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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]

Numerous studies have demonstrated the in vitro and in vivo neurotoxicity of nanoparticulate titanium dioxide (nano‐TiO2), a mass‐produced material for a large number of commercial and industrial applications. The mechanism of nano‐TiO2‐induced inhibition of axonal development, however, is still unclear. In our study, primary cultured hippocampal neurons of 24‐hour‐old fetal Sprague‐Dawley rats were exposed to 5, 15, or 30 μg/mL nano‐TiO2 for 6, 12, and 24 hours, and the toxic effects of nano‐TiO2 exposure on the axons development were detected and its molecular mechanism investigated. Nano‐TiO2 accumulated in hippocampal neurons and inhibited the development of axons as nano‐TiO2 concentrations increased. Increasing time in culture resulted in decreasing axon length by 32.5%, 36.6%, and 53.8% at 6 hours, by 49.4%, 53.8%, and 69.5% at 12 hours, and by 44.5%, 58.2%, and 63.6% at 24 hours, for 5, 15, and 30 μg/mL nano‐TiO2, respectively. Furthermore, nano‐TiO2 downregulated expression of Netrin‐1, growth‐associated protein‐43, and Neuropilin‐1, and promoted an increase of semaphorin type 3A and Nogo‐A. These studies suggest that nano‐TiO2 inhibited axonal development in rat primary cultured hippocampal neurons and this phenomenon is related to changes in the expression of axon growth‐related factors. [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]

ABSTRACT It has been demonstrated that the organic damages of animals can be caused by exposure to lanthanide oxides or compounds. However, the molecular mechanism of CeCl3-induced kidney injury remains unclear. In this study, the mechanism of nephric damage in mice induced by an intragastric administration of CeCl3 was investigated. The results showed that Ce3+ was accumulated in the kidney, which in turn led to oxidative stress, severe nephric inflammation, and dysfunction in mice. Furthermore, CeCl3 activated nucleic factor κB, which in turn increased the expression levels of tumor necrosis factor α, macrophage migration inhibitory factor, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-18, interleukin-1β, cross-reaction protein, transforming growth factor-β, interferon-γ, and CYP1A1, while suppressed heat shock protein 70 expression. These findings implied that Ce3+-induced kidney injury of mice might be associated with oxidative stress, alteration of inflammatory cytokine expression, and reduction of detoxification of CeCl3. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1420-1427, 2014. [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]

Numerous studies have demonstrated the in vitro and in vivo neurotoxicity of nanoparticulate titanium dioxide (nano-TiO 2 ), a mass-produced material for a large number of commercial and industrial applications. The mechanism of nano-TiO 2 -induced inhibition of axonal development, however, is still unclear. In our study, primary cultured hippocampal neurons of 24-hour-old fetal Sprague-Dawley rats were exposed to 5, 15, or 30 μg/mL nano-TiO 2 for 6, 12, and 24 hours, and the toxic effects of nano-TiO 2 exposure on the axons development were detected and its molecular mechanism investigated. Nano-TiO 2 accumulated in hippocampal neurons and inhibited the development of axons as nano-TiO 2 concentrations increased. Increasing time in culture resulted in decreasing axon length by 32.5%, 36.6%, and 53.8% at 6 hours, by 49.4%, 53.8%, and 69.5% at 12 hours, and by 44.5%, 58.2%, and 63.6% at 24 hours, for 5, 15, and 30 μg/mL nano-TiO 2 , respectively. Furthermore, nano-TiO 2 downregulated expression of Netrin-1, growth-associated protein-43, and Neuropilin-1, and promoted an increase of semaphorin type 3A and Nogo-A. These studies suggest that nano-TiO 2 inhibited axonal development in rat primary cultured hippocampal neurons and this phenomenon is related to changes in the expression of axon growth-related factors., (© 2020 Wiley Periodicals, Inc.)

Background: Nanoparticulate titanium dioxide (nano-TiO 2 ) enters the body through various routes and causes organ damage. Exposure to nano-TiO 2 is reported to cause testicular injury in mice or rats and decrease testosterone synthesis, sperm number, and motility. Importantly, nano-TiO 2 suppresses testosterone production by Leydig cells (LCs) and impairs the reproductive capacity of animals., Methods: In an attempt to establish the molecular mechanisms underlying the inhibitory effect of nano-TiO 2 on testosterone synthesis, primary cultured rat LCs were exposed to varying concentrations of nano-TiO 2 (0, 10, 20, and 40 µg/mL) for 24 hours, and alterations in cell viability, cell injury, testosterone production, testosterone-related factors (StAR, 3βHSD, P450scc, SR-BI, and DAX1), and signaling molecules (ERK1/2, PKA, and PKC) were investigated., Results: The data show that nano-TiO 2 crosses the membrane into the cytoplasm or nucleus, triggering cellular vacuolization and nuclear condensation. LC viability decreased in a time-dependent manner at the same nano-TiO 2 concentration, nano-TiO 2 treatment (10, 20, and 40 µg/mL) decreased MMP (36.13%, 45.26%, and 79.63%), testosterone levels (11.40% and 44.93%), StAR (14.7%, 44.11%, and 72.05%), 3βHSD (26.56%, 50%, and 79.69%), pERK1/2 (27.83%, 63.61%, and 78.89%), PKA (47.26%, 70.54%, and 85.61%), PKC (30%, 50%, and 71%), SR-BI (16.41%, 41.79%, and 67.16%), and P450scc (39.41%, 55.26%, and 86.84%), and upregulated DAX1 (1.31-, 1.63-, and 3.18-fold) in primary cultured rat LCs., Conclusion: Our collective findings indicated that nano-TiO 2 -mediated suppression of testosterone in LCs was associated with regulation of ERK1/2-PKA-PKC signaling pathways., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Titanium dioxide nanoparticles (TiO 2 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 TiO 2 NPs inhibited development of dendritic morphology and identified possible molecular mechanisms associated with this inhibition in primary cultured rat hippocampal neurons. Results showed that TiO 2 NPs decreased neurite length, the number of branches and the spine density, and impaired mitochondrial function in the developing neurons. Furthermore, TiO 2 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, TiO 2 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 TiO 2 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., (© 2017 Wiley Periodicals, Inc.)

Although numerous studies have demonstrated that titanium dioxide nanoparticles (TiO 2 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 TiO 2 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 TiO 2 NPs for 24 h, and TiO 2 NPs internalization, expression of PKC (p-PKC) and p38 MAPK (p-p38 MAPK) as well as calcium homeostasis were examined. Our findings demonstrated that TiO 2 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 TiO 2 NPs was involved in the increased expression of NF-κB, TNF-α, and IL-1β, and decreased IκB expression. TiO 2 NPs significantly decreased Ca 2+ -ATPase and Ca 2+ /Mg 2+ -ATPase activity and enhanced intracellular Ca 2+ 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 TiO 2 NPs may induce immunological dysfunction of primary cultured rat Sertoli cells by stimulating the Ca 2+ /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., (© 2017 Wiley Periodicals, Inc.)

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., (© 2014 Wiley Periodicals, Inc.)

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 (ΔΨm), 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., (© 2015 Wiley Periodicals, Inc.)

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 [Ca(2+)]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.)