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Abstract Although it is known that nano-TiO2or other nanoparticles can induce liver toxicities, the mechanisms and the molecular pathogenesis are still unclear. In this study, nano-anatase TiO2(5 nm) was injected into the abdominal cavity of ICR mice for consecutive 14 days, and the inflammatory responses of liver of mice was investigated. The results showed the obvious titanium accumulation in liver DNA, histopathological changes and hepatocytes apoptosis of mice liver, and the liver function damaged by higher doses nano-anatase TiO2. The real-time quantitative RT-PCR and ELISA analyses showed that nano-anatase TiO2can significantly alter the mRNA and protein expressions of several inflammatory cytokines, including nucleic factor-κB, macrophage migration inhibitory factor, tumor necrosis factor-α, interleukin-6, interleukin-1β, cross-reaction protein, interleukin-4, and interleukin-10. Our results also implied that the inflammatory responses and liver injury may be involved in nano-anatase TiO2-induced liver toxicity.

Abstract Nano-TiO2 was shown to cause various toxic effects in both rats and mice; however, the molecular mechanism by which TiO2 exerts its toxicity is poorly understood. In this report, an interaction of nano-anatase TiO2 with liver DNA from ICR mice was systematically studied in vivo using ICP-MS, various spectral methods and gel electrophoresis. We found that the liver weights of the mice treated with higher amounts of nano-anatase TiO2 were significantly increased. Nano-anatase TiO2 could be accumulated in liver DNA by inserting itself into DNA base pairs or binding to DNA nucleotide that bound with three oxygen or nitrogen atoms and two phosphorous atoms of DNA with the Ti–O(N) and Ti–P bond lengths of 1.87 and 2.38 Å, respectively, and alter the conformation of DNA. And gel electrophoresis showed that higher dose of nano-anatase TiO2 could cause liver DNA cleavage in mice.

Numerous studies have shown that lung injury can be caused by respiratory exposure to nanoparticulate titanium dioxide (nano‐TiO2), but whether pulmonary inflammation and fibrosis are related to the activation of the TGF‐β/Smad/p38MAPK/Wnt pathways remains unclear. In this study, mice were administrated nano‐TiO2 by nasal instillation for nine consecutive months, and the molecular mechanisms of nano‐TiO2 on the pulmonary toxicity of mice were examined. The findings suggested that nano‐TiO2 caused pneumonia and pulmonary fibrosis. Furthermore, the results also showed that an overproduction of reactive free radicals occurred in mouse lungs, and that the expression of TGF‐β/p38MAPK/Wnt pathway‐related factors, including hypoxia‐inducible factor 1α (HIF‐1α), transforming growth factor‐β1 (TGF‐β1), phosphorylated p38 mitogen activated protein kinases (p‐p38MAPK), small mothers against decapentaplegic homolog 2 (Smad2), extracellular matrix (ECM), Wingless/Integrated 3 (Wnt3), Wingless/Integrated 4 (Wnt4), integrin‐linked kinase (ILK), β‐catenin, nuclear factor‐κB (NF‐κB), α‐smooth muscle actin (α‐SMA), c‐Myc, Type I collage (collagen I), and Type collage III (collagen III) were remarkably elevated, while phosphorylated glycogen synthase kinase‐3β (p‐GSK‐3β) expression was decreased. Those data implied that the pulmonary inflammation and fibrosis caused by nano‐TiO2 exposure may be involved in reactive free radical‐mediated activation of the TGF‐β/Smad/p38MAPK/Wnt pathways. [ABSTRACT FROM AUTHOR]

Chronic inhalation bioassays in rodents are used to assess pulmonary carcinogenicity for purposes of hazard identification and potentially for risk characterization. Numerous studies have been confirmed that exposure to titanium dioxide nanoparticles (TiO2 NPs) may result in chronic pulmonary inflammation in both mice and rats. However, very few studies have focused on the pulmonary tumorigenesis. In this study, to examine whether chronic TiO2 NP exposure induce tumorigenesis in the lung, forty mice (each group) were nasally exposed to 1.25, 2.5, and 5 mg/kg body weight TiO2 NPs for nine consecutive months, lung pathology was then evaluated, and the biochemical function parameters in bronchoalveolar lavage (BAL) and tumor markers in the serum were investigated using an ELISA method. We observed that nasal exposure to TiO2 NPs caused infiltration of inflammatory cells, tumorigenesis in the lung, and accompanied by significant increases of lactate dehydrogenase, alkaline phosphatase, and total protein levels in BLAF, significant increases in tumor markers including cytokeratin 19, neuron-specific enolase, carcinoembryonic antigen, squamous cell carcinoma antigen, and cancer antigen-125 in the serum. It implies that chronic inhaled TiO2 NPs may increase possibility of pulmonary tumor formation for human. Therefore, the production and application of TiO2 NPs should be paid more attention. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1651-1657, 2017. [ABSTRACT FROM AUTHOR]

