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Titanium dioxide nanoparticles (TiO2 NPs) have been shown to induce reproductive system damages in animals. To better underline how TiO2 NPs act in reproductive system, female mice were exposed to 2.5, 5, or 10 mg/kg TiO2 NPs by gavage administration for 60 days, the ovary injuries, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels as well as ovarian follicular development‐related molecule expression were investigated. The results showed that TiO2 NPs exposure resulted in reduction of ovary weight and inhibition of ovarian follicular development. Furthermore, the suppression of follicular development was demonstrated to be closely related to higher FSH and LH levels, and higher expression of activin, follistatin, BMP2, BMP4, TGF‐β1, Smad2, Smad3, and Smad4 as well as decreased inhibin‐α expression in mouse ovary in a dose‐dependent manner. It implies that the impairment of ovarian follicular development caused by TiO2 NPs exposure may be mediated by TGF‐β signal pathway. [ABSTRACT FROM AUTHOR]

Titanium dioxide nanoparticles (TiO 2 -NPs) are widely used in food, paint, coating, cosmetic, and composite orthodontic material. As a common food additive, TiO 2 -NPs can accumulate in various organs of human body, but the effect and underlying mechanism of bone remain unclear. Here mice were exposed to TiO 2 -NPs by oral gavage, and histological staining of femoral sections showed that TiO 2 -NPs reduced bone formation and enhanced osteoclast activity and lipogenesis, contributing to decreased trabecula bone. Transmission electron microscope (TEM) as well as biochemical and flow cytometry analysis of osteoblast exhibited that TiO 2 -NPs accumulated in osteoblast cytoplasm and impaired mitochondria ultrastructure with increased reactive oxygen species (ROS) and lipid hyperoxide, resulting in osteoblast apoptosis. In terms of mechanism, TiO 2 -NPs treatment inhibited expression of AKT and then increased pro-apoptotic protein Bax expression which was failure to form heterodimers with decreased anti-apoptotic Bcl-2, activating downstream Caspase-9 and Caspase-3 and inducing apoptosis. Additionally, TiO 2 -NPs suppressed Wnt3a level and then activated anti-Glycogen synthesis kinase (GSK-3β) phosphorylation, and ultimately resulted in degradation of β-catenin which down-regulated Runt-related transcription factor 2 (Runx2) and Osterix, inhibiting expression of osteogenic related proteins. Together, these results revealed that exposure of TiO 2 -NPs induced apoptosis and inhibited osteoblast differentiation through suppressing PI3K/AKT and Wnt/β-catenin signaling pathways, resulting in reduction of trabecula bone. • TiO 2 -NPs inhibited osteogenesis and enhanced lipogenesis, decreasing trabecula bone. • TiO 2 -NPs activated intrinsic apoptosis via inhibiting PI3K/AKT pathway. • TiO 2 -NPs inhibited osteoblast differentiation through Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Titanium dioxide nanoparticles (TiO2 NPs) are increasingly used in daily life, in industry, and in environmental clearing, but their potential neurodevelopmental toxicity has been highly debated. In this study, we explored whether TiO2 NPs inhibited development of dendritic morphology and identified possible molecular mechanisms associated with this inhibition in primary cultured rat hippocampal neurons. Results showed that TiO2 NPs decreased neurite length, the number of branches and the spine density, and impaired mitochondrial function in the developing neurons. Furthermore, TiO2 NPs significantly reduced the expression of several proteins involved in canonical Wnt3a/β-catenin signaling including Wnt3a, β-catenin, p-GSK-3β, and CyclinD1 and conversely, elevated GSK-3β expression. In addition to altering expression of proteins involved in canonical Wnt3a/β-catenin signaling, TiO2 NPs decreased expression of proteins invovled in non-canonical Wnt signaling, including, MKLP1, CRMP3, ErbB4, and KIF17. Taken together, these results indicate that suppression of dendritic development caused by TiO2 NPs is associated with inhibition of activation of the Wnt/β-catenin pathway or non-canonical Wnt pathway-induced expression of microtubule cytoskeletal components in the developing neurons. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2139-2149, 2017. [ABSTRACT FROM AUTHOR]

