Table 2.

Toxic effects of TiO2 NPs on CNS in in vivo studies

Crystal type	Animals	Cell type	Parameters/dose	Main findings	Reference
Rutile 80 nm anatase 155 nm	CD-1 (ICR) female mice	Nasal instillation	500 μg; every other day for 30 days	Ti contents detected in the brain; GFAP-positive cell, CAT, SOD, MDA, protein carbonyls, AChE activities, glutamic acid, and NO increased	[25]
Anatase bulk	CD-1 (ICR) female mice	Delivered to the abdominal cavity	5 nm; 5, 10, 50, 100, 150 mg/kg BW; every day for 14 days	Ti contents detected in brain; O2, H2O2, MDA, NOS, NO increased; Glu contents, antioxidative enzymes, non-enzymatic antioxidant contents, and AChE activity decreased	[79]
Anatase	CD-1 male mice	Intranasal administration	5–6 nm; 2. 5, 5, 10 mg/kg BW. every day for 90 days	Ti contents detected in brain; no daily behavioral changes; O2, H2O2, MDA, protein carbonyl, 8-OHdg, p38, JNK, NF-κB, Nrf-2, and HO-1 increased	[80]
Anatase	Sprague–Dawley rats (male and female)	Subcutaneous injection	5 nm; 500 μl (1 μg/μl) on GD 6, 9, 12, 15, and 18	CAT, GSH-PX, and T-AOC decreased; MDA and 8-hydroxydeoxyguanosine (8-OHdG) increased	[72]
Rutile 80 nm anatase 155 nm	CD-1 (ICR) female mice	Intranasal instillation	500 μg; every other day for 30 days; evaluated at 2, 10, 20, and 30 days of post-instillation time points	Ti contents detected in brain; GSH-Px, GST, SOD and GSH not changed; MDA, TNF-α and IL-1β increased	[53]
Anatase	CD-1 (ICR) female mice	Intranasal administration	5–6 nm; 2.5, 5, 10 mg/kg BW; every day for 90 days	TLR2, TLR4, TNF-α, IKK1, IKK2, NF-κB, NF-κBP52, NF-κBP65, NIK, and IL-1β increased; spatial recognition memory and locomotor activity affected	[81]
Rutile	Male C57BL/6 mice	Intraperitoneal injection	Fine (<1 μm), ultrafine (21 nm); 40 mg/kg BW; one injection 30 min after LPS or vehicle injection	IL-1β, TNF-α, iNOS, ROS production, and OX-42 enhanced by ultrafine TiO2 in the LPS-stimulated group	[82]
Anatase	CD-1 (ICR) female mice	Intragastric administration	6.5 nm; 5, 10, 50 mg/kg BW; every day for 60 days	Ti contents in the hippocampus increased; caspase-9, caspase-3, Bax, cytochrome c, O2 and H2O2 upregulated; Bcl-2, SOD, CAT, APx, and GSH-Px reduced	[83]
Anatase	CD-1 female mice	Nasal administration	5–6 nm; 2.5, 5, 10 mg/kg BW; every day for 90 days	NR2A, NR2B, CREB-1, CREB-2, FosB/DFosB, CaMKIV, and pCREB decreased	[85]
Anatase	CD-1 female mice	Intragastric administration	5 nm; 5, 10, 50 mg/kg BW; every day for 60 days	Ti contents in brain upregulated; reduction in the activities of Na+/K+-ATPase, Ca2+-ATPase, Ca2+/Mg2+-ATPase; Ache, Glu, and NO elevated; NE, DA, DOPAC, 5-HT, and 5-HIAA reduced	[86]
Anatase	Pregnant ICR mice	Subcutaneous injection	2570 nm; 100 μg, injection on GD 6, 9, 12, 15	Genes related with cell death, apoptosis, oxidative stress, inflammation and neurotransmitters changed	[70]
Rutile	Pregnant BALB/c mice	Intravenous injection	35 nm; 0.8 mg, injections on GD 16 and 17	Lower uterine weights and smaller fetuses; fetal resorption and retarded fetal growth	[67]
Anatase	Pregnant Wistar rats	Intragastric administration	10 nm; 100 mg/kg BW, every day from GD 2 to 21	Ti contents elevated and Ki-67-positive cells reduced; learning and memory in offspring disrupted	[66]