Titanium dioxide nanoparticles (TiO2 NPs) are used in many fields, such as paints, medicine additives, food additives, sunscreens, and agriculture. The aim of this study was to investigate the mechanism behind the formation of inflammation induced by TiO2 NPs. ICR mice were exposed to TiO2 NPs through intragastric administration at 2.5, 5, and 10 mg/kg body weight every day for 90 consecutive days. The experiment suggested that long-term exposure to TiO2 NPs resulted in an obvious inflammatory response in mice lung tissues, which led to a thickened alveoli septum, lung hyperemia, and titanium accumulation. Furthermore, our results show that TiO2 NPs exposure remarkably altered the expression of inflammation-related cytokines, with increases in proinflammatory cytokines-such as nucleic factor-κB, interferon-α, interferon-β, interleukin-1β, interleukin-6, cyclo-oxygen-ase, interleukin-8, interferon-inducible protein-10, and platelet-derived growth factor AB-and decreases in anti-inflammatory cytokines-such as inhibitor of NF-κB suppressor of cytokine signaling 1, endothelin 1, peroxisome proliferators-activated receptors-γ, and peroxisome proliferators-activated receptors coactivator-1α. This finding indicated that TiO2 NPs cause lung inflammation in mice after intragastric administration, primarily through the NF-κB signaling pathways. Therefore, more attention should be placed on the application of TiO2 NPs and their potential long-term effects, especially in human beings. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 720-727, 2017. [ABSTRACT FROM AUTHOR]

In the past two decades, titanium dioxide nanoparticles (TiO2 NPs) have been extensively used in medicine, food industry and other daily life, while their possible interactions with the their influence and human body on human health remain not well understood. Thus, the study was designed to examine whether long-term exposure to TiO2 NPs cause myocardial dysfunction which is involved in cardiac lesions and alter expression of genes and proteins involving inflammatory response in the mouse heart. The findings showed that intragastric feeding for nine consecutive months with TiO2 NPs resulted in titanium accumulation, infiltration of inflammatory cells and apoptosis of heart, reductions in net increases of body weight, cardiac indices of function (LV systolic pressure, maximal rate of pressure increase over time, maximal rate of pressure decrease over time and coronary flow), and increases in heart indices, cardiac indices of function (LV end-diastolic pressure and heart rate) in mice. TiO2 NPs also decreased ATP production in the hearts. Furthermore, TiO2 NPs increased expression of nuclear factor-κB, interleukin-lβ and tumour necrosis factor-α, and reduced expression of anti-inflammatory cytokines including suppressor of cytokine signaling (SOCS) 1 and SOCS3 in the cardiac tissue. These results suggest that TiO2 NPs may modulate the cardiac function and expression of inflammatory cytokines. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2917-2927, 2016. [ABSTRACT FROM AUTHOR]

The evaluation of toxicological effects of nanoparticles (NPs) is increasingly important due to their growing occupational use and presence as compounds in consumer products. Recent researches have demonstrated that long-term exposure to air particulate matter can induce cardiovascular events, but whether cardiovascular disease, such as cardiac damage, is induced by NP exposure and its toxic mechanisms is rarely evaluated. In the present study, when mice were continuously exposed to TiO 2 NPs at 2.5, 5 or 10 mg/kg BW by intragastric administration for 90 days, obvious histopathological changes, and great alterations of NF-κB and its inhibitor I-κB, as well as TNF-α, IL-1β, IL-6 and IFN-α expression were induced. The NPs significantly decreased Ca 2+ -ATPase, Ca 2+ /Mg 2+ -ATPase and Na + /K + -ATPase activities and enhanced NCX-1 content. The NPs also considerably increased CAMK II and α1/β1-AR expression and up-regulated p-PKCε and p-ERK 1/2 in a dose-dependent manner in the mouse heart. These data suggest that low-dose and long-term exposure to TiO 2 NPs may cause cardiac damage such as cardiac fragmentation or disordered myocardial fibre arrangement, tissue necrosis, myocardial haemorrhage, swelling or cardiomyocyte hypertrophy, and the inflammatory response was potentially mediated by NF-κB activation via the PKCε or ERK 1/2 signalling cascades in mice. [ABSTRACT FROM AUTHOR]

