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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 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.)

Nano-titanium dioxide (nano-TiO₂) has been widely used in food and cosmetic industries, and the medical sector. However, nano-TiO₂ is potentially toxic to the reproductive system. Previous research has shown that nano-TiO₂ can reduce sperm concentration but do not yet known whether this effect occurs because of dysfunctional meiosis in spermatogenic cells. In the present paper, we demonstrate that Nano-TiO₂ can penetrate through the blood-testis barrier of a mouse model and enter the testicular tissue, thus causing damage to the testis and epididymis. This reduced the number of developing sperm; we demonstrated that the mechanism underlying this effect was the inhibition or destruction of meiosis in spermatogenic cells, particularly during meiosis I. We also found that the inhibition of meiosis I caused by nano-TiO₂ exposure was related to dysfunctional meiosis and that the abnormal expression of meiosis-related factors. Therefore, our data demonstrate that nano-TiO₂ reduces sperm concentration by disrupting meiosis and related signaling pathways.

Numerous studies have shown that lung injury can be caused by respiratory exposure to nanoparticulate titanium dioxide (nano-TiO 2 ), but whether pulmonary inflammation and fibrosis are related to the activation of the TGF-β/Smad/p38MAPK/Wnt pathways remains unclear. In this study, mice were administrated nano-TiO 2 by nasal instillation for nine consecutive months, and the molecular mechanisms of nano-TiO 2 on the pulmonary toxicity of mice were examined. The findings suggested that nano-TiO 2 caused pneumonia and pulmonary fibrosis. Furthermore, the results also showed that an overproduction of reactive free radicals occurred in mouse lungs, and that the expression of TGF-β/p38MAPK/Wnt pathway-related factors, including hypoxia-inducible factor 1α (HIF-1α), transforming growth factor-β1 (TGF-β1), phosphorylated p38 mitogen activated protein kinases (p-p38MAPK), small mothers against decapentaplegic homolog 2 (Smad2), extracellular matrix (ECM), Wingless/Integrated 3 (Wnt3), Wingless/Integrated 4 (Wnt4), integrin-linked kinase (ILK), β-catenin, nuclear factor-κB (NF-κB), α-smooth muscle actin (α-SMA), c-Myc, Type I collage (collagen I), and Type collage III (collagen III) were remarkably elevated, while phosphorylated glycogen synthase kinase-3β (p-GSK-3β) expression was decreased. Those data implied that the pulmonary inflammation and fibrosis caused by nano-TiO 2 exposure may be involved in reactive free radical-mediated activation of the TGF-β/Smad/p38MAPK/Wnt pathways., (© 2019 Wiley Periodicals, Inc.)

Nanoparticulate titanium dioxide (nano TiO 2 ) is extensively applied in biological tissue engineering materials, food additives, cosmetics, and sunscreens. Numerous studies to date have demonstrated that nano TiO 2 penetrates through the digestive system and possibly the blood circulation, leading to accumulation in the ovary and consequent reproductive toxicity. However, the mechanisms underlying the toxic effects of nano TiO 2 on the female reproductive system remain to be established. In this study, female mice were exposed to different doses of nano TiO 2 (1.25, 2.5, or 5 mg/kg body weight) via intragastric administration for 60 consecutive days, followed by investigation of follicular development, regulation of TGF-β-mediated signaling pathways, and expression of the pathway components. Subchronic exposure to nano TiO 2 induced a decrease in the number of primordial, secondary, and antral follicles and corpus luteum and concomitant increase in atretic follicles. Furthermore, follicular development disorder induced by nano TiO 2 was associated with upregulation of TGF-β1, TGF-βR1, PTEN, and Foxo3a involved in cell growth and apoptosis and downregulation of several growth factors (PI3K, AKT, p-mTOR, p70S6K, p-p70S6K1, rpS6, p-rpS6, TSC1, and TSC2) in mouse ovaries. Our data collectively implied that suppression of ovarian follicle development by nano TiO 2 was triggered by dysfunction of the TGF-β, PI3K/AKT/mTOR, and AKT/p70S6K-rpS6/TSC/mTOR pathways. The adverse effects of nano TiO 2 on follicular development highlights the necessity for caution in the use of nanomaterials in the food industry. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 414-422, 2019., (© 2018 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.