Although numerous studies have demonstrated that titanium dioxide nanoparticles (TiO2 NPs) can be accumulated in various animal organs and can cause toxicity, there is currently only limited data regarding reproductive toxicity especially on the toxic mechanisms of TiO2 NPs in Sertoli cells. In order to investigate the mechanism of reproductive toxicity, primary cultured rat Sertoli cells were exposed to 5, 15, or 30 μg/mL TiO2 NPs for 24 h, and TiO2 NPs internalization, expression of PKC (p-PKC) and p38 MAPK (p-p38 MAPK) as well as calcium homeostasis were examined. Our findings demonstrated that TiO2 NPs crossed the membrane into the cytoplasm or nucleus, and significantly suppressed cell viability of primary cultured rat Sertoli cells in a concentration-dependent manner. Furthermore, immunological dysfunction caused by TiO2 NPs was involved in the increased expression of NF-κB, TNF-α, and IL-1β, and decreased IκB expression. TiO2 NPs significantly decreased Ca2+-ATPase and Ca2+/Mg2+-ATPase activity and enhanced intracellular Ca2+ levels, and up-regulated the expression of p-PKC and p-p38 MAPK in a dose-dependent manner in primary cultured rat Sertoli cells. Taken together, these findings indicate that TiO2 NPs may induce immunological dysfunction of primary cultured rat Sertoli cells by stimulating the Ca2+/PKC/p38 MAPK cascade, which triggers NF-κB activation and ultimately induces the expression of inflammatory cytokines in primary cultured rat Sertoli cells. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1374-1382, 2017. [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]

Titanium dioxide nanoparticles (TiO2 NPs), as largest production and use of nanomaterials, have been demonstrated to have a potential toxicity on reproductive system. However, the mechanism underlying male reproductive toxicity of TiO2 NPs remains limited. Thus, our study was designed to examine the cellular viability, apoptosis, oxidative stress, antioxidant capacity, and expression of apoptotic cytokines in primary cultured Sertoli cells isolated from mice under TiO2 NPs exposure. Results showed that TiO2 NPs exposure from 5 to 30 μg/mL resulted in reduction of cell viability, lactate dehydrogenase release, and induction of apoptosis or death on Sertoli cells. TiO2 NPs could migrate to Sertoli cells, which induced mitochondria-mediated or endoplasmic-reticulum-mediated apoptotic changes including elevation in reactive oxygen species (ROS) generation and reductions in superoxide dismutase, catalase, and glutathione peroxidase activities, decreases in mitochondrial membrane potential (DWm), and releases of cytochrome c into the cytosol. In addition, upregulation of cytochrome c, Bax, caspase-3, glucose-regulated protein 78, and C/ EBP homologous protein and caspase-12 protein expression, and downregulation of bcl-2 protein expression in primary cultured Sertoli cells induced by TiO2 NPs treatment. All of the results suggested that ROS generation may play a critical role in the initiation of TiO2 NPs-induced apoptosis by mediation of the disruption of Δψm, the cytochrome c release, and further the activation of caspase cascade and unfolded protein response signaling pathway. [ABSTRACT FROM AUTHOR]

