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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Titanium dioxide nanoparticles (TiO 2 NPs) have been shown to induce reproductive system damages in animals. To better underline how TiO 2 NPs act in reproductive system, female mice were exposed to 2.5, 5, or 10 mg/kg TiO 2 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 TiO 2 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 TiO 2 NPs exposure may be mediated by TGF-β signal pathway., (© 2022 Wiley Periodicals LLC.)

Numerous studies have proven that nano titanium dioxide (nano TiO₂) can accumulate in animal brains, where it damages the blood brain barrier (BBB); however, whether this process involves destruction of tight junction proteins in the mouse brain has not been adequately investigated. In this study, mice were exposed to nano TiO₂ for 30 consecutive days, and then we used transmission electron microscopy to observe the BBB ultrastructure and the Evans blue assay to evaluate the permeability of the BBB. Our data suggested that nano TiO₂ damaged the BBB ultrastructure and increased BBB permeability. Furthermore, we used immunofluorescence and Western blotting to examine the expression of key tight junction proteins, including Occludin, ZO-1, and Claudin-5 in the mouse brain. Our data showed that nano TiO₂ reduced Occludin, ZO-1 and Claudin-5 expression. Taken together, nano TiO₂-induced damage to the BBB structure and function may involve the destruction of key tight junction proteins.

Nano-titanium dioxide (nano-TiO₂) has been shown to inhibit testosterone synthesis in male mice or rats; however, the mechanisms underlying these effects have yet to be elucidated. In this study, we investigated whether the inhibition of testosterone synthesis by nano-TiO₂ on Leydig cells (LCs) was related to the dysfunction of the cAMP/CGMP/EGFR/MMP signaling pathway in primary cultures of LCs prepared from rat testis exposed to nano-TiO₂. We found that the early apoptotic rate of LCs increased by 4.34 and 4.94 times, respectively, after exposure to 20 g/mL and 40 g/mL nano-TiO₂ ; we also found that NO increased by 1.1 and 2.86 times, respectively. ROS increased by times of 0.71, 3.15 and 3.43; RNS increased by 0.62, 1.34 and 1.14 times; and SOD activity decreased by 18.3%, 28.16%, and 67.6%, respectively, when the concentration of nano-TiO₂ was 10, 20 and 40 g/mL. These results indicated that nano-TiO₂ treatment resulted caused damage to the LCs, including an imbalance of oxidation and antioxidation. Following nano-TiO₂ treatment, the cAMP content had decreased by 48%, 48% and 47.6%; cGMP content had decreased by 18.7%, 52.2% and 56.7%; the levels of ATP in the LCs had decreased by 15.15%, 45.75% and 66.67%; the expression of HCGR protein had decreased by 26.7%, 45.07% and 74.64%; the expression of LHR protein had decreased by 18.3%, 28.16% and 67.6%; and the levels of T had decreased by 34.48%, 46.62% and 44.12%. Collectively, our results indicated that the inhibition of testosterone production by nano-TiO₂ is related to the dysfunction of the cAMP/CGMP/EGFR/MMP signaling pathway.