Background: Exposure to titanium dioxide nanoparticles (TiO 2 NPs) that are widely used in food, medicine, sunscreen products and cosmetics is reported to cause ovarian damage and lower fertility in animals. However, the potential effects of TiO 2 NPs application on premature ovarian failure (POF) have rarely been evaluated to date., Methods: In this study, female mice were continuously exposed to TiO 2 NPs at doses of 2.5, 5 or 10 mg/kg via gavage instillation for 30 days, and investigated the serum hormones and autoimmunity markers associated with POF., Results: Exposure to TiO 2 NPs resulted in POF, reductions in the levels of estradiol, progesterone and inhibin B and increases in luteinizing hormone, follicle-stimulating hormone, follicle-stimulating hormone/luteinizing hormone ratio, anti-Müllerian hormone, thyroid-stimulating hormone, free triiodothyronine, free tetraiodothyronine, anti-nuclear antibody and anti-thyroid peroxidase antibody levels in serum., Conclusion: Exposure to TiO 2 NPs induced POF triggered by alterations in hormones and autoimmunity markers. Our findings highlight the necessity for significant caution in handling and usage of TiO 2 NPs by female consumers., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Although nanoscale titanium dioxide (nano-TiO 2 ) has been extensively used in industrial food applications and daily products for pregnant women, infants, and children, its potential toxicity on fetal development has been rarely studied. The main objective of this investigation was to establish the effects of maternal exposure of nano-TiO 2 on developing embryos. Female imprinting control region mice were orally administered nano-TiO 2 from gestational day 0 to 17. Our findings showed that Ti concentrations in maternal serum, placenta, and fetus were increased in nano-TiO 2 -exposed mice when compared to controls, which resulted in reductions in the contents of calcium and zinc in maternal serum, placenta, and fetus, maternal weight gain, placental weight, fetal weight, number of live fetuses, and fetal crown-rump length as well as cauda length, and caused an increase in the number of both dead fetuses and resorptions. Furthermore, maternal nano-TiO 2 exposure inhibited development of the fetal skeleton, suggesting a significant absence of cartilage, reduced or absent ossification, and an increase in the number of fetuses with dysplasia, including exencephaly, spina bifida, coiled tail, scoliosis, rib absence, and sternum absence. These findings indicated that nano-TiO 2 can cross the blood-fetal barrier and placental barrier, thereby delaying the development of fetal mice and inducing skeletal malformation. These factors may be associated with reductions in both calcium and zinc in maternal serum and the fetus, and both the placenta and embryos may be major targets of developmental toxicity following maternal exposure to nano-TiO 2 during the prenatal period. Therefore, the application of nano-TiO 2 should be carried out with caution., 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.)

Sertoli cells provide appropriate mitogens, differentiation factors and sources of energy for developing germ cells throughout the lifetime of males, and protect these germ cells from harmful agents and from the host's own immune system. Therefore, reductions in the rate and quality of spermatogenesis caused by nanoparticulate titanium dioxide (nano-TiO 2 ) may be closely involved in the immunoregulation of Sertoli cells. However, the underlying mechanism of this response is still unclear. To address this issue, we used mouse primary cultured Sertoli cells to examine the toxic effects of nano-TiO 2 via alterations in morphology, cell viability, and activation of the TAM/TLR3 signal pathway. The results demonstrated that nano-TiO 2 could cross the cytomembrane into the cytoplasm or nucleus, decrease Sertoli cell viability, damage morphology (such as elongated fusiform, cellular and nuclear shrinkage) and induce the expression of various immune mediators and inflammatory cytokines, including TLR3(+0.31-fold to +0.81-fold), IL-lβ(+0.33-fold to +5.0-fold), NF-κB(+0.22-fold to +3.65-fold), IL-6(+0.47-fold to +3.53-fold), TNF-α(+0.14-fold to +2.44-fold), IFN-α(+0.17-fold to +2.27-fold), and IFN-β(+0.09-fold to +2.29-fold), and suppress the expression of Tyro3(-9.33% to -61.93%), Axl(-19.03% to -60.67%), Mer(-8.04% to -59.16%), and IκB(-34.35% to -86.59%) in primary cultured Sertoli cells. These results suggest that testicular innate immune responses to pathogens caused by nano-TiO 2 may be involved in the regulatory mechanisms of TAM/TLR3 signaling in testicular Sertoli cells. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 198-208, 2017., (© 2016 Wiley Periodicals, Inc.)

In the past two decades, titanium dioxide nanoparticles (TiO 2 NPs) have been extensively used in medicine, food industry and other daily life, while their possible interactions with the their influence and human body on human health remain not well understood. Thus, the study was designed to examine whether long-term exposure to TiO 2 NPs cause myocardial dysfunction which is involved in cardiac lesions and alter expression of genes and proteins involving inflammatory response in the mouse heart. The findings showed that intragastric feeding for nine consecutive months with TiO 2 NPs resulted in titanium accumulation, infiltration of inflammatory cells and apoptosis of heart, reductions in net increases of body weight, cardiac indices of function (LV systolic pressure, maximal rate of pressure increase over time, maximal rate of pressure decrease over time and coronary flow), and increases in heart indices, cardiac indices of function (LV end-diastolic pressure and heart rate) in mice. TiO 2 NPs also decreased ATP production in the hearts. Furthermore, TiO 2 NPs increased expression of nuclear factor-κB, interleukin-lβ and tumour necrosis factor-α, and reduced expression of anti-inflammatory cytokines including suppressor of cytokine signaling (SOCS) 1 and SOCS3 in the cardiac tissue. These results suggest that TiO 2 NPs may modulate the cardiac function and expression of inflammatory cytokines. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2917-2927, 2016., (© 2016 Wiley Periodicals, Inc.)

Nanoparticles (NPs; < 100 nm) are increasingly being applied in various fields due to their unique physicochemical properties. The increase in human exposure to NPs has raised concerns regarding their health and safety profiles. The potential correlation between NP exposure and several cardiovascular (CV) events has been demonstrated. The aim of this review is to provide a comprehensive evaluation of the current knowledge regarding the bio-toxic impacts of titanium oxide, silver, silica, carbon black, carbon nanotube, and zinc oxide NPs exposure on the CV system in terms of in vivo and in vitro experiments, which is not fully understood presently. Moreover, the potential toxic mechanisms of NPs in the CV system that are still being questioned are elaborately discussed, and the underlying capacity of NPs used in medicine for CV events are summarized. It will be an important instrument to extrapolate relevant data for human CV risk evaluation and management. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2881-2897, 2016., (© 2016 Wiley Periodicals, Inc.)

