Toxicological Effects of Titanium Dioxide Nanoparticles: A Review of In Vivo Studies

Table 8

In vivo studies that investigated the adverse effects of TiO₂ NPs on musculoskeletal and reproductive systems.

Musculoskeletal system
References	Crystal phase composition (particle size in nm)	Type of exposure	Type and number of animals	Results
Hansen et al., 2006 [143]	TiO2 (70); Bulk TiO2 (diameter: 0.9 mm; height: 1 mm)	Subcutaneous (bulk) and intramuscular (NPs) implantation in rat back for 6 or 12 months.	10 Male SpragueDawley rats	Local reaction: presence of granulomas (NPs), inflammatory infiltrates (bulk); no local intolerance (both).
Gatti et al., 2008 [144]	TiO2 (70); Bulk TiO2 (diameter: 6–12 mm; height: 2 mm)	Subcutaneous (bulk) and intramuscular (NPs) implantation in rat back for 6 or 12 months.	10 male SpragueDawley rats	Local reaction: granulomas (NPs), inflammatory infiltrates (bulk).
Wang et al., 2009 [134]	Anatase TiO2 (diameter: 45.87±7.75; thickness: 10–15)	Intraarticular injection: 0.2, 2, 20 mg/kg TiO2 in the knee joints every other day for 4 times.	10 male Sprague Dawley rats per group	Oxidative stress in synovium: GSH-Px, GSH, GSSG, MDA, and SOD increased.; Histology: synovium hypertrophy, LYMs, plasma cell infiltration, and fibroblast proliferation.
Onuma et al., 2009 [145]	Hydrophilic rutile TiO2 treated with ZrO2Al(OH)3 (minor axis: 40–70; major axis 200–300); Hydrophobic rutile TiO2 treated with ZrO2Al(OH)3 and steric acid (minor axis: 40–70; major axis 200–300)	Subcutaneous injections: QR-32 cells alone; QR-32 cells mixed with 5 mg/0.1 mL TiO2; and 5 mg/0.1 mL TiO2 30 and 70 days before QR-32 cells injection.; Intravenous injections: tumor cell lines into mice (5/line).	15 female C57BL/6 mice per group	Carcinogenicity: QR-32 cells became tumorigenic after injection in sites implanted for 30 days or 70 days with hydrophilic TiO2.; Metastatic ability: acquired by tumor cell lines derived from QR-32 cells injected in site preimplanted with both TiO2.
Reproductive system
Guo et al., 2009 [131]	N.A.	Intraperitoneal injections: 200 and 500 mg/kg TiO2 every other day for 5 times.	15 male ICR mice per group	Reproductive effects: reduced sperm density and motility, increased sperm abnormality, and germ cell apoptosis.
Takeda et al., 2009 [101]	Anatase TiO2 (25–70)	Subcutaneous injections: 100 μL of TiO2 at 1 mg/mL at 3, 7, 10 and 14 days post-coitum.	6 pregnant Slc:ICR mice per group	Reproductive effects: disorganised and disrupted seminiferous tubules, few mature sperm, decreased sperm production, epidididymal sperm motility, number of Sertoli cells.

GSH, reduced glutathione; GSH-Px, glutathione peroxidase; GSSG, oxidized glutathione; LYM, lymphocyte; MDA, malondialdehyde; SOD, superoxide dismutase; TiO₂ NPs, titanium dioxide nanoparticles.