Background: Nanoparticulate titanium dioxide (Nano-TiO 2 ) has been widely used in food industry, and it has been demonstrated to have adverse effects on mice and human stomach, but its mechanism is rarely concerned. The aim of this study is to determine the effects of nano-TiO 2 on the stomach and confirm the role of oxidative stress and apoptosis in the mice gastric damage caused by nano-TiO 2 , as well as its molecular mechanisms., Methods: Mice were continuously exposed to nano-TiO 2 with 1.25, 2.5 and 5 mg/kg bw by intragastric administration for 9 months in the present study. The ultrastructure, levels of reactive oxygen species (ROS) and peroxides, activities of antioxidant enzymes and mitochondria-related enzymes, ATP contents as well as apoptosis-related factors expression in mice stomach were examined., Results: Oxidative stress, apoptosis and nano-TiO 2 aggregation were found in gastric mucosal smooth muscle cells after nano-TiO 2 exposure. Nano-TiO 2 exposure also resulted in the over-production of ROS and peroxides, decrease of ATP production and activities of antioxidant enzymes and mitochondria-related ATPases, upregulation of apoptosis-related factors including γH2AX, Cyt c, caspase 3, and p-JNK expression, and down-regulation of Bcl-2 expression in mice stomach., Conclusions: The gastric toxicity of mice induced by chronic exposure to low dose nano-TiO 2 may be associated with oxidative stress and mitochondria-mediated apoptosis in mice., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Nanoparticulate titanium dioxide (nano-TiO₂) is a commonly used nanoparticle material and has been widely used in the fields of medicine, cosmetics, construction, and environmental protection. Numerous studies have demonstrated that nano-TiO₂ has toxic effects on neuronal development, which lead to defects in learning and memory functions. However, it is still unclear whether nano-TiO₂ inhibits the development of synapse and the underlying molecular mechanism is still unknown. In this study, nano-TiO₂ was administered to rat primary hippocampal neurons for 24 h to investigate the underlying molecular mechanisms behind the inhibition of neuronal synaptic development by nano-TiO₂. We used hippocampal neurons as a model to study the effect of nano-TiO₂ on synaptic development. Our results demonstrated that dendritic development that represented synaptic plasticity in hippocampal neurons was significantly inhibited in a concentration-dependent manner after exposure to nano-TiO₂ for 24 h. Experiments with varying concentrations of nano-TiO₂ (5, 15, and 30 g/mL) indicated that the apoptotic rate of hippocampal neurons increased, development of neuronal synapses were inhibited, and synaptic densities decreased by 24.29%, 54.29%, and 72.86%, respectively, in post-treatment with nano-TiO₂. Furthermore, the results indicated that the expressions of Synapsin I (SYN I) and postsynaptic density 95 (PSD95) in neuron synapse were also significantly inhibited, particularly SYN I decreased by 18.43%, 37.2%, and 51.6%, and PSD95 decreased by 16.02%, 24.06%, and 38.74% after treatment with varying concentrations of nano-TiO₂, respectively. In addition, experiments to assess the BDNF-TrkB signaling pathway indicated that nano-TiO₂ inhibited the expressions of key proteins in the downstream MEK/ERK and PI3K/Akt signaling pathways by inhibiting the expression of BDNF. With concentrations of nano-TiO₂ at 5, 15, and 30 μ g/mL, the expression of BDNF decreased by 22.64%, 33.3%, and 53.58% compared with the control group. Further, the expression ratios of downstream key proteins p-CREB/CREB decreased by 3.03%, 18.11%, and 30.57%; p-ERK1/2/ERK1/2 ratios decreased by 19.11%, 28.82%, and 58.09%, and p-Akt1/Akt1 ratios decreased by 1.92%, 27.79%, and 41.33%, respectively. These results demonstrated that nano-TiO₂ inhibited the normal function of the BDNF-TrkB signaling pathway, which is closely related to neuronal synapse. Thus, it can be hypothesized that the inhibition of neuronal synaptic growth by nano-TiO₂ may be related to the inhibition of BDNF-TrkB signaling pathway.

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.)

Titanium dioxide (TiO₂) and nano-sized titanium dioxide (nano-TiO₂), which are used in food production, may be harmful to the body. Long-term exposure to nano-TiO₂ can lead to hepatic injury; however, the effect of nano-TiO₂ on liver fibrosis and the underlying mechanism remain unclear. The TGF- β /Smad/MAPK/Wnt signaling pathway is important for tissue fibrosis. In this study, mice were fed nano-TiO₂ (2.5, 5, and 10 mg/kg body weight) for nine consecutive months to investigate its effect on liver fibrosis. Nano-TiO₂ induced hepatic inflammatory cell infiltration and hepatic fibrosis and upregulated the expression of HIF-1 α (+75-fold to +2.38-fold), Wnt3 (+12% to +135%), Wnt4 (1.33-fold to 6-fold), NF- κ B (+3.13% to +34.38%), TGF- β 1 (+1307-fold to +1.85-fold), TGF- β 1R (+0.8-fold to 1.33-fold), Smad-2 (+0.58-fold to +1.58-fold), ILK (+0.43-fold to +1.19-fold), ECM (+1.82-fold to 2.36-fold), calpain 2 (+0.11-fold to +0.78-fold), α -SMA (+0.63-fold to +1.56-fold), c-Myc (+0.27-fold to +0.46-fold), and collagen I (+8% to +36%), and increased the phosphorylation level of p38MAPK (+66.67% to +153.33%) in inflammatory and fibrotic liver tissues, whereas it downregulated cyclin D (-6.25% to -43.75%) and decreased the phosphorylation levels of GSK-3 β (-3.12% to -46.88%) and β -catenin (-19.57% to -45.65%). These results indicate that hepatic fibrosis induced by nano-TiO₂ is mediated by the TGF- β /Smads/MAPK/Wnt signaling pathway. This study provides insight into the mechanism underlying hepatic toxicity induced by nano-TiO₂ .

Nanosized titanium dioxide (Nano TiO₂) has been widely used in daily lives, medicine, industry, and caused the potential reproduction toxicity for animals and human, however, the underlying molecular mechanisms for the reproductive toxicity of nano TiO₂ are still largely unclear. In the present study, when primary cultured rat Sertoli cells (SCs) were exposed to nano TiO₂, cell injury and alterations in wingless related MMTV integration site (Wnt) pathway-related factors including Wnt1, Wnt3a, Wnt5a, Wnt11, β -catenin, and p-GSK-3 β expression were investigated. The results suggested that nano TiO₂ could be translocated to cytoplasm or nucleus, and decreased cell viability, and impaired morphological structures of SCs, induced apoptosis and dead of primary cultured rat SCs. Furthermore, nano TiO₂-induced the toxicity of primary cultured rat SCs was associated with increased expression of Wnt1, Wnt3a, Wnt5a, Wnt11, and β -catenin and involved with reduced p-GSK-3 β expression. Therefore, this implies that nano TiO₂-induced toxic effects on SCs may be associated with Wnt signaling pathways.

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.