Zebrafish (Danio rerio) has been used historically for evaluating the toxicity of environmental and aqueous toxicants, and there is an emerging literature reporting toxic effects of manufactured nanoparticles (NPs) in zebrafish embryos. Few researches, however, are focused on the neurotoxicity on adult zebrafish after subchronic exposure to TiO2 NPs. This study was designed to evaluate the morphological changes, alterations of neurochemical contents, and expressions of memory behavior-related genes in zebrafish brains caused by exposures to 5, 10, 20, and 40 μg/L TiO2 NPs for 45 consecutive days. Our data indicated that spatial recognition memory and levels of norepinephrine, dopamine, and 5-hydroxytryptamine were significantly decreased and NO levels were markedly elevated, and over proliferation of glial cells, neuron apoptosis, and TiO2 NP aggregation were observed after low dose exposures of TiO2 NPs. Furthermore, the low dose exposures of TiO2 NPs significantly activated expressions of C-fos, C-jun, and BDNF genes, and suppressed expressions of p38, NGF, CREB, NR1, NR2ab, and GluR2 genes. These findings imply that low dose exposures of TiO2 NPs may result in the brain damages in zebrafish, provide a developmental basis for evaluating the neurotoxicity of subchronic exposure, and raise the caution of aquatic application of TiO2 NPs., (© 2014 Wiley Periodicals, Inc.)

Although TiO2 nanoparticles (NPs) as endocrine disruptors have been demonstrated to be able to cross the blood-testis barriers and induce reproductive toxicity in male animals, whether the reproductive toxicity of male animals due to exposure to endocrine disruptor TiO2 NPs is related to immunological dysfunction in the testis remains not well understood. This study determined whether the reproductive toxicity and immunological dysfunction induced by exposure to TiO2 NPs is associated with activation or inhibition of TAM/TLR-mediated signal pathway in mouse testis. The results showed that male mice exhibited significant reduction of fertility, infiltration of inflammatory cells, rarefaction, apoptosis, and/or necrosis of spermatogenic cells and Sertoli cells due to TiO2 NPs. Furthermore, these were associated with decreased expression of Tyro3 (-18.16 to -66.6%), Axl (-14.7 to -57.99%), Mer (-7.98 to -72.62%), and IκB (-11.25 to -63.16%), suppression of cytokine signaling (SOCS) 1 (-21.99 to -73.8%) and SOCS3 (-8.11 to -34.86%), and increased expression of Toll-like receptor (TLR)-3 (21.4-156.03%), TLR-4 (37.0-109.87%), nuclear factor-κB (14.75-69.34%), interleukin (IL)-lβ (46.15-123.08%), IL-6 (2.54-81.98%), tumor necrosis factor-α (6.95-88.39%), interferon (IFN)-α (2.54-37.25%), and IFN-β (10.19-80.56%), which are involved in the immune environment in the testis. The findings showed that reproductive toxicity of male mice induced by exposure to endocrine disruptor TiO2 NPs may be associated with biomarkers of impairment of immune environment or dysfunction of TAM/TLR3-mediated signal pathway in mouse testitis. Therefore, the potential risks to reproductive health should be attended, especially in those who are occupationally exposed to TiO2 NPs.

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.)

TiO2 nanoparticles (NPs) have been demonstrated to suppress spermatogenesis in animals, while there is little data related to the biochemical dysfunctions during spermatogenesis due to exposure to TiO2 NPs. In this study, male mice have been exposed to TiO2 NPs via intragastric administration for 60 consecutive days. The findings showed that TiO2 NP exposure resulted in lesions of testis and epididymis, deductions in sperm concentration and sperm motility, and an increase of the number of abnormal sperm in mice. Furthermore, TiO2 NP exposure with 2.5, 5, or 10 mg/kgbw decreased activities of lactate dehydrogenase (-11.59% to -39.84%), sorbitol dehydrogenase (-23.56% to -57.33%), succinate dehydrogenase (-27.04% to -57.85%), glucose-6-phosphate dehydrogenase (-28.3% to -56.42%), Na(+)/K(+)-ATPase (-15.59% to -53.11%), Ca(2+)-ATPase (-12.44% to -55.41%), and Ca(2+)/Mg(2+)-ATPase (-28.25% to -65.72%), and elevated activities of acid phosphatase (+10.48% to +40.0%), alkaline phosphatase (+20.65% to +64.07%), and total nitric oxide synthase (+0.68- to +2.3-fold) in the testes of mice, respectively. In addition, TiO2 NP exposure caused excessive production of reactive oxygen species (+16.15% to +110.62%), and increased malondialdehyde of lipid peroxidation product (+38.96% to +118.07%), carbonyl of protein oxidative product (+20.98% to +108.1%), and 8-hydroxydeoxyguanosine of DNA oxidative product (+0.9- to +1.83-fold) in the testes, respectively. It implied that spermatogenesis suppression caused by TiO2 NP exposure may be associated with alterations of testicular marked enzymes and oxidative stress in the testes.

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.)