ABSTRACT Titanium dioxide nanoparticles (TiO2 NPs) have been used in environmental management, food, medicine, and industry. But TiO2 NPs have been demonstrated to cross the blood-brain barrier and store up in the brain organization, leading to glutamate-mediated neurotoxicity. However, the neurotoxicity in the brain is not well understood. In this study, mice were exposed to 1.25, 2.5, or 5 mg/kg body weight TiO2 NPs for 9 months, and the glutamate-glutamine cyclic pathway and expressions of glutamate receptors associated with the hippocampal neurotoxicity were investigated. Our findings showed elevations of glutamate release and phosphate-activated glutaminase activity, and reductions in glutamine and glutamine synthetase in the hippocampus following exposure to TiO2 NPs. Furthermore, TiO2 NPs significantly inhibited the expression of N-methyl- d-aspartate receptor subunits (including NR1, NR2A, and NR2B) and metabotropic glutamate receptor 2 in mouse hippocampus. These findings suggest that the imbalance of glutamate metabolism triggered inhibitions of glutamate receptor expression in the TiO2 NP-exposed hippocampus. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 655-662, 2016. [ABSTRACT FROM AUTHOR]

Although TiO 2 nanoparticles (NPs) exposure has been demonstrated to cross blood–testis barrier and accumulate in the testis resulting in the reduction of sperm numbers, limited data with respect to the molecular mechanism of decreased spermatogenesis caused by TiO 2 NP exposure. In this research, testicular damage, sperm number and alterations in testis-specific gene expressions in male mice induced by intragastric administration with TiO 2 NPs for six months were investigated. It was found out that TiO 2 NPs could migrate to cells, deposit in the testis and epididymis and thus cause damages to relevant organs, which are, to be more specific, the reductions of total sperm concentrations and sperm motility and an enhancement in the number of abnormal sperms in the cauda epididymis. Furthermore, the individual expression regarding to the mRNAs and proteins of testis-specific genes, including Cdc2, Cyclin B1, Dmcl, TERT, Tesmin, TESP-1, XPD and XRCCI, were significantly declined, whereas Gsk3-β and PGAM4 expressions were greatly elevated in mouse testis due to the exposures, which in fact implied that the reduced spermatogenesis may be involved in the alternated testis-specific gene expressions in those exposed male mice. [ABSTRACT FROM AUTHOR]

ABSTRACT Exposure to lanthanoids (Ln) elicits an adverse response such as oxidative injury of lung in animals and human. The molecular targets of Ln remain unclear. In the present study, the function and signal pathway of nuclear factor erythroid 2 related factor 2 (Nrf2) in LaCl3-induced oxidative stress in mouse lung were investigated. Mice were exposed to 2, 5, and 10 mg/kg body weight by nasal administration for 6 consecutive months. With increased doses, La was markedly accumulated and promoted the reactive oxygen species (ROS) production in the lung, which in turn resulted in peroxidation of lipids, proteins and DNA, and severe pulmonary damages. Furthermore, LaCl3 exposure could significantly increase levels of Nrf2, heme oxygenase 1 (HO-1) and glutamate-cysteine ligase catalytic subunit (GCLC) expressions in the LaCl3-exposed lung. These findings imply that the induction of Nrf2 expression is an adaptive intracellular response to LaCl3-induced oxidative stress in mouse lung, and that Nrf2 may regulate the LaCl3-induced pulmonary damages. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 357-365, 2015. [ABSTRACT FROM AUTHOR]