Background : Numerous studies have demonstrated that, upon maternal exposure, nano-TiO 2 can cross the placental barrier, accumulate in offspring animals, and cause neurotoxicity. However, the neurotoxic mechanisms are not fully understood. The aim of this study is to determine the effects of nano-TiO 2 on the dendritic outgrowth of hippocampal neurons and confirm the role of apoptosis and excessive autophagy in the neurotoxicity of offspring mice caused by nano-TiO 2 , as well as its molecular mechanisms. Methods : Pregnant mice were intragastrically administered 1, 2, or 3 mg per kg body weight nano-TiO 2 consecutively from prenatal day 7 to postpartum day 21. The ultrastructure, mitochondrial membrane potential (MMP), levels of reactive oxygen species (ROS) and peroxides, and ATP contents, along with the expression of apoptosis- and autophagy-related factors, were investigated. Results : The dendritic length of hippocampal neurons was lower in the group treated with nano-TiO 2 than in the control group. Apoptosis, excessive autophagy, and nano-TiO 2 aggregation in hippocampal neurons resulted from maternal exposure to nano-TiO 2 . Maternal exposure to nano-TiO 2 also resulted in the over-production of ROS, increases in malondialdehyde and protein carbonylation, reductions in MMP and ATP contents, up-regulation of apoptosis- or autophagy-related factors including histone H2AX at serine 139 (γH2AX), cytochrome C (Cyt C), caspase 3, phosphoinositide 3-kinase (PI3K3C), Beclin 1, c-Jun, LC3I, LC3II, JNK and p-JNK expression, and an increase of LC3II/LC3I, as well as down-regulation of Bcl-2 expression in hippocampal neurons of offspring mice. Conclusions : Maternal exposure to nano-TiO 2 inhibited the dendritic outgrowth of hippocampal neurons. This effect is closely associated with excessive autophagy, which is related to severe oxidative stress and alterations in the expressions of apoptosis- and autophagy-related factors in the hippocampal neurons of offspring mice, due to maternal exposure to nano-TiO 2 .

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.)

Although TiO2 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 TiO2 NP exposure. In this research, testicular damage, sperm number and alterations in testis-specific gene expressions in male mice induced by intragastric administration with TiO2 NPs for six months were investigated. It was found out that TiO2 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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Numerous studies have indicated that nano-titanium dioxide (TiO2) can induce neurotoxicity in vitro and in vivo, however, it is unclear whether nano-TiO2 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-TiO2 for 24 h, and nano-TiO2 internalization, dendritic growth, glutamate metabolism, expression of N-methyl-D-aspartate (NMDA) receptor subunits (NR1, NR2A and NR2B), calcium homeostasis, sodium current (INa) and potassium current (IK) were examined. Our findings demonstrated that nano-TiO2 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-TiO2 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 INa and IK. In addition, nano-TiO2 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-TiO2 inhibits neurite outgrowth of hippocampal neurons by interfering with glutamate metabolism and impairing NMDA receptor function., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.)

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 Ce(3+) 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 Ce(3+) -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.)

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.)

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 TiO2 nanoparticles (NPs) at 1.25, 2.5, or 5mg/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 TiO2 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 TiO2 NPs with atherosclerosis and pulmonary inflammation. This finding demonstrates the hypothesized role of TiO2 NPs as a risk factor for atherogenesis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Due to the increased application of titanium dioxide nanoparticles (TiO₂ NPs) in the food industry and daily life, their potential toxic effects in humans and animals have been investigated. However, very few studies have focused on testicular oxidative stress and/or apoptosis., Methods: In order to understand the possible molecular mechanisms of testicular lesions following exposure to TiO₂ NPs, male mice were exposed to 2.5, 5, or 10 mg/kg body weight TiO₂ NPs for 90 consecutive days. Testicular oxidative stress and apoptosis were then evaluated, and the testicular mRNA expression of several genes and their proteins involved in oxidative stress and/or apoptosis was investigated., Results: TiO₂ NPs entered Sertoli cells and caused severe testicular oxidative damage and/or apoptosis, accompanied by excessive production of reactive oxygen species and peroxidation of lipids, proteins and DNA as well as a significant reduction in antioxidant capacity. Furthermore, exposure to TiO₂ NPs resulted in the up-regulation of caspase-3, Nrbp2, and cytochrome c expression, and caused down-regulation of SOD, CAT, GPx, GST, GR, Cyp1b1, Car3, Bcl-2, Acaa2, and Axud1 expression in mouse testis., Conclusions: TiO₂ NPs entered Sertoli cells via the blood-testis barrier and were deposited in mouse seminiferous cord and/or Sertoli cells, causing oxidative damage and apoptosis.

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.