Bombyx mori (B. mori) is often subjected to phoxim poisoning in China due to phoxim exposure, which leads to a decrease in silk production. Nanoparticulate (NP) titanium dioxide (nano-TiO2) has been shown to attenuate damages in B. mori caused by phoxim exposure. However, little is known about the molecular mechanisms of midgut injury due to organophosphorus insecticide exposure and its repair by nano-TiO2 pretreatment. In this study, phoxim exposure for 36 h led to significant decreases in body weight and survival and increased oxidative stress and midgut injury. Pretreatment with nano-TiO2 attenuated the phoxim-induced midgut injury, increased body weight and survival, and decreased oxidative stress in the midgut of B. mori. Digital gene-expression data showed that exposure to phoxim results in significant changes in the expression of 254 genes in the phoxim-exposed midgut and 303 genes in phoxim + nano-TiO2-exposed midgut. Specifically, phoxim exposure led to upregulation of Tpx, α-amylase, trypsin, and glycoside hydrolase genes involved in digestion and absorption. Phoxim exposure also led to the downregulation of Cyp450 and Cyp4C1 genes involved in an antioxidant capacity. In contrast, a combination of both phoxim and nano-TiO2 treatment significantly decreased the change in α-amylase, trypsin, and glycoside hydrolases (GHs), which are involved in digestion and absorption. These results indicated that Tpx, α-amylase, trypsin, GHs, Cyp450, and Cyp4C1 may be potential biomarkers of midgut toxicity caused by phoxim exposure and the attenuation of these toxic impacts by nano-TiO2.

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.)

Chronic exposure to nano-TiO2 may induce renal fibrosis, and the mechanism of this process is not well understood. Therefore, in this study, mice were administered nano-TiO2 by intragastric feeding for 9 months, and the urinary levels of nephrotoxicity biomarkers, activation of the Wnt pathway, and markers of the epithelial-to-mesenchymal transition (EMT) in the kidneys were investigated. The findings suggested that exposure to nano-TiO2 increased the level of renal titanium accumulation, urinary levels of kidney injury molecule-1 (1.18 ± 0.13- to 3.60 ± 0.41-fold), clusterin (1.40 ± 0.16- to 5.14 ± 0.58-fold), and osteopontin (0.71 ± 0.08- to 2.41 ± 0.29-fold), and increased levels of renal inflammation and fibrosis. Furthermore, nano-TiO2 increased the level of expression of Wnt ligands (Wnt1, Wnt2, Wnt3, Wnt4, Wnt5a, Wnt6, Wnt7a, Wnt9a, Wnt10a, and Wnt11, 0.09 ± 0.02- to 4.84 ± 0.52-fold), Wnt receptors Frizzled (Fz1, Fz5, and Fz7, 0.37 ± 0.04- to 8.57 ± 0.91-fold), and coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (0.73 ± 0.09- to 5.27 ± 0.56-fold) in the kidney. Wnt signaling components induced by nano-TiO2 were corroborated by decreased levels of expression of Wnt antagonist-related markers (Dkk1, Dkk2, Dkk3, Dkk4, and sFRP/FrzB, -0.06 ± 0.01- to -0.87 ± 0.09-fold) and increased levels of expression of Wnt target genes (Abcb1b, cyclin D1, and Myc, 0.03 ± 0.01- to 2.73 ± 0.28-fold) and EMT markers Colla1, Fn, Twist, and α-SMA (0.06 ± 0.02- to 5.80 ± 0.61-fold). These findings indicate that nano-TiO2 induced renal fibrosis that may be mediated via Wnt signaling.

Phoxim (O,O-diethyl O-(alpha-cyanobenzylideneamino) phosphorothioate) is a powerful organophosphorus pesticide with high potential for Bombyx mori larvae of silkworm exposure. However, it is possible that during the phoxim metabolism, there is generation of reactive oxygen species (ROS) and phoxim may produce oxidative stress and neurotoxicity in an intoxicated silkworm. Titanium dioxide nanoparticles (TiO2 NPs) pretreatment has been demonstrated to increase antioxidant capacity and acetylcholinesterase (AChE) activity in organisms. This study was, therefore, undertaken to determine phoxim-induced oxidative stress and neurotoxicity to determine whether phoxim intoxication alters the antioxidant system and AChE activity in the B. mori larval midgut, and to determine whether TiO2 NPs pretreatment attenuates phoxim-induced toxicity. The findings suggested that phoxim exposure decreased survival of B. mori larvae, increased malondialdehyde (MDA), carbonyl and 8-OHdG levels, and ROS accumulation in the midgut. Furthermore, phoxim significantly decreased the activities of AChE, superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR), glutathione-S-transferase (GST), and levels of ascorbic acid (AsA), reduced glutathione (GSH), and thiol in the midgut. TiO2 pretreatment, however, could increase AChE activity, and remove ROS via activating SOD, CAT, APX, GR, and GST, and accelerating AsA-GSH cycle, thus attenuated lipid, protein, and DNA peroxidation and improve B. mori larval survival under phoxim-induced toxicity. Moreover, this experimental system would help nanomaterials to be applied in the sericulture., (© 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.)

Titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various areas, and its potential toxicity has gained wide attention. However, the molecular mechanisms of multiple genes working together in the TiO2 NP-induced splenic injury are not well understood. In the present study, 2.5, 5, or 10mg/kg body weight TiO2 NPs were administered to the mice by intragastric administration for 90 consecutive days, their immune capacity in the spleen as well as the gene-expressed characteristics in the mouse damaged spleen were investigated using microarray assay. The findings showed that with increased dose, TiO2 NP exposure resulted in the increases of spleen indices, immune dysfunction, and severe macrophage infiltration as well as apoptosis in the spleen. Importantly, microarray data showed significant alterations in the expressions of 1041 genes involved in immune/inflammatory responses, apoptosis, oxidative stress, stress responses, metabolic processes, ion transport, signal transduction, cell proliferation/division, cytoskeleton and translation in the 10 mg/kg TiO2 NP-exposed spleen. Specifically, Cyp2e1, Sod3, Mt1, Mt2, Atf4, Chac1, H2-k1, Cxcl13, Ccl24, Cd14, Lbp, Cd80, Cd86, Cd28, Il7r, Il12a, Cfd, and Fcnb may be potential biomarkers of spleen toxicity following exposure to TiO2 NPs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

TiO2 nanoparticles (NPs) are used in the food industry but have potential toxic effects in humans and animals. The resulting immune response is driven by the production of Th2 cytokines IL-4 and IL-5, which contribute to the development of hepatic inflammation. However, TiO2 NPs have been demonstrated to impair liver function and cause liver inflammation in animal models, which may be associated with activation of Th2 factor-mediated pathways. Mice were administered a gavage instillation of 2.5, 5, or 10 mg/kg body weight TiO2 NPs for six consecutive months. We investigated whether TiO2 NPs activate the Th2 factor-mediated signaling pathway under TiO2 NP-induced hepatic toxicity. The results showed that mice exhibited an accumulation of titanium in the liver, which in turn led to reductions in body weight, increases in liver indices, liver dysfunction, infiltration of inflammatory cells, and hepatocyte apoptosis or necrosis. Furthermore, hepatic inflammation was accompanied by increased (0.67 ± 0.09- to 2.14 ± 0.19-fold) IL-4 expression and up-regulation of its target genes including IL-5 (0.1 ± 0.06- to 0.69 ± 0.12-fold), IL-12 (0.08 ± 0.03- to 0.83 ± 0.21-fold), IFN-γ (0.17 ± 0.09- to 0.87 ± 0.15-fold), GATA3 (0.05 ± 0.02- to 1.29 ± 0.18-fold), GATA4 (0.04 ± 0.01- to 0.87 ± 0.13-fold), T-bet (0.3 ± 0.06- to 0.93 ± 0.15-fold), RORγt (0.32 ± 0.11- to 1.67 ± 0.17-fold), STAt3 (0.16 ± 0.06- to 2.14 ± 0.23-fold), STAT6 (0.2 ± 0.05- to 0.63 ± 0.12-fold), eotaxin (0.53 ± 0.13- to 1.49 ± 0.21-fold), MCP-1 (0.5 ± 0.11- to 0.74 ± 0.18-fold), and MIP-2 (0.27 ± 0.07- to 0.71 ± 0.18-fold) and significant down-regulation of its target gene STAT1 (-0.15 ± 0.05 to -0.81 ± 0.11-fold). Taken together, the alteration of Th2 factor expression may be involved in the control of hepatic inflammation induced by chronic TiO2 NP toxicity.

Phoxim is a useful organophosphate (OP) pesticide used in agriculture in China, however, exposure to this pesticide can result in a significant reduction in cocooning in Bombyx mori (B. mori). Titanium dioxide nanoparticles (TiO2 NPs) have been shown to decrease phoxim-induced toxicity in B. mori; however, very little is known about the molecular mechanisms of silk gland damage due to OP exposure and repair of gland damage by TiO2 NP pretreatment. In the present study, exposure to phoxim resulted in a significant reduction in cocooning rate in addition to silk gland damage, whereas TiO2 NP attenuated phoxim-induced gland damage, increased the antioxidant capacity of the gland, and increased cocooning rate in B. mori. Furthermore, digital gene expression data suggested that phoxim exposure led to significant alterations in the expression of 833 genes. In particular, phoxim exposure caused significant down-regulation of Fib-L, Ser2, Ser3, and P25 genes involved in silk protein synthesis, and up-regulation of SFGH, UCH3, and Salhh genes involved in silk protein hydrolysis. A combination of both phoxim and TiO2 NP treatment resulted in marked changes in the expression of 754 genes, while treatment with TiO2 NPs led to significant alterations in the expression of 308 genes. Importantly, pretreatment with TiO2 NPs increased Fib-L, Ser2, Ser3, and P25 expression, and decreased SFGH, UCH3, and Salhh expression in silk protein in the silk gland under phoxim stress. Therefore, Fib-L, Ser2, Ser3, P25, SFGH, UCH3, and Salhh may be potential biomarkers of silk gland toxicity in B. mori caused by phoxim exposure., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This study aimed to investigate the effects of titanium dioxide nanoparticles (TiO2 NPs) on feed efficiency of silkworm (Bombyx mori) (B. mori). The results showed that the amount of ingested food was increased by 3.31%, the percentage of ingested food was increased by 16.36%, the instar was prolonged by 6.77 h, the body mass of mature silkworm was increased by 11.41%, the cocoon mass was increased by 5.47%, the cocoon shell mass was increased by 9.80%, and the ratio of cocoon shell was increased by 3.54%. Average cocoon filament length, reelability, and neatness were increased by 3.15, 17.57, and 1.72%, respectively, whereas the cocoon filament size was decreased by 0.19%. The gene expression profiles were also examined with digital gene expression (DGE). The results showed that among 4,011 genes detected, 127 genes were differentially expressed including 57 genes whose expression was upregulated and 70 genes whose expression was downregulated. The expression levels of five genes related to metabolism were verified with quantitative real-time PCR, and the results were consistent with the DGE data. The activities of three major digestive enzymes in the midgut were also assayed; the results showed that the activities of trehalase, protease, and lipase in TiO2 NP-fed group were increased by 42.55, 78.13, and 33.33%, respectively. These results indicate that feeding B. mori with TiO2 NPs can stimulate the transcriptional level of genes related to digestion and absorption of nutrients in the midgut and increase the activities of trehalase, protease, and lipase and, thus, increase the feed efficiency of B. mori.