Immune injuries following the exposure of titanium dioxide nanoparticles (TiO2 NPs) have been greatly concerned along with the TiO2 NPs are widely used in pharmacology and daily life. However, very little is known about the immunomodulatory mechanisms in the spleen-injured mice due to TiO2 NPs exposure. In this study, mice were continuously exposed to 2.5, 5, or 10 TiO2 NPs mg kg−1 body weight for 90 days with intragastric administration to investigate the immunomodulatory mechanisms in the spleen. The findings showed that TiO2 NPs exposure resulted in significant increases in spleen and thymus indices, and titanium accumulation, in turn led to histopathological changes and splenocyte apoptosis. Furthermore, the exposure of TiO2 NPs could significantly increase the levels of macrophage inflammatory protein (MIP)−1α, MIP-2, Eotaxin, monocyte chemotactic protein-1, interferon-γ, vascular cell adhesion molecule-1, interleukin-13, interferon-γ-inducible protein-10, migration inhibitory factor, CD69, major histocompatibility complex, protein tyrosine phosphatase, protein tyrosine kinase 1, basic fibroblast growth factor, Fasl, and GzmB expression, whereas markedly decrease the levels of NKG2D, NKp46, 2B4 expression involved in immune responses, lymphocyte healing and apoptosis. These findings would better understand toxicological effects induced by TiO2 NPs exposure. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3562-3572, 2014. [ABSTRACT FROM AUTHOR]

In an effort to investigate the effects of exposure to lanthanoids (Ln) on the immune response and liver function, mice were orally exposed to LaCl3, CeCl3, and NdCl3 at 2, 10, and 20 mg/kg doses for 30 days, respectively; lymphocyte counts, serum IgM level, hematological indices, biochemical parameters of liver functions, and histopathological changes in Ln3+-treated mice were assessed. Indeed, 20 mg/kg Ln3+ significantly inhibited mice growth and reduced the counts of white blood cells, platelets, and reticulocyte in mice blood. Specifically, in these Ln3+-treated mice, CD3+, CD4+, CD8+, CD19+ and NK cells, and CD4+/CD8+ ratio as well as serum IgM level were decreased. Furthermore, liver function was disrupted, as evidenced by the increased alanine aminotransferase, total bilirubin, total bile acid and triglycerides, and the decreased glucose and ratio of albumin to globulin. The cytoarchitecture damage and fatty degeneration in liver caused by Ln3+ at 20 mg/kg dose were also observed. Our findings showed that exposure to Ln affected the cell and humoral immunity and disturbed liver function in mice. In addition, Ce3+ was found to exhibit higher toxicity than La3+ and Nd3+. © 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 64-73, 2014. [ABSTRACT FROM AUTHOR]

To investigate the molecular mechanism of inflammatory response in the mouse liver caused by exposure to CeCl3, we measured the liver indices, and cerium content, evaluated the liver histopathological section, detected serum biochemical parameters of liver function, and the immunoglobulin M (IgM) content, analyzed the liver mRNA and protein expression levels of Toll-like receptor 2, 4 (TLR2, TLR4), and inflammatory cytokines in liver using real-time quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that exposure to CeCl3 decreased body weight and caused cerium accumulation in the mouse liver and histopathological changes of liver (such as inflammatory cell infiltration). Furthermore, biochemical assays suggested that CeCl3 could promote the activities of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase, pseudocholinesterase, and leucine aminopeptidase, decrease serum IgM, upregulate the levels of TLR2, TLR4, nuclear factor-κB (NF-κB), NF-κBp52, NF-κBp65, NF-κB-inducing kinase (NIK), IκB kinase α (IKK-α), IκB kinase β (IKK-β), and tumor necrosis factor-α (TNF-α) expression, and suppress NF-κB-inhibiting factor (IκB) and interleukin-2 (IL-2) expression in liver. Taken together, the inflammation of mice liver caused by exposure to CeCl3 might be closely associated with the alteration of inflammatory cytokine expressions in the mouse liver, the signal-transducing events happening in CeCl3-induced macrophages of liver sequentially might occur via activation of TLRs→TNF-α→NIK→IκB kinase (including IKK1, IKK2)→NF-κB (including NF-κBP52, NF-κBP65)→ inflammation. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013. [ABSTRACT FROM AUTHOR]

Although liver toxicity induced by titanium dioxide nanoparticles (TiO2 NPs) has been demonstrated, very little is known about the molecular mechanisms of multiple genes working together underlying this type of liver injury in mice. In this study, we used the whole-genome microarray analysis technique to determine the gene expression profile in the livers of mice exposed to 10 mg/kg body weight TiO2 NPs for 90 days. The findings showed that long-term exposure to TiO2 NPs resulted in obvious titanium accumulation in the liver and TiO2 NP aggregation in hepatocyte nuclei, an inflammatory response, hepatocyte apoptosis, and liver dysfunction. Furthermore, microarray data showed striking changes in the expression of 785 genes related to the immune/inflammatory response, apoptosis, oxidative stress, the metabolic process, response to stress, cell cycle, ion transport, signal transduction, cell proliferation, cytoskeleton, and cell differentiation in TiO2 NP–exposed livers. In particular, a significant reduction in complement factor D (Cfd) expression following long-term exposure to TiO2 NPs resulted in autoimmune and inflammatory disease states in mice. Therefore, Cfd may be a potential biomarker of liver toxicity caused by TiO2 NPs exposure. [ABSTRACT FROM PUBLISHER]