Titanium dioxide nanoparticles (TiO2 NPs) are widely used in toothpastes, sunscreens, and products for cosmetic purpose that the human use daily. Although the neurotoxicity induced by TiO2 NPs has been demonstrated, very little is known about the molecular mechanisms underlying the brain cognition and behavioral injury. In this study, mice were exposed to 2.5, 5, and 10 mg/kg body weight (BW) TiO2 NPs by nasal administration for 90 consecutive days, respectively, and their brains' injuries and brain gene-expressed profile were investigated. Our findings showed that TiO2 NPs could be translocated and accumulated in brain, led to oxidative stress, overproliferation of all glial cells, tissue necrosis as well as hippocampal cell apoptosis. Furthermore, microarray data showed significant alterations in the expression of 249 known function genes, including 113 genes upregulation and 136 genes downregulation following exposure to 10 mg/kg BW TiO2 NPs, which were associated with oxidative stress, immune response, apoptosis, memory and learning, brain development, signal transduction, metabolic process, DNA repair, response to stimulus, and cellular process. Especially, significant increases in Col1a1, serine/threonine-protein kinase 1, Ctnnb1, cysteine-serine-rich nuclear protein-1, Ddit4, Cyp2e1, and Krev interaction trapped protein 1 (Krit1) expressions and great decreases in DA receptor D2, Neu1, Fc receptor-like molecules, and Dhcr7 expressions following long-term exposure to TiO2 NPs resulted in neurogenic disease states in mice. Therefore, these genes may be potential biomarkers of brain toxicity caused by TiO2 NPs exposure, and the application of TiO2 NPs should be carried out cautiously., (© 2013 Society of Plastics Engineers.)

Due to the increased application of titanium dioxide nanoparticles (TiO2 NPs) in various areas, numerous studies have been conducted which have confirmed that exposure to TiO2 NPs may result in neurological damage in both mice and rats. However, very few studies have focused on the molecular mechanisms of spatial recognition injury. In the present study, to understand the possible neurobiological responses of the mouse hippocampus following subchronic peroral exposure to low level TiO2 NPs, mice were exposed to 2.5, 5, and 10mg/kg body weight TiO2 NPs for 90 consecutive days. Hippocampal pathology and neuron ultrastructure, and long-term potentiation (LTP) were then evaluated, and the hippocampal mRNA-expression of several genes and their proteins involved in homeostasis of neuronal synaptic plasticity were investigated using a quantitative real-time PCR and ELISA method. We observed that subchronic peroral exposure to TiO2 NPs caused severe pathological changes, spatial recognition impairment, and resulted in significant LTP reduction and down-regulation of N-methyl-D-aspartate (NMDA) receptor subunits (NR2A and NR2B) expression associated with the simultaneous inhibition of CaMKIV, cyclic-AMP responsive element binding proteins (CREB-1, CREB-2), and FosB/DFosB in mouse hippocampal tissues. Therefore, our findings suggest that the application of TiO2 NPs in the various areas should be paid more attention., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Nanoparticulate titanium dioxide (nano-TiO2 ) is a widely used powerful nanoparticulate material with high stability, anticorrosion, and photocatalytic property. However, it is possible that during nano-TiO2 exposure, there may be negative effects on cardiovascular system in intoxicated mice. The present study was therefore undertaken to determine nano-TiO2 -induced oxidative stress and to determine whether nano-TiO2 intoxication alters the antioxidant system in the mouse heart exposed to 2.5, 5, and 10 mg/kg body weight nano-TiO2 for 90 consecutive days. The findings showed that long-term exposure to nano-TiO2 resulted in obvious titanium accumulation in heart, in turn led to sparse cardiac muscle fibers, inflammatory response, cell necrosis, and cardiac biochemical dysfunction. Nano-TiO2 exposure promoted remarkably reactive oxygen species production such as superoxide radicals, hydrogen peroxide, and increased malondialdehyde, carbonyl and 8-OHdG levels as degradation products of lipid, protein, and DNA peroxidation in heart. Furthermore, nano-TiO2 exposure attenuated the activities of antioxidative enzymes, such as superoxide dismutase, ascorbate peroxidase, glutathione reductase, glutathione-S-transferase, and levels of antioxidants including ascorbic acid, glutathione, and thiol in heart. Therefore, TiO2 NPs exposure may impair cardiovascular system in mice, and attention should be aroused on the application of nano-TiO2 and their potential long-term exposure effects especially on human beings., (Copyright © 2013 Wiley Periodicals, Inc.)