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.)

Organophosphate pesticides are applied widely in the world for agricultural purposes, and their exposures often resulted in non-cocooning of Bombyx mori in China. TiO2 nanoparticles have been demonstrated to increase pesticide resistance of Bombyx mori. While the toxicity of phoxim is well-documented, very limited information exists on the mechanisms of TiO2 nanoparticles improving the cocooning function of Bombyx mori following exposure to phoxim. The present study was, therefore, undertaken to determine whether TiO2 nanoparticles attenuate silk gland injury and elevate cocooning of B. mori following exposure to phoxim. The findings suggested that phoxim exposure resulted in severe damages of the silk gland structure and significantly decreased the cocooning in the silk gland of Bombyx mori. Furthermore, phoxim exposure significantly resulted in reductions of total protein concentrations and suppressed expressions of silk protein synthesis-related genes, including Fib-L, Fib-H, P25, Ser-2, and Ser-3, in the silk gland. TiO2 nanoparticle pretreatment, however, could significantly relieve silk gland injury of Bombyx mori. Importantly, TiO2 nanoparticles could remarkably elevate cocooning and total protein contents and promote expressions of Fib-L, Fib-H, P25, Ser-2, and Ser-3 in the silk gland following exposure to phoxim.

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.

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.

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.

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.)

Phoxim insecticide is widely used in agriculture, which is toxic to insect pests and nontarget organisms. The phoxim poisoning is hard to prevent for silkworms. TiO(2) NPs have been widely applied in whitening, brightening foods, toothpaste or sunscreens, and orally-administered drugs. However, whether TiO(2) NPs can increase resistance of silkworm to phoxim poisoning has not been reported. The results demonstrated that added TiO(2) NPs significantly decreased reduction of protein, glucose and pyruvate contents, lactate dehydrogenase, succinate dehydrogenase and malate dehydrogenase activities, and attenuated increases of free amino acids, urea, uric acid and lactate levels, activities of protease, alanine aminotransferase and aspartate aminotransferase in the hemolymph of silkworms caused by phoxim exposure. From the present study, it is clearly evident that added TiO(2) NPs may relieve toxic impacts of phoxim insecticide on silkworm metabolism, which in turn may result in an increase in silk yield., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Exposure to titanium dioxide nanoparticles (TiO(2) NPs) elicits an adverse response such as oxidative damage. The molecular targets of TiO(2) NPs remain largely unidentified. In the present study, the function and signal pathway of nuclear factor erythroid 2 related factor 2 (Nrf2) in protection against TiO(2) NPs-induced oxidative stress in the mouse lung were investigated. Mice were exposed to 10 mg/kg body weight by an intratracheal administration for 15-90 days. With increasing exposed terms, TiO(2) NPs were significantly accumulated and increased the reactive oxygen species (ROS) production in lung, which resulted in severe pulmonary edema, inflammatory response and pneumonocyte apoptosis for 90 days. Furthermore, TiO(2) NPs exposure could greatly induce expression of Nrf2, heme oxygenase 1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) from 15-day to 75-day exposure, whereas 90-day exposure caused significant decreases of three factors expression levels in lung. Our findings imply that the induction of Nrf2 expression is an adaptive intracellular response to TiO(2) NPs-induced oxidative stress in the mouse lung, and that Nrf2 is protective against TiO(2) NPs-induced pulmonary damages during certain exposure terms., (Copyright © 2012 Wiley Periodicals, Inc.)

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.