While the nephrotoxicity of high-dose nano-TiO2 has been demonstrated, very little is known about the mechanism of oxidative stress to the animal kidney. In order to understand the nephrotoxicity of nano-anatase TiO2 particles, various biochemical and chemical parameters were assayed in mouse kidneys. Abdominal exposures of high-dose nano-anatase TiO2 caused nephritis and oxidative stress to kidney. An increase in coefficients of the kidney, Ti accumulation and histopathological changes in kidney could be observed, followed by increased reactive oxygen species generation and lipid peroxidation, and decreased activities of superoxide dismutase, catalase, ascorbate peroxidase and total antioxidant capacity as well as antioxidants such as glutathione and ascorbic acid content. In addition, kidney functions were disrupted, including increase of the creatinine, calcium and phosphonium, and reduction of uric acid and blood urea nitrogen. Our results suggest that nephritis generation in mice caused by nano-anatase TiO2 particles is closely related to oxidative stress. [ABSTRACT FROM AUTHOR]

The evaluation of toxicological effects of nanoparticulate matter is increasingly important due to their growing occupational use and presence as compounds in consumer products. Numerous studies have shown that exposure to nanosized particles lead to systemic inflammation in experimental animals, but whether long-term exposure to nanosized particles induces atherogenesis is rarely evaluated. In the current study, mice were continuously exposed to TiO 2 nanoparticles (NPs) at 1.25, 2.5, or 5 mg/kg body weight, administered by nasal instillation for nine consecutive months, and the association between serum parameter changes and atherosclerosis in mice were investigated. The present findings suggested that chronic exposure to TiO 2 NPs resulted in atherogenesis coupling with pulmonary inflammation, increased levels of serum triglycerides, glucose, total cholesterol, low-density lipoprotein cholesterol, advanced glycation end products, reactive oxygen species, NAD(P)H oxidases 4, C-reaction protein, E-selectin, endothelin-1, tissue factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and reduced levels of serum high-density lipoprotein cholesterol, nitric oxide and tissue plasminogen activator. Our study suggests an association of long-term exposure to TiO 2 NPs with atherosclerosis and pulmonary inflammation. This finding demonstrates the hypothesized role of TiO 2 NPs as a risk factor for atherogenesis. [ABSTRACT FROM AUTHOR]

Highlights: [•] TiO2 NPs exposure resulted in hippocampus injury and decreased spatial recognition of mice. [•] TiO2 NPs exposure resulted in decreased long-term potentiation. [•] TiO2 NPs exposure caused down-regulation of NR2A and NR2B expression in hippocampus. [•] TiO2 NPs decreased expression of CaMKIV, CREB-1 and FosB/DFosB. [Copyright &y& Elsevier]

Abstract: Previous studies demonstrate that the exposure to titanium dioxide nanoparticles (TiO2 NPs) damages the central nervous system of mice; however, very little is known about the effects of TiO2 NPs on hippocampal apoptosis or its molecular mechanism. The present study investigated the molecular mechanism associated with hippocampal apoptosis in mice induced by intragastric administration of TiO2 NPs for consecutive 60 days. Our findings indicate that TiO2 NPs accumulate in the mouse hippocampus, and this accumulation, in turn, led to hippocampal apoptosis and impairment in spatial recognition memory in mice. In addition, TiO2 NPs significantly activated caspase-3 and -9, inhibited Bcl-2, and promoted the levels of Bax and cytochrome c. Furthermore, TiO2 NPs induced accumulation of reactive oxygen species in the mouse hippocampus. These findings suggest that TiO2 NP-induced apoptosis in the mouse hippocampus may result from an intrinsic pathway, and workers and consumers should take great caution when handling nanomaterials. [Copyright &y& Elsevier]