Environmental pollution from lanthanides (Ln) has been recognized as a major problem due to a grab exploitation of Ln mine in China. Exposure to Ln has been demonstrated to cause the nephrotoxicity, very little is known about the mechanism of oxidative damage to kidney in animals. In order to understand Ln-induced nephrotoxicity, various biochemical and chemical parameters were assayed in mouse kidney. Intragastric exposures of LaCl₃, CeCl₃, and NdCl₃ at doses of 2, 5, and 10 mg kg(-1) BW for 90 consecutive days caused nephritis or epithelial cell necrosis and oxidative stress to kidney. An increase in coefficients of the kidney, La, Ce, and Nd accumulation and histopathological changes in the kidney could be observed, followed by increased reactive oxygen species production and peroxidation levels of lipid, protein and DNA, and decreased activities of superoxide dismutase, catalase, glutathione-S-transferase and glutathione reductase as well as antioxidants such as glutathione, ascorbic acid and thiol contents. Furthermore, La, Ce, and Nd significantly suppressed expression of genes and proteins of these antioxidative enzymes in mouse kidney. In addition, kidney functions were disrupted, including an increase of the creatinine, and reductions of uric acid, urea nitrogen, calcium and phosphonium. These findings suggest that nephritis generation or epithelial cell necrosis in mice following exposure to Ln is closely associated with oxidative stress. Of these damages, the most severe was in the Ce(3+)-exposed kidneys, next in the Nd(3+)-exposed kidneys, and the least in the La(3+)-exposed kidneys, which may be attributed to the 4f electron of Ln., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Added Ce(3+) can partly substitute for Ca(2+) or Mg(2+) and improve photosynthesis under the deficiency of these elements, but very few studies focused on photosynthetic improvement in maize seedlings caused by K(+) deficiency, salt stress, especially a combination of K(+) deficiency and salt stress. In the present study, the effects of Ce(3+) on the photosynthesis of maize seedlings under the three different stresses were investigated. The results showed that added Ce(3+) under various stresses increased the ratios of free water/bound water and of K(+)/Na(+), the pigment contents, the values of Fv/Fm, Y(II), ETR(II), Y(NPQ), Qp, qL, NPQ, and qN of photosystem II (PSII), the values of Y(I) and ETR(I) of photosystem I (PSI) and the expression levels of LhcII cab1 and rbcL, and decreased the values of Y(NO) and Y(NA). This implied that added Ce(3+) depressed ion toxicity, photodamage of PSII, and acceptor side constraints of PSI, and enhanced adjustable energy dissipation, the responses of photochemistry, and carbon assimilation caused by K(+) deficiency, salt stress, and the combination of K(+) deficiency and salt stress. However, Ce(3+) mitigation of photosynthetic inhibition in maize seedlings caused by the combined stresses was greater than that of salt stress, and Ce(3+) mitigation under salt stress was greater than that under K(+) deficiency. In addition, the results also showed that Ce(3+) cannot improve photosynthesis and growth of maize seedlings under K(+) deficiency by substituting for K(+).

TiO₂ nanoparticles (NPs) are used in the food industry but have potential toxic effects in humans and animals. TiO₂ NPs impair renal function and cause oxidative stress and renal inflammation in mice, associated with inhibition of nuclear factor erythroid-2-related factor 2 (Nrf2), which regulates genes encoding many antioxidants and detoxifying enzymes. This study determined whether TiO₂ NPs activated the Nrf2 signaling pathway. Mice exhibited accumulation of reactive oxygen species and peroxidation of lipid, protein, and DNA in the kidney, coupled with renal dysfunction, glutathione depletion, inflammatory cell infiltration, fatty degeneration, and apoptosis. These were associated with increased expression of NOX4, cyclooxygenase-2, and nuclear factor-κB. Oxidative stress and inflammation were accompanied by decreased expression of Nrf2 and down-regulation of its target gene products including heme oxygenase 1, glutamate-cysteine ligase catalytic subunit, and glutathione S-transferase. Chronic TiO₂ NP exposure is associated with suppression of Nrf2, which contributes to the pathogenesis of oxidative stress and inflammation.

Although titanium dioxide nanoparticles (TiO2 NPs) have been demonstrated to accumulate in organs resulting in toxicity, there is currently only limited data regarding male reproductive toxicity by TiO2 NPs. In this study, testicular damage and alterations in gene expression profiles in male mice induced by intragastric administration of 2.5, 5, and 10mg/kg body weight of TiO2 NPs for 90 consecutive days were examined. Our findings showed that TiO2 NPs can cross the blood-testis barrier to reach the testis and accumulate therein, which, in turn, results in testicular lesions, sperm malformations, and alterations in serum sex hormone levels. Furthermore, microarray analysis showed that 70 genes with known functions were up-regulated, while 72 were down-regulated in TiO2 NPs-exposed testes. Of the altered gene expressions, Ly6e, Adam3, Tdrd6, Spata19, Tnp2, and Prm1 are involved in spermatogenesis, whereas Sc4mol, Psmc3ip, Mvd, Srd5a2, Lep, and Cyp2e1 are associated with steroid and hormone metabolism. Hence, the production and application of TiO2 NPs should be carried out cautiously, especially by humans of reproductive age., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

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., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

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.

Rare earth element (REE) exposure has been shown to induce central nerve system intoxication, but the molecular mechanisms by which this occurs are poorly understood. In this study, cerium (Ce), in the form of CeCl3, was administered by way of gavage to mice for 90 consecutive days, and cytokine expression, associated with neuroinflammation of hippocampus, as well as spatial memory were increased in mice. Significant Ce accumulation in hippocampus, which led to neuroinflammation and decreased spatial memory of mice, was observed. Furthermore, CeCl3 remarkably increased levels of Toll-like receptors 2 and 4, tumor necrosis factor-α, nucleic IκB kinase, factor-κB-inducible kinase, nucleic factor-κB, and p52 and p65 expression as well as significantly decreased levels of IκB and interleukin-2 expression. These results showed that neuroinflammation and damaged hippocampal function may be associated with CeCl3-induced neuerotoxicity. Our findings suggest the need for workers and consumers to exercise caution when handling REEs.