While the hepatocyte apoptosis induced by TiO(2) nanoparticles (NPs) has been demonstrated, very little is known about the molecular mechanisms underlying this mouse liver apoptosis. In order to understand the hepatocyte apoptosis induced by intragastric administration of TiO(2) NPs for consecutive 60 days, the hepatocyte apoptosis, various oxidative stress parameters and the stress-related gene expression levels were assayed for the mouse liver. 60 days of TiO(2) NPs exposure, hepatocyte apoptosis in the liver could be observed, which was followed by increased reactive oxygen species accumulation, and decreased the stress-related gene expression levels of superoxide dismutase, catalase, glutathione peroxidase, metallothionein, heat shock protein 70, glutathione S transferase, P53, and transferrin; and the significant enhancement of the cytochrome p450 1A expression level. It implied that hepatocyte apoptosis, oxidative stresses, and alteration of expression levels of the genes related with TiO(2) NPs detoxification/metabolism regulation and radical scavenging action. Therefore, the application of TiO(2) NPs and exposure effects especially on human liver for long-term and low-dose treatment should be cautious., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Titanium dioxide nanoparticles (TiO(2) NPs) are now in daily use including popular sunscreens, toothpastes, and cosmetics. However, the effects of TiO(2) NPs on human body, especially on the central nervous system, are still unclear. The aim of this study was to determine whether TiO(2) NPs exposure results in persistent alternations in nervous system function. ICR mice were exposed to TiO(2) NPs through intragastric administration at 0, 5, 10 and 50 mg/kg body weight every day for 60 days. The Y-maze test showed that TiO(2) NPs exposure could significantly impair the behaviors of spatial recognition memory. To fully investigate the neurotoxicological consequence of TiO(2) NPs exposure, brain elements and neurochemicals were also investigated. The contents of Ca, Mg, Na, K, Fe and Zn in brain were significantly altered after TiO(2) NPs exposure. Moreover, TiO(2) NPs significantly inhibited the activities of Na(+)/K(+)-ATPase, Ca(2+)-ATPase, Ca(2+)/Mg(2+)-ATPase, acetylcholine esterase, and nitric oxide synthase; the function of the central cholinergic system was also noticeably disturbed and the contents of some monoamines neurotransmitters such as norepinephrine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid were significantly decreased, while the contents of acetylcholine, glutamate, and nitric oxide were significantly increased. These first findings indicated that exposure to TiO(2) NPs could possibly impair the spatial recognition memory ability, and this deficit may be possibly attributed to the disturbance of the homeostasis of trace elements, enzymes and neurotransmitter systems in the mouse brain. Therefore, the application of TiO(2) NPs and exposure effects especially on human brain for long-term and low-dose treatment should be cautious., (Copyright 2010 Elsevier Ltd. All rights reserved.)

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

Lactate dehydrogenase (LDH, EC1.1.1.27), widely expressed in the heart, liver, and other tissues, plays an important role in glycolysis and glyconeogenesis. The activity of LDH is often altered upon inflammatory responses in animals. Nano-TiO(2) was shown to provoke various inflammatory responses both in rats and mice; however, the molecular mechanism by which TiO(2) exerts its toxicity has not been completely understood. In this report, we investigated the mechanisms of nano-anatase TiO(2) (5 nm) on LDH activity in vitro. Our results showed that LDH activity was greatly increased by low concentration of nano-anatase TiO(2), while it was decreased by high concentration of nano-anatase TiO(2). The spectroscopic assays revealed that the nano-anatase TiO(2) particles were directly bound to LDH with mole ratio of [nano-anatase TiO(2)] to [LDH] was 0.12, indicating that each Ti atom was coordinated with five oxygen/nitrogen atoms and a sulfur atoms of amino acid residues with the Ti-O(N) and Ti-S bond lengths of 1.79 and 2.41 A. We postulated that the bound nano-anatase TiO(2) altered the secondary structure of LDH, created a new metal ion-active site for LDH, and thereby enhanced LDH activity.

Previous research on the biological and toxic effects of nano-TiO(2) particles on animals only limit to a single dose. However, the toxicity caused by single dose nano-TiO(2) does not truly represent ecological and health effects of nano-TiO(2) retained in the environment. In order to further evaluate the toxicity of nano-TiO(2) particles, nano-anatase TiO(2) (5 nm) was injected into the abdominal cavity of ICR mice everyday for 14 days and the coefficients of organs and serum biochemical parameters were investigated. The results showed that, with increasing doses of nano-anatase TiO(2), the coefficients of liver, kidney, and spleen increased gradually, while the coefficients of lung and brain decreased gradually, and the coefficient of heart had little change. The order of the titanium accumulation in the organs was liver > kidneys > spleen > lung > brain > heart. The serum biochemical parameters with lower dose of nano-anatase TiO(2) showed little difference compared with the control mice, while with higher dose of nano-anatase TiO(2), the indicators of liver function, such as alkaline phosphatase, alanine aminotransferase, leucine acid peptide, pseudocholinesterase, total protein, and albumin level, were enhanced significantly; the indicators of kidney function, such as uric acid and blood urea nitrogen, were decreased; the activities of aspartate aminotransferase, creatine kinase, lactate dehydrogenase, and alpha-hydroxybutyrate dehydrogenase, indicator of the myocardium function, were increased. The contents of triglycerides, glucose, and high-density lipoprotein cholesterol were significantly elevated. Taken together, nano-anatase TiO(2) in higher dose caused serious damage to the liver, kidney, and myocardium of mice and disturbed the balance of blood sugar and lipid in mice. The accumulation of titanium in the organs might be closely related to the coefficients of organs and the inflammatory responses of mice.