Abstract: With their widespread application in agriculture, industry, culture, medicine, and daily life, lanthanide compounds are being brought into the ecological environment and human body through food chains. It is important to know the acute and chronic effects of lanthanides on the environment, nature balance, and the human body after their entry into bodies and the environment. Lanthanides have been demonstrated to cause spleen apoptosis and decreased immunity of mice, but very little is known about the molecular aspects of these mechanism. In order to understand the spleen apoptotic mechanism induced by intragastric administration of 2, 10 and 20mgkg−1 body weight CeCl3 for consecutive 60d, we investigated the cerium accumulation, apoptosis, the expression levels of the apoptosis-related cytokines into apoptosis-related genes and proteins. The results demonstrated that cerium had obvious accumulation in the mouse spleen, leading to the significant increase of the spleen indices and splenocyte apoptosis. Furthermore, CeCl3 could effectively activate caspase-3 and -9, decrease the Bcl-2 the levels of gene and protein, and increase the levels of Bax, and cytochrome c genes and their protein expressions, and promote reactive oxygen species production. It implied CeCl3-induced apoptosis in the mouse spleen via intrinsic pathway. Our findings suggest the need for great caution to handle the lanthanides for workers and consumers. [Copyright &y& Elsevier]

Abstract: While the hepatocyte apoptosis induced by TiO2 nanoparticules (NPs) has been demonstrated, very little is known about the molecular mechanisms underlying this mouse liver apoptosis. In order to understand the hepatocyte apoptosis induced by intragastric administration of TiO2 NPs for consecutive 60 days, the hepatocyte apoptosis, various oxidative stress parameters and the stress-related gene expression levels were assayed for the mouse liver. 60 days of TiO2 NPs exposure, hepatocyte apoptosis in the liver could be observed, which was followed by increased reactive oxygen species accumulation, and decreased the stress-related gene expression levels of superoxide dismutase, catalase, glutathione peroxidase, metallothionein, heat shock protein 70, glutathione S transferase, P53, and transferrin; and the significant enhancement of the cytochrome p450 1A expression level. It implied that hepatocyte apoptosis, oxidative stresses, and alteration of expression levels of the genes related with TiO2 NPs detoxification/metabolism regulation and radical scavenging action. Therefore, the application of TiO2 NPs and exposure effects especially on human liver for long-term and low-dose treatment should be cautious. [Copyright &y& Elsevier]

Abstract: Titanium dioxide nanoparticles (TiO2 NPs) are now in daily use including popular sunscreens, toothpastes, and cosmetics. However, the effects of TiO2 NPs on human body, especially on the central nervous system, are still unclear. The aim of this study was to determine whether TiO2 NPs exposure results in persistent alternations in nervous system function. ICR mice were exposed to TiO2 NPs through intragastric administration at 0, 5, 10 and 50 mg/kg body weight every day for 60 days. The Y-maze test showed that TiO2 NPs exposure could significantly impair the behaviors of spatial recognition memory. To fully investigate the neurotoxicological consequence of TiO2 NPs exposure, brain elements and neurochemicals were also investigated. The contents of Ca, Mg, Na, K, Fe and Zn in brain were significantly altered after TiO2 NPs exposure. Moreover, TiO2 NPs significantly inhibited the activities of Na+/K+-ATPase, Ca2+-ATPase, Ca2+/Mg2+-ATPase, acetylcholine esterase, and nitric oxide synthase; the function of the central cholinergic system was also noticeably disturbed and the contents of some monoamines neurotransmitters such as norepinephrine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid were significantly decreased, while the contents of acetylcholine, glutamate, and nitric oxide were significantly increased. These first findings indicated that exposure to TiO2 NPs could possibly impair the spatial recognition memory ability, and this deficit may be possibly attributed to the disturbance of the homeostasis of trace elements, enzymes and neurotransmitter systems in the mouse brain. Therefore, the application of TiO2 NPs and exposure effects especially on human brain for long-term and low-dose treatment should be cautious. [Copyright &y& Elsevier]

Abstract: Nanoparticulate titanium dioxide (TiO2) has been demonstrated to decrease immunity of mice, but very little is known about the injury of spleen involved immunomodulation and its molecular mechanism. In order to understand the spleen injury induced by intraperitoneal injection of TiO2 nanoparticules (NPs) for consecutive 45 days, the spleen pathological changes, apoptosis, the expression levels of the apoptotic genes and their proteins, and oxidative stress in the mouse spleen were investigated. The results demonstrated that TiO2 NPs had obvious accumulation in the mouse spleen, leading to congestion and lymph nodule proliferation of spleen tissue, and splenocyte apoptosis. TiO2 NPs effectively activated caspase-3 and -9, decreased the Bcl-2 the levels of gene and protein, and increase the levels of Bax, and cytochrome c genes and their protein expression, promoted ROS accumulation. Taken together, this study indicated that TiO2 NPs-induced apoptosis in the mouse splenocyte via mitochondrial-mediated pathway. These findings provide strong evidence that the TiO2 NPs can induce the spleen pathological changes, apoptosis, leading to the reduction of immunity of mice. [Copyright &y& Elsevier]