Background: Numerous studies have demonstrated that titanium dioxide nanoparticles (TiO2 NPs) induced nephrotoxicity in animals. However, the nephrotoxic multiple molecular mechanisms are not clearly understood., Methods: Mice were exposed to 2.5, 5 and 10 mg/kg TiO2 NPs by intragastric administration for 90 consecutive days, and their growth, element distribution, and oxidative stress in kidney as well as kidney gene expression profile were investigated using whole-genome microarray analysis technique., Results: Our findings suggest that TiO2 NPs resulted in significant reduction of renal glomerulus number, apoptosis, infiltration of inflammatory cells, tissue necrosis or disorganization of renal tubules, coupled with decreased body weight, increased kidney indices, unbalance of element distribution, production of reactive oxygen species and peroxidation of lipid, protein and DNA in mouse kidney tissue. Furthermore, microarray analysis showed significant alterations in the expression of 1, 246 genes in the 10 mg/kg TiO2 NPs-exposed kidney. Of the genes altered, 1006 genes were associated with immune/inflammatory responses, apoptosis, biological processes, oxidative stress, ion transport, metabolic processes, the cell cycle, signal transduction, cell component, transcription, translation and cell differentiation, respectively. Specifically, the vital up-regulation of Bcl6, Cfi and Cfd caused immune/ inflammatory responses, the significant alterations of Axud1, Cyp4a12a, Cyp4a12b, Cyp4a14, and Cyp2d9 expression resulted in severe oxidative stress, and great suppression of Birc5, Crap2, and Tfrc expression led to renal cell apoptosis., Conclusions: Axud1, Bcl6, Cf1, Cfd, Cyp4a12a, Cyp4a12b, Cyp2d9, Birc5, Crap2, and Tfrc may be potential biomarkers of kidney toxicity caused by TiO2 NPs exposure.

The pulmonary damage induced by nanosized titanium dioxide (nano-TiO2) is of great concern, but the mechanism of how this damage may be incurred has yet to be elucidated. Here, we examined how multiple genes may be affected by nano-TiO2 exposure to contribute to the observed damage. The results suggest that long-term exposure to nano-TiO2 led to significant increases in inflammatory cells, and levels of lactate dehydrogenase, alkaline phosphate, and total protein, and promoted production of reactive oxygen species and peroxidation of lipid, protein and DNA in mouse lung tissue. We also observed nano-TiO2 deposition in lung tissue via light and confocal Raman microscopy, which in turn led to severe pulmonary inflammation and pneumonocytic apoptosis in mice. Specifically, microarray analysis showed significant alterations in the expression of 847 genes in the nano-TiO2-exposed lung tissues. Of 521 genes with known functions, 361 were up-regulated and 160 down-regulated, which were associated with the immune/inflammatory responses, apoptosis, oxidative stress, the cell cycle, stress responses, cell proliferation, the cytoskeleton, signal transduction, and metabolic processes. Therefore, the application of nano-TiO2 should be carried out cautiously, especially in humans.

Cerium is widely used in many aspects of modern society, including agriculture, industry and medicine. It has been demonstrated to enter the ecological environment, is then transferred to humans through food chains, and causes toxic actions in several organs including the brain of animals. However, the neurotoxic molecular mechanisms are not clearly understood. In this study, mice were exposed to 0.5, 1, and 2 mg/kg BW cerium chloride (CeCl(3)) for 90 consecutive days, and their learning and memory ability as well as hippocampal gene expression profile were investigated. Our findings suggested that exposure to CeCl(3) led to hippocampal lesions, apoptosis, oxidative stress and impairment of spatial recognition memory. Furthermore, microarray data showed marked alterations in the expression of 154 genes involved in learning and memory, immunity and inflammation, signal transduction, apoptosis and response to stress in the 2 mg/kg CeCl(3) exposed hippocampi. Specifically, the significant up-regulation of Axud1, Cdc37, and Ube2v1 caused severe apoptosis, and great suppression of Adcy8, Fos, and Slc5a7 expression led to impairment of mouse cognitive ability. Therefore, Axud1, Cdc37, Ube2v1, Adcy8, Fos, and Slc5a7 may be potential biomarkers of hippocampal toxicity caused by CeCl3 exposure.

Recent studies have demonstrated nanosized titanium dioxide (nano-TiO2)-induced fertility reduction and ovary injury in animals. To better understand how nano-TiO2 act in mice, female mice were exposed to 2.5, 5, and 10 mg/kg nano-TiO2 by intragastric administration for 90 consecutive days; the ovary injuries, fertility, hormone levels, and inflammation-related or follicular atresia-related cytokine expression were investigated. The results showed that nano-TiO2 was deposited in the ovary, resulting in significant reduction of body weight, relative weight of ovary and fertility, alterations of hematological and serum parameters and sex hormone levels, atretic follicle increases, inflammation, and necrosis. Furthermore, nano-TiO2 exposure resulted in marked increases of insulin-like growth factor-binding protein 2, epidermal growth factor, tumor necrosis factor-α, tissue plasminogen activator, interleukin-1β, interleukin -6, Fas, and FasL expression, and significant decreases of insulin-like growth factor-1, luteinizing hormone receptor, inhibin α, and growth differentiation factor 9 expression in mouse ovary. These findings implied that fertility reduction and ovary injury of mice following exposure to nano-TiO2 may be associated with alteration of inflammation-related or follicular atresia-related cytokine expressions, and humans should take great caution when handling nano-TiO2.

