Fashui Hong

Although nanoscale titanium dioxide (nano-TiO₂) 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-TiO₂ on developing embryos. Female imprinting control region mice were orally administered nano-TiO₂ from gestational day 0 to 17. Our findings showed that Ti concentrations in maternal serum, placenta, and fetus were increased in nano-TiO₂-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-TiO₂ 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-TiO₂ 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-TiO₂ during the prenatal period. Therefore, the application of nano-TiO₂ should be carried out with caution.

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

Titanium dioxide nanoparticles (TiO₂NPs) are inorganic materials with a diameter of 1–100 nm.

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‐TiO₂) 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‐TiO₂ via alterations in morphology, cell viability, and activation of the TAM/TLR3 signal pathway. The results demonstrated that nano‐TiO₂ 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‐TiO₂ 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.

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

Titanium dioxide nanoparticles (TiO₂ NPs) have been demonstrated to damage the kidneys. However, whether chronic nephritis leads to renal fibration or the fibrosis is associated with the activation of TGF‐β/Smads/p38MAPK pathway caused by TiO₂ NPs exposure is not well understood. Forty male mice were separately exposed to 0, 2.5, 5, or 10 mg/kg body weight TiO₂ NPs for 6 months. Renal biochemical functions and levels of TGF‐β/Smads/p38MAPK pathway‐related markers and extracellular matrix (ECM) expression in the kidneys were investigated. The findings showed that subchronic TiO₂ NPs exposure increased levels of urinary creatisix (Cr), N‐acetyl‐glucosaminidase, and vanin‐1, resulted in severe renal inflammation and fibration. Furthermore, TiO₂ NP exposure upregulated expression of transforming growth factor‐β1 (TGF‐β1, 0.07‐ to 2.72‐fold), Smad2 (0.42‐ to 1.63‐fold), Smad3 (0.02‐ to 1.94‐fold), ECM (0.15‐ to 2.75‐fold), α‐smooth muscle actin (0.14‐ to 3.06‐fold), p38 mitogen‐activated protein kinase (p38MAPK, 0.11‐ to 3.78‐fold), and nuclear factor‐κB (0.4‐ to 2.27‐fold), and downregulated Smad7 (0.05‐ to 0.61‐fold) expression in mouse kidney. Subchronic TiO₂ NPs exposure induced changes of renal characteristics towards inflammation and fibration may be mediated via TGF‐β/Smads/p38MAPK pathway, and the uses of TiO₂ NPs should be carried out cautiously, especially in humans. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1452–1461, 2016.

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.

Currently, impacts of exposure to TiO2 nanoparticles (NPs) on the cardiovascular system are not well understood. The aim of this study was to investigate whether TiO2 NPs induce myocarditis and its underlying molecular mechanism in the cardiac inflammation in mice. Mice were exposed to TiO2 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 TiO2 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 TiO2 NP exposure may increase the occurrence and development of cardiovascular diseases.