Toxicological Mechanisms of Nanosized Titanium Dioxide-Induced Spleen Injury in Mice after Repeated Peroral Application

Abstract

Due to an increase in surface area per particle weight, nanosized titanium dioxide (nano-TiO2) has greatly increased its function as a catalyst and is used for whitening and brightening foods. However, concerns over the safety of nano-TiO2 have been raised. The purpose of this study was to determine whether the protein kinase MAPKs/PI3-K/Akt signaling pathways and transcription factors are activated prior to or concurrent with COX-2 up-regulation in mouse spleen following exposure to 10 mg/kg BW of pure anatase nano-TiO2 by the intragastric route for 15-90 days. The study clearly showed that nano-TiO2 was deposited in the spleen and resulted in reactive oxygen species production, time-dependent splenic inflammation, and necrosis, coupled with a 12.64-64.06% increase in COX-2 and prostaglandin E2 expression, respectively. Furthermore, nano-TiO2 elevated the expressions of ERK, AP-1, CRE, Akt, JNK2, MAPKs, PI3-K, c-Jun, and c-Fos in the spleen by 1.08-6-fold with increased exposure duration, respectively. These findings suggested that nano-TiO2-induced COX-2 expression may be mediated predominantly through the induction of AP-1 and CRE and that AP-1/CRE induction occurred via the MAPKs/PI3-K/Akt signaling pathways in the spleen. Therefore, the findings suggest the need for caution when using nanomaterials as food additives.

Nano-sized titanium dioxide-induced splenic toxicity: A biological pathway explored using microarray technology

“…In this paper, therefore, the down-regulation of Pf4, Cxcl13, and Ccl24 revealed that immune function of spleen was impaired under TiO 2 NP-induced toxicity. Our previous studies have shown that the immune dysfunction of spleen caused by TiO 2 NP exposure were related to up-regulation of NF-ÄB, TNF-˛, MIF, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IL-1ˇ, CRP, TGF-␤, and INF-␥ expressions, and down-regulation of IÄB expression [40]. Taken together, TiO 2 NP exposure would cause overwhelming damage to immune function of mice.…”

“…For example, TiO 2 NP exposure was demonstrated to result in the neutrophilic cell proliferation [36], lymph nodule proliferation [37], splenic apoptosis [38], disperative replication of white pulp, anemia of red pulpin [39], and macrophage infiltration [40,41] in the mouse spleen, leading immune dysfunction. Furthermore, these studies mentioned above suggested that TiO 2 NP-induced splenic damages were closely associated with oxidative stress, P38-Nrf-2 signaling pathway [37], mitochondrion-mediated intrinsic apoptotic pathway [38] and NF-B-mediated inflammatory pathways as well as MAPKs/PI3-K/Akt signaling pathways [39][40][41]. Taken together, the mechanisms of splenic damages caused by TiO 2 NP exposure are complex and diverse, we hypothesized that TiO 2 NP-induced splenic toxicity in animals may have special biomarkers of toxicity.…”

Decreased spermatogenesis led to alterations of testis-specific gene expression in male mice following nano-TiO2 exposure

“…The photocatalytic properties of TiO 2 NPs have been proved to raise various issues with respect to its poisonous impacts in the lungs [11][12][13][14], livers [15][16][17][18][19][20][21], kidneys [22][23][24][25], spleens [26][27][28][29], brains [30][31][32][33][34][35][36] and hearts [37,38] of animals.…”

Toxicology of nanosized titanium dioxide: an update

“…Furthermore, increased proliferation of spleen-derived T cells and B cells following mitogen stimulation and enhanced NK cell killing activity were found by repeated instillation of nano-TiO 2 . Sang et al (2013) paid more attention to the molecular mechanism in splenic injury induced by repeated administration of nano-TiO 2 . They found that increasing expression of cyclooxygenase (COX)-2 had a vital role in splenic injury.…”