (anatase: rutile = 75:25)	Rutile – 50 nm; Anatase – 50 nm; P25 – 21 nm (TEM)	Primary hepatocytes of Sprague Dawley rats	50 μg/mL, 72 h	ROS (upregulated); Urea, albumin, MnSOD, MMP, Mfn 1, Opa 1 (downregulated)	[122]
				Perturbation of mitochondrial dynamics, oxidative stress
TiO2NPs; Rutile	12-18 nm (TEM)	BRL 3A cells; sprague dawley rats	0.1-100 μg/mL for 6 h; 0.5-50 mg/kg BW intraperitoneal injection 24 h	Rapid G0/G1 to S transition, G2/M arrest; ALT, AST, ALP, LDH (upregulated)	[123]
				Hepatocytes with oxidative stress show more cytotoxicity
TiO2NPs; Anatase	10 (TEM)	B6C3F1 mice	50 mg/kg b.w. daily for 3 d (i.p.)	DNA strand break nucleotide oxidization; MT1H, MT1E (upregulation); Differential gene expression(increased)	[121]
				Oxidative stress, Genotoxicity, metabolic imbalance
TiO2NPs; Anatase	19 (XRD)	Wistar rat	100 mg/kg daily for 60 d (oral)	ALT, AST, ALP, LPO (increased); GSH, SOD, GPx, CAT (decreased); vacuolization, Sinusoidal dilation, inflammatory cells infiltration	[124]
				Oxidative stress
TiO2NPs; Anatase	10 nm (TEM)	Albino rats	100 mg/kg daily	ALT, AST, ALP, Bax, LPO (increased); GPx, SOD, GSH, Bcl-2, (decreased); hepatic apoptosis; Sinusoidal dilation, infiltration inflammatory cells, steatosis, hepatocellular necrosis	[125]
			60 d (oral)	Oxidative stress
TiO2NPs; anatase: Rutile (80: 20)	20 nm (TEM)	Wistar rat	300 mg/kg daily for 2 wk (oral)	ALT, AST, ALP, LDH, TNFα, NF-Kβ, TOS, LPO (upregulated); SOD, CAT, GPx, TAC (downregulated)	[118]
				Inflammation, Oxidative stress
TiO2NPs; Anatase	29 ± 9 nm (SEM)	Sprague dawley rats	2, 10, 50 mg/kg b.w. daily for 90 d (oral)	LPO, GPx, SOD, GSSG, IL-1α, IL-4 and TNFα (increased); GSH (decreased); Mitochondrial swelling increased gut microbiota altered glycerophospholipid, Phosphatidylcholines metabolism; Hepatotoxicity indirectly through gut liver axis	[126,127]
				Oxidative stress, inflammation

A20: Alpha-induced protein-3; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Bax: Bcl-2 associated X protein; Bcl2: B-cell lymphoma 2; CAT: Catalase; CYP1A: Cytochrome p450 1A; DNA: Deoxy ribonucleic acid; ERK1/2: Extracellular signal-regulated protein kinases 1 and 2; gadd45α: Growth arrest and DNA damage 45 alpha; GPx/GSH-Px: Glutathione peroxidase; GSH: Glutathione; GSSG: Glutathione disulfide; GST: Glutathione S transferase; HSP70: Heat shock protein 70; IkB: Inhibitor kappa B; IKK1,2: IκB kinase; IL-1α: Interleukin 1 alpha; IL-2,4: Interleukin-2,4; LAP: Leucine acid peptide; LDH: Lactate dehydrogenase; LPO: Lipid peroxidation; MAPK: Mitogen activated protein kinase; mdm2: Murine double minute 2; Mfn 1: Mitofusin 1; MMP: Mitochondrial membrane potential; MnSOD: Manganese superoxide dismutase; MT: Metallothionein; MTIE: Metallothionein 1E; MTIH: Metallothionein 1H; NF-kB: Nuclear factor kappa beta; NIK: NF-κB-inducible kinase; Opa 1: Optic atrophy 1; p21: Cyclin-dependent kinase inhibitor 1; p38: Puncture38; p53: Tumor suppressor protein p53; PCh: Pseudocholinesterase; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TLR2/4: Toll like receptor 2/4; TNF-α: Tumor necrosis factor α; TOS: Total oxidant status.