<p>NLRP3 inflammasome, oxidative stress, and apoptosis induced in the intestine and liver of rats treated with titanium dioxide nanoparticles: in vivo and in vitro study</p>

Abstract

Purpose This study evaluated the effects of titanium dioxide nanoparticles (TiO 2 NPs) on liver and intestine of normal rats. Methods Male rats were divided into four groups as follows: 1) control rats, 2) control rats that orally received 10 mg/kg TiO 2 NPs, 3) control rats that orally received 50 mg/kg TiO 2 NPs, and 4) control rats that orally received 100 mg/kg TiO 2 NPs. After 30 days, the NLRP3 inflammasome pathway (NLRP3, caspase-1, and IL-1β), antioxidant pathway (superoxide dismutase [SOD], glutathione peroxidase [GPx], and catalase [CAT]), inflammatory pathway (inducible nitric oxide synthase [iNOS] and tumor necrosis factor-α [TNF-α]), and the apoptosis pathway (p53, Bax, Bcl-2, and caspase-3) were determined in the intestine and liver of the rats. H&E and Masson’s trichrome (MT) staining as well as TUNEL assay were used to examine the liver and the intestine. Biochemical factors, cytotoxicity, ROS generation, and apoptosis rate were also determined in HepG2 and Caco-2 cells. Results TiO 2 NPs in a dose-dependent manner increased cytotoxicity, oxidative stress, and apoptosis rate in Caco-2 and HepG2 cells. The administration of TiO 2 NPs significantly reduced antioxidant enzyme activity and gene expressions (SOD, CAT, and GPx) as well as glutathione (GSH) levels and total antioxidant capacity (TAC) in a dose-dependent manner. TiO 2 NPs also induced the apoptosis pathway and inflammatory pathway gene expressions and caspase-3 activity in the intestine and liver. TUNEL assay was in agreement with gene expressions. TiO 2 NPs also led to morphological changes in the liver and intestine. Conclusion TiO 2 NPs could have cytotoxic effects on the intestine and liver structure and function by inducing oxidative stress, inflammation, and apoptosis.

Rethinking Nano‐TiO2 Safety: Overview of Toxic Effects in Humans and Aquatic Animals

“…injections, indicators of the liver (assessed by an increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in blood plasma [48] ) increased in a concentrationdependent manner in the serum of mice. [37,66,67] Mice IP-treated with a high dose of nano-TiO 2 (2592 mg kg −1 body weight) showed anorexia, diarrhea, lethargy, tremor, body weight loss and lusterless skin, indicating acute hepato-and gastrointestinal toxicity. [37] Similar signs were initially found mice exposed to the medium-dose (324 mg kg −1 body weight) but these signs gradually disappeared indicating adjustment to the mild toxic stress.…”

“…[37,66] After oral administration of 10-50 mg kg −1 of nano-TiO 2 , SOD and GPx decreased in first 30 days but increased after 90 days. [67,68] However, the elevated levels of SOD and GPx after the long-term exposure failed to restore the normal redox status as indicated by a depletion of GSH and elevated levels of oxidized to reduced glutathione. [68] Malondialdehyde (MDA) is a common product of lipid peroxidation and indicator of oxidative membrane damage.…”

“…injection (25-50 mg kg −1 ) led to a strong upregulation of apoptotic gene expression and in increase in the percentage of apoptotic cells in the liver of exposed rats. [66,67]…”

Differential influence of Streptococcus mitis on host response to metals in reconstructed human skin and oral mucosa

“…27 Further contradicting reports from in vitro assays describe titanium as being inert; for example, titanium scored as a very weak irritant and nonsensitizer in the reconstructed human epidermis assay with IL-18 release as readout, 21 whereas titanium was described to have sensitization and irritation potentials by triggering host innate immune responses in pulmonary macrophages (mice and human) and keratinocytes (human) 28,29 as well as in intestine and liver (rat). 30 Therefore, it is currently unclear whether the titanium-related complaints observed in the clinic-which appear as edema, erosions, ulcers, or lichenoid lesions on the oral mucosa or skin-are due to allergy to titanium or a localized inflammation caused by mechanical load and cytotoxic leachables from titanium or titanium alloys. 7,31,32 Because microbes trigger innate immune responses similar to those triggered by metals, it can be expected that microbes will also influence sensitization to metals.…”

Titanium Dioxide Nanoparticles Induced HeLa Cell Necrosis under UVA Radiation through the ROS-mPTP Pathway

“…Typical apoptotic bodies in A549 cells treated with nano-TiO 2 were observed by scanning electron microscope [ 13 ]. Administration of nano-TiO 2 for 30 days, the gene expressions of bax and p53 were elevated, bcl-2 expression was reduced, and cleaved caspase-3 activity was increased in the intestinal and liver of rats, which suggested that nano-TiO 2 induced apoptosis [ 14 ]. Cell necrosis is contrasted with apoptosis, characterized by cell swelling and membrane rupture [ 15 ].…”