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]

Currently, impacts of exposure to TiO nanoparticles (NPs) on the cardiovascular system are not well understood. The aim of this study was to investigate whether TiO NPs induce myocarditis and its underlying molecular mechanism in the cardiac inflammation in mice. Mice were exposed to TiO NPs for 6 months; biochemical parameters of serum and expression of Th1-related and Th2-related cytokines in the heart were investigated. The results showed that TiO NP exposure resulted in cardiac lesions coupling with pulmonary inflammation; increases of aspartate aminotransferase (AST), creatine kinase (CK), C-reaction protein (CRP), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH), adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) levels; and a reduction of nitric oxide (NOx) level in the serum. These were associated with increases of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), interleukin (IL)-4, IL-6, transforming growth factor-β (TGF-β), creatine kinase, CRP, adhesion molecule-1, and monocyte chemoattractant protein-1, interferon-γ (IFN-γ), signal transducers and activators of transcription (STAT)1, STAT3, or STAT6, GATA-binding domain-3, GATA-binding domain-4, endothelin-1 expression levels, and T-box expressed in T cells expression level that is the master regulator of pro-inflammatory cytokines and transcription factors in the heart. These findings imply that TiO NP exposure may increase the occurrence and development of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Bombyx mori (B. mori), silkworm, is one of the most important economic insects in the world, while phoxim, an organophosphorus (OP) pesticide, impact its economic benefits seriously. Phoxim exposure can damage the brain, fatbody, midgut and haemolymph of B. mori. However the metabolism of proteins and carbohydrates in phoxim-exposed B. mori can be improved by Titanium dioxide nanoparticles (TiO2 NPs). In this study, we explored whether TiO2 NPs treatment can reduce the phoxim-induced brain damage of the 5th larval instar of B. mori. We observed that TiO2 NPs pretreatments significantly reduced the mortality of phoxim-exposed larva and relieved severe brain damage and oxidative stress under phoxim exposure in the brain. The treatments also relieved the phoxim-induced increases in the contents of acetylcholine (Ach), glutamate (Glu) and nitric oxide (NO) and the phoxim-induced decreases in the contents of norepinephrine (NE), Dopamine (DA), and 5-hydroxytryptamine (5-HT), and reduced the inhibition of acetylcholinesterase (AChE), Na+/K+-ATPase, Ca2+-ATPase, and Ca2+/Mg2+-ATPase activities and the activation of total nitric oxide synthase (TNOS) in the brain. Furthermore, digital gene expression profile (DGE) analysis and real time quantitative PCR (qRT-PCR) assay revealed that TiO2 NPs pretreatment inhibited the up-regulated expression of ace1, cytochrome c, caspase-9, caspase-3, Bm109 and down-regulated expression of BmIap caused by phoxim; these genes are involved in nerve conduction, oxidative stress and apoptosis. TiO2 NPs pretreatment also inhibited the down-regulated expression of H+ transporting ATP synthase and vacuolar ATP synthase under phoxim exposure, which are involved in ion transport and energy metabolism. These results indicate that TiO2 NPs pretreatment reduced the phoxim-induced nerve toxicity in the brain of B. mori. [ABSTRACT FROM AUTHOR]

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

Bombyx mori (B. mori), silkworm, is one of the most important economic insects in the world, while phoxim, an organophosphorus (OP) pesticide, impact its economic benefits seriously. Phoxim exposure can damage the brain, fatbody, midgut and haemolymph of B. mori. However the metabolism of proteins and carbohydrates in phoxim-exposed B. mori can be improved by Titanium dioxide nanoparticles (TiO2 NPs). In this study, we explored whether TiO2 NPs treatment can reduce the phoxim-induced brain damage of the 5th larval instar of B. mori. We observed that TiO2 NPs pretreatments significantly reduced the mortality of phoxim-exposed larva and relieved severe brain damage and oxidative stress under phoxim exposure in the brain. The treatments also relieved the phoxim-induced increases in the contents of acetylcholine (Ach), glutamate (Glu) and nitric oxide (NO) and the phoxim-induced decreases in the contents of norepinephrine (NE), Dopamine (DA), and 5-hydroxytryptamine (5-HT), and reduced the inhibition of acetylcholinesterase (AChE), Na+/K+-ATPase, Ca2+-ATPase, and Ca2+/Mg2+-ATPase activities and the activation of total nitric oxide synthase (TNOS) in the brain. Furthermore, digital gene expression profile (DGE) analysis and real time quantitative PCR (qRT-PCR) assay revealed that TiO2 NPs pretreatment inhibited the up-regulated expression of ace1, cytochrome c, caspase-9, caspase-3, Bm109 and down-regulated expression of BmIap caused by phoxim; these genes are involved in nerve conduction, oxidative stress and apoptosis. TiO2 NPs pretreatment also inhibited the down-regulated expression of H+ transporting ATP synthase and vacuolar ATP synthase under phoxim exposure, which are involved in ion transport and energy metabolism. These results indicate that TiO2 NPs pretreatment reduced the phoxim-induced nerve toxicity in the brain of B. mori. [ABSTRACT FROM AUTHOR]

Abstract: Numerous studies have demonstrated that damage of kidney of mice can be caused by exposure to titanium dioxide nanoparticles (TiO2 NPs). However, the molecular mechanism of TiO2 NPs-induced nephric injury remains unclear. In this study, the mechanism of nephric injury in mice induced by an intragastric administration of TiO2 NPs was investigated. The results showed that TiO2 NPs were accumulated in the kidney, resulting in nephric inflammation, cell necrosis and dysfunction. Nucleic factor-κB was activated by TiO2 NPs exposure, promoting 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 heat shock protein 70 expression was inhibited. These findings implied that TiO2 NPs-induced nephric injury of mice might be associated with alteration of inflammatory cytokine expression and reduction of detoxification of TiO2 NPs. [Copyright &y& Elsevier]

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