Exposure to titanium dioxide nanoparticles (TiO2 NPs) has been demonstrated to decrease learning and memory of animals. However, whether the impacts of these NPs on the recognition function are involved in hippocamal neuron damages is poorly understood. In this study, primary cultured hippocampal neurons from one-day-old fetal Sprague-Dawley rats were exposed to 5, 15, or 30 µg/mL TiO2 NPs for 24 h, we investigated cell viability, ultrastructure, and mitochondrial membrane potential (MMP), calcium homeostasis, oxidative stress, antioxidant capacity, apoptotic signaling pathway associated with the primary cultured hippocamal neuron apoptosis. Our findings showed that TiO2 NP treatment resulted in reduction of cell viability, promoted lactate dehydrogenase release, apoptosis, and increased neuron apoptotic rate in a dose-dependent manner. Furthermore, TiO2 NPs led to [Ca2+]i elevation, and MMP reduction, up-regulated protein expression of cytochrome c, Bax, caspase-3, glucose-regulated protein 78, C/EBP homologous protein and caspase-12, and down-regulated bcl-2 expression in the primary cultured hippocampal neurons. These findings suggested that hippocampal neuron apoptosis caused by TiO2 NPs may be associated with mitochondria-mediated signal pathway and endoplasmic reticulum-mediated signal pathway. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 1141-1149, 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]

Titanium dioxide nanoparticles (TiO2 NPs) have been used in various medical and industrial areas. However, the impacts of these nanoparticles on neuroinflammation in the brain are poorly understood. In this study, mice were exposed to 2.5, 5, or 10 mg/kg body weight TiO2 NPs for 90 consecutive days, and the TLRs/TNF-α/NF-κB signaling pathway associated with the hippocampal neuroinflammation was investigated. Our findings showed titanium accumulation in the hippocampus, neuroinflammation and impairment of spatial memory in mice following exposure to TiO2 NPs. Furthermore, TiO2 NPs significantly activated the expression of Toll-like receptors (TLR2, TLR4), tumor necrosis factor-α, nucleic IκB kinase, NF-κB-inducible kinase, nucleic factor–κB, NF-κB2(p52), RelA(p65), and significantly suppressed the expression of IκB and interleukin-2. These findings suggest that neuroinflammation may be involved in TiO2 NP-induced alterations of cytokine expression in mouse hippocampus. Therefore, more attention should be focused on the application of TiO2 NPs in the food industry and their long-term exposure effects, especially in the human central nervous system. [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: Numerous studies have demonstrated that the brain is one of the target organs in acute or chronic titanium dioxide (TiO2) nanoparticles (NPs) toxicity, and oxidative stress plays an important role in this process. However, whether brain oxidative injury responds to TiO2 NPs by activating the P38-nuclear factor-E2-related factor-2 (Nrf-2) pathway is not fully understood. The present study aimed to examine activation of the P38-Nrf-2 signaling pathway associated with oxidative stress in the mouse brain induced by intranasal administration of TiO2 NPs for 90 consecutive days. Our findings indicate that TiO2 NPs caused overproliferation of spongiocytes and hemorrhage in the mouse brain. Furthermore, TiO2 NPs significantly activated p38, c-Jun N-terminal kinase, nuclear factor kappa B, Nrf-2 and heme oxygenase-1 expression in the brain, which in turn, led to increased production of reactive oxygen species, as well as lipid, protein and DNA peroxidation. These findings suggest that TiO2 NPs-induced oxidative damage in the mouse brain may occur via the p38-Nrf-2 signaling pathway. Therefore, application of TiO2 NPs in the environment should be performed with caution. [Copyright &y& Elsevier]

Highlights: [•] Exposure to TiO2 NPs could cross blood–testis barrier and be accumulated in testis. [•] Exposure to TiO2 NPs caused testis and sperm lesions in male mice. [•] Exposure to TiO2 NP decreased sperm numbers and sperm motility in male mice. [•] Exposure to TiO2 NP resulted in imbalance of sex hormones in male mice. [•] Exposure to TiO2 NP caused alteration of 142 genes expression of known function in testis. [ABSTRACT FROM AUTHOR]