Abstract: In an effort to examine liver injury, immune response, and other physiological effects in mice caused by intragastric administration of nanoparticulate anatase titanium dioxide (5nm), we assessed T lymphocytes, B lymphocyte and NK lymphocyte counts, hematological indices, biochemical parameters of liver functions, and histopathological changes in nanoparticulate titanium dioxide -treated mice. Indeed, mice treated with higher dose nanoparticulate titanium dioxide displayed a reduction in body weight, an increase in coefficients of the liver and histopathological changes in the liver. Specifically, in these nanoparticulate titanium dioxide -treated mice, interleukin-2 activity, white blood cells, red blood cells, haemoglobin, mean corpuscular haemoglobin concentration, thrombocytes, reticulocytes, T lymphocytes (CD3+, CD4+, CD8+), NK lymphocytes, B lymphocytes, and the ratio of CD4 to CD8 of mice were decreased, whereas NO level, mean corpuscular volume, mean corpuscular haemoglobin, red (cell) distribution width, platelets, hematocrit, mean platelet volume of mice were increased. Furthermore, liver functions were also disrupted, as evidenced by the enhanced activities of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase and cholinesterase, an increase of the total protein, and the reduction of ratio of albumin to globulin, the total bilirubin, triglycerides, and the total cholesterol levels. These results suggested that the liver function damage observed in mice treated with higher dose nanoparticulate titanium dioxide is likely associated with the damage of haemostasis blood system and immune response. However, low dose nanoparticulate anatase TiO2 has little influences on haemostasis blood system and immune response in mice. [Copyright &y& Elsevier]

Abstract: The organ-toxicity of high-dose lanthanides on organisms had been recognized, but very little is known about the injury of immune organ such as spleen induced by Ln. In order to understand the splenic toxicity of Ln, various biochemical and chemical parameters were assayed in the mouse spleen. Abdominal exposure to LaCl3, CeCl3, and NdCl3 at dose of 20mg/kg body weight caused splenomegaly and oxidative stress to the spleen. Evident Ln deposition, congestion, mitochondria swelling, and apoptosis in the spleen could be observed, followed by increased generation of reactive oxygen species, lipid peroxidation and SOD activity, and decreased GSH-Px activity as well as nonenzymatic antioxidants such as glutathione and ascorbic acid content. In addition, the high amount of NO and increased NOS activities caused by Ln were measured. Furthermore, both Ce3+ and Nd3+ exhibited higher oxidative stress and toxicity on spleen than La3+, and Ce3+ caused more serve splenocyte injuries and oxidative stress than Nd3+, implying that the difference in the splenic injuries caused by Ln was related to the number of 4f electrons of Ln. [Copyright &y& Elsevier]

Abstract: In order to study the mechanisms underlying the effects of TiO2 nanoparticles on the brain, ICR mice were injected with nanoparticulate anatase TiO2 (5nm) of various doses into the abdominal cavity daily for 14 days. We then examined the coefficient of the brain, the brain pathological changes and oxidative stress-mediated responses, and the accumulation of nanoparticulate anatase TiO2 and levels of neurochemicals in the brain. The results showed that high-dose nanoparticulate anatase TiO2 could induce some neurons to turn into filamentous shapes and others into inflammatory cells. The concentration of nanoparticulate anatase TiO2 in the brain was increased as increases in nanoparticulate anatase TiO2 dosages used. The oxidative stress and injury of the brain occurred as nanoparticulate anatase TiO2 appeared to trigger a cascade of reactions such as lipid peroxidation, the decreases of the total anti-oxidation capacity and activities of antioxidative enzymes, the excessive release of nitric oxide, the reduction of glutamic acid, and the downregulated level of acetylcholinesterase activities. We concluded that TiO2 nanoparticles injected at the abdominal cavity could be translocated into the brain and in turn caused the brain injury. [Copyright &y& Elsevier]