Although numerous studies have described the accumulation of titanium dioxide nanoparticles (TiO(2) NPs) in the liver, kidneys, lung, spleen, and brain, and the corresponding damage, it is unclear whether or not TiO(2) 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 TiO(2) NPs (10mg/kg) for 90 consecutive days were investigated. Our findings indicated that TiO(2) 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 TiO(2) 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 TiO(2) NPs treatment suggested that the increase in estradiol biosynthesis may be a consequence of increased TiO(2) 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 TiO(2) NPs directly affects ovarian function., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

Exposure to titanium dioxide nanoparticles (TiO(2) 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 TiO(2) 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 TiO(2) NPs for 90 consecutive days in mice. Our findings suggest that TiO(2) NPs are significantly accumulated in the lung, leading to an obvious increase in lung indices, inflammation and bleeding in the lung. Exposure to TiO(2) NPs significantly increased the accumulation of reactive oxygen species and the level of lipid peroxidation, and decreased antioxidant capacity in the lung. Furthermore, TiO(2) 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, TiO(2) NPs exposure decreased NF-κB-inhibiting factor and heat shock protein 70 expression. Our results suggest that the generation of pulmonary inflammation caused by TiO(2) NPs in mice is closely related to oxidative stress and the expression of inflammatory cytokines., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Although liver toxicity induced by titanium dioxide nanoparticles (TiO(2) 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 TiO(2) NPs for 90 days. The findings showed that long-term exposure to TiO(2) NPs resulted in obvious titanium accumulation in the liver and TiO(2) 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 TiO(2) NP-exposed livers. In particular, a significant reduction in complement factor D (Cfd) expression following long-term exposure to TiO(2) NPs resulted in autoimmune and inflammatory disease states in mice. Therefore, Cfd may be a potential biomarker of liver toxicity caused by TiO(2) NPs exposure.

The main aim of this work is to identify how the combined stresses affect the interdependent nitrogen and photosynthetic carbon assimilations in maize. Maize plants were cultivated in Meider's solution. They were subjected to salt stress and potassium deficiency in the K-present Meider's media and K-deficient Meider's media. After 5 weeks, we measured chlorophyll a fluorescence and the activities of several enzymes in metabolic checkpoints coordinating primary nitrogen and carbon assimilation in the leaves of maize. The study showed that the combination of salt stress and potassium-deficient stress more significantly decreased nitrate uptake, plant growth, the activities of nitrate reductase, glutamate dehydrogenase, glutamate synthase, urease, glutamic-pyruvic transaminase, glutamic-oxaloace transaminase, sucrose-phosphate synthase, phosphoenolpyruvate carboxylase, and the synthesis of free amino acids, chlorophyll, and protein than those of each individual stress, respectively. However, the combined stresses significantly increased the accumulation of ammonium and carbohydrate products. The combined stresses also significantly decreased the oxygen evolution, the electron transport, and the efficiency of photochemical energy conversion by photosystem II in maize seedlings. Taken together, a combination of salt stress and potassium-deficient stress impaired the assimilations of both nitrogen and carbon and decreased the photosystem II activity in maize.

Recent studies demonstrated that titanium dioxide nanoparticles (TiO2 NPs) could significantly promote photosynthesis and plant growth, but its mechanism is still unclear. In this article, we studied the mechanism of light absorption and transfer of chloroplasts of Arabidopsis thaliana caused by TiO2 NPs treated. The results showed that TiO2 NPs could induce significant increases of light-harvesting complex II (LHCII) b gene expression and LHCII II content on the thylakoid membrane in A. thaliana, and the increases in LHCII were higher than the non-nano TiO2 (bulk-TiO2) treatment. Meanwhile, spectroscopy assays indicated that TiO2 NPs obviously increased the absorption peak intensity of the chloroplast in red and blue region, the fluorescence quantum yield near 680 nm, the excitation peak intensity near 440 and 480 nm and/or near 650 and 680 nm of the chloroplast. TiO2 NPs treatment could reduce F480/F440 ratio and increase F650/F680 ratio and accelerate the rate of whole chain electron transport and oxygen evolution of the chloroplast. However, the photosynthesis improvement of the non-nanoTiO2 treatment was far less effective than TiO2 NPs treatment. Taken together, TiO2 NPs could promote the light absorption of chloroplast, regulate the distribution of light energy from PS I to PS II by increasing LHCII and accelerate the transformation from light energy to electronic energy, water photolysis, and oxygen evolution.