Abstract: Although numerous studies have described the accumulation of titanium dioxide nanoparticles (TiO2 NPs) in the liver, kidneys, lung, spleen, and brain, and the corresponding damage, it is unclear whether or not TiO2 NPs can be translocated to the ovary and cause ovarian injury, thus impairing fertility. In the current study, ovarian injury and gene-expressed characteristics in female mice induced by intragastric administration of TiO2 NPs (10mg/kg) for 90 consecutive days were investigated. Our findings indicated that TiO2 NPs can accumulate in the ovary and result in ovarian damage, cause an imbalance of mineral element distribution and sex hormones, decrease fertility or the pregnancy rate and oxidative stress in mice. Microarray analysis showed that in ovaries from mice treated with TiO2 NPs compared to controls, 223 genes of known function were up-regulated, while 65 ovarian genes were down-regulated. The increased expression of Cyp17a1 following TiO2 NPs treatment suggested that the increase in estradiol biosynthesis may be a consequence of increased TiO2 NPs. In addition, the elevated expression of Akr1c18 implied that progesterone metabolism was accelerated, thus causing a decrease in the progesterone concentration. Taken together, the apparent regulation of key ovarian genes supports the hypothesis that TiO2 NPs directly affects ovarian function. [Copyright &y& Elsevier]

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]

Numerous studies have indicated that nano-titanium dioxide (TiO 2 ) can induce neurotoxicity in vitro and in vivo , however, it is unclear whether nano-TiO 2 affects neurite outgrowth of hippocampal neurons. In order to investigate the mechanism of neurotoxicity, rat primary cultured hippocampal neurons on the fourth day of culture were exposed to 5, 15, and 30 μg/mL nano-TiO 2 for 24 h, and nano-TiO 2 internalization, dendritic growth, glutamate metabolism, expression of N-methyl- d -aspartate (NMDA) receptor subunits (NR1, NR2A and NR2B), calcium homeostasis, sodium current (I Na ) and potassium current (I K ) were examined. Our findings demonstrated that nano-TiO 2 crossed the membrane into the cytoplasm or nucleus, and significantly suppressed dendritic growth of primary cultured hippocampal neurons in a concentration-dependent manner. Furthermore, nano-TiO 2 induced a marked release of glutamate to the extracellular region, decreased glutamine synthetase activity and increased phosphate-activated glutaminase activity, elevated intracellular calcium ([Ca 2+ ]i), down-regulated protein expression of NR1, NR2A and NR2B, and increased the amplitudes of the I Na and I K . In addition, nano-TiO 2 increased nitric oxide and nitrice synthase, attenuated the activities of Ca 2+ -ATPase and Na + /K + -ATPase, and increased the ADP/ATP ratio in the primary neurons. Taken together, these findings indicate that nano-TiO 2 inhibits neurite outgrowth of hippocampal neurons by interfering with glutamate metabolism and impairing NMDA receptor function. [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]

Abstract: Exposure to titanium dioxide nanoparticles (TiO2 NPs) has been demonstrated to result in pulmonary inflammation in animals; however, very little is known about the molecular mechanisms of pulmonary injury due to TiO2 NPs exposure. The aim of this study was to evaluate the oxidative stress and molecular mechanism associated with pulmonary inflammation in chronic lung toxicity caused by the intratracheal instillation of TiO2 NPs for 90 consecutive days in mice. Our findings suggest that TiO2 NPs are significantly accumulated in the lung, leading to an obvious increase in lung indices, inflammation and bleeding in the lung. Exposure to TiO2 NPs significantly increased the accumulation of reactive oxygen species and the level of lipid peroxidation, and decreased antioxidant capacity in the lung. Furthermore, TiO2 NPs exposure activated nuclear factor-κB, increased the levels of tumor necrosis factor-α, cyclooxygenase-2, heme oxygenase-1, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-18, interleukin-1β, and CYP1A1 expression. However, TiO2 NPs exposure decreased NF-κB-inhibiting factor and heat shock protein 70 expression. Our results suggest that the generation of pulmonary inflammation caused by TiO2 NPs in mice is closely related to oxidative stress and the expression of inflammatory cytokines. [Copyright &y& Elsevier]

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]