Cerium (Ce) was shown to cause various toxic effects both in rats and mice; however, the molecular mechanism by which Ce exert theirs toxicity is still understood. In this report, the impairment of liver DNA conformation and liver apoptosis of mice caused by CeCl(3) was studied in vivo using inductively coupled plasma-mass spectrometry, various spectral methods, gel electrophoresis, and transmission electron micrograph. We found that the coefficients of liver to body weight of the mice treated with CeCl(3) were significantly increased. Ce(3+) could be significantly accumulated in the liver, and it insert itself into DNA base pairs and/or bind to DNA nucleotide, and alter the conformation of DNA. Furthermore, the evaluation by gel electrophoresis and transmission electron micrograph showed that higher dose of Ce(3+) could cause DNA cleavage and hepatocyte apoptosis in mice. Therefore, our study aroused the attention of Ce application and exposure effects especially on human liver for long-term and low-dose treatment.

It has been proven that higher dose of lanthanoid (Ln) can induce liver toxicities, but the mechanisms and the molecular pathogenesis are still unclear. In this study, LaCl₃, CeCl₃, and NdCl₃ at a higher dose of 20 mg/kg body weight was injected into the abdominal cavity of ICR mice for 14 consecutive days, and the inflammatory responses of liver of mice were investigated by histopathological test, real-time quantitative reverse transcription polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) methods. The results showed the significant accumulation of Ln in the liver results in liver histopathological changes and, therefore, liver malfunctions. The real-time quantitative RT-PCR and ELISA analyses showed that Ln could significantly alter the mRNA and protein expressions of several inflammatory cytokines, including nucleic factor-κB, macrophage migration inhibitory factor, tumor necrosis factor-α, interleukin-1β, interleukin-6, cross-reaction protein, interleukin-4, and interleukin-10. Our results also implied that the inflammatory responses and liver injury likely are caused by 4f shell and alterable valence properties of Ln-induced liver toxicity.

In order to study the mechanisms underlying the effects of lanthanoid (Ln) on the liver, ICR mice were injected with LaCl₃, CeCl₃, and NdCl₃ at a dose of 20 mg/kg BW into the abdominal cavity daily for 14 days. We then examined oxidative stress-mediated responses in the liver. The increase of lipid peroxide in the liver produced by Ln suggested an oxidative attack that was activated by a reduction of antioxidative defense mechanisms as measured by analyzing the activities of superoxide dismutase, catalase, and ascorbate peroxidase, as well as antioxidant levels such as glutathione and ascorbic acid, which were greatest in Ce(3+) treatment, medium in Nd(3+), and least in La(3+). Our results also implied that the oxidative stress in the liver caused by Ln likely is Ce(3+) > Nd(3+) >La(3+), but the mechanisms need to be further studied in future.

Magnesium is one of the essential elements for plant growth and cerium is a beneficial element for plant growth. However, the effects of the fact that cerium improves the nitrogen metabolism of plants under magnesium deficiency is poorly understood. The main aim of the study was to determine the role of cerium in the amelioration of magnesium-deficiency effects in spinach plants. Spinach plants were cultivated in Hoagland's solution. They were subjected to magnesium deficiency and to cerium chloride administered in the magnesium-present media and magnesium-deficient media. Spinach plants grown in the magnesium-present media and magnesium-deficient media were measured for key enzyme activities involved in nitrogen metabolism such as nitrate reductase, nitrite reductase, glutamate dehydrogenase, glutamate synthase, urease, glutamic–pyruvic transaminase, and glutamic–oxaloace protease transaminase. As the nitrogen metabolism in spinach was significantly inhibited by magnesium deficiency, it caused a significant reduction of spinach plant weight, leaf turning chlorosis. However, cerium treatment grown in magnesium-deficiency media significantly promoted the activities of the key enzymes as well as the contents of the free amino acids, chlorophyll, soluble protein, and spinach growth. It implied that Ce3+ could partly substitute for magnesium to facilitate the transformation from inorganic nitrogen to organic nitrogen, leading to the improvement of spinach growth, although the metabolism needs to be investigated further.

Magnesium-deficiency conditions applied to spinach cultures caused an oxidative stress status in spinach chloroplast monitored by an increase in reactive oxygen species (ROS) accumulation. The enhancement of lipids peroxide of spinach chloroplast grown in magnesium-deficiency media suggested an oxidative attack that was activated by a reduction of antioxidative defense mechanism measured by analysing the activities of superoxide dismutase, catalase, ascorbate peroxidase, guaiacol peroxidase, and glutathione reductase, as well as antioxidants such as carotenoids and glutathione content. As the antioxidative response of chloroplast was reduced in spinach grown in magnesium-deficiency media, it caused a significant reduction of spinach plant weight, old leaves turning chlorosis. However, cerium treatment grown in magnesium-deficiency conditions decreased the malondialdehyde and ROS, and increased activities of the antioxidative defense system, and improved spinach growth. Together, the experimental study implied that cerium could partly substitute for magnesium and increase the oxidative stress-resistance of spinach chloroplast grown in magnesium-deficiency conditions, but the mechanisms need further study.