Xiaoyang Zhao

Renal Injury and Nrf2 Modulation in Mouse Kidney Following Chronic Exposure to TiO2 Nanoparticles

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.

Toxicological Mechanisms of Nanosized Titanium Dioxide-Induced Spleen Injury in Mice after Repeated Peroral Application

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.

Th2 Factors May Be Involved in TiO2 NP-Induced Hepatic Inflammation

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.

TiO2 Nanoparticle Exposure Decreases Spermatogenesis via Biochemical Dysfunctions in the Testis of Male Mice

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.

BmNPV Resistance of Silkworm Larvae Resulting from the Ingestion of TiO2 Nanoparticles

Bombyx mori nucleopolyhedrovirus (BmNPV) causes infection in the silkworm that is often lethal. The infection is hard to prevent, partly because of the nature of the virus particles and partly because of the different strains of B. mori. Titanium dioxide nanoparticles (TiO2 NPs) have been demonstrated to have antimicrobial properties. The present study investigated whether TiO2 NPs added to an artificial diet can increase the resistance of B. mori larvae to BmNPV and examined the molecular mechanism behind any resistance shown. The results indicated that ingested TiO2 NPs decreased reactive oxygen species and NO accumulation in B. mori larvae under BmNPV infection, which in turn led to a decrease in their growth inhibition and mortality. In addition, the TiO2 NPs significantly promoted the expression of resistance-related genes, including those encoding superoxide dismutase, catalase, glutathione peroxidase, acetylcholine esterase, carboxylesterase, heat shock protein 21, glutathione S transferase o1, P53, and transferring and of genes encoding cytochrome p302 and nitric oxide synthase. These findings are a useful addition to the understanding of the mechanism of BmNPV resistance of B. mori larvae in response to TiO2 NPs addition. Such information also provides a theoretical basis for the use of TiO2 NPs in sericulture.

Hippocampal Damage and Alterations of Inflammatory Cytokine Expression in Mice Caused by Exposure to Cerium Chloride

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.

Effects of Manganese Deficiency on Spectral Characteristics and Oxygen Evolution in Maize Chloroplasts

The effects of Mn2+ deficiency on light absorption, transmission, and oxygen evolution of maize chloroplasts were investigated by spectral methods. Several effects of Mn2+ deficiency were observed: (1) the skeleton of pigment protein complexes and oxygen-evolving center and the combination between pigment and protein were damaged; (2) the light absorption of chloroplasts was obviously decreased; (3) the energy transfer among amino acids within PS II protein–pigment complex and decreased energy transport from tyrosine residue to chlorophyll a and from chlorophyll b and carotenoid to chlorophyll a were inhibited; (4) the oxygen-evolving of chloroplast was significantly inhibited. However, Mn2+ addition decreased the damage of light absorption, transmission, and oxygen evolution of maize chloroplasts caused by Mn2+ deficiency.

Pulmonary Toxicity in Mice Following Exposure to Cerium Chloride

The widespread application of lanthanoids (Lns) in manufacturing industries has raised occupational and environmental health concerns about the possible increased health risks to humans exposed to Lns in their working and living environments. Numerous studies have shown that exposures to Ln cause pulmonary injury in animals, but very little is known about the molecular mechanisms of the pulmonary inflammation caused by cerium chloride (CeCl3) exposure. In this study, we evaluated the oxidative stress and molecular mechanism underlying with the pulmonary inflammation associated with chronic lung toxicity in mice treated with nasally instilled CeCl3 for 90 consecutive days. Our findings suggest that significant cerium accumulated in the lung, leading the obvious increase of the lung indices, significant increases in inflammatory cells and levels of lactate dehydrogenase, alkaline phosphate, and total protein, overproduction of reactive oxygen species and peroxidation of lipids, reduced antioxidant capacity, and pulmonary inflammation. CeCl3 exposure also activated nuclear factor κB, increased the expression 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. However, CeCl3 reduced the expression of nuclear factor κB (NF-κB)-inhibiting factor and heat shock protein 70. These findings suggest that the pulmonary inflammation caused by CeCl3 in mice is closely associated with oxidative stress and inflammatory cytokine expression.

Nanosized TiO2 Exposure Resulted in Neurotoxicity via Impairing NMDA Receptor-mediated Postsynaptic Signaling Cascade in Mice

The central nervous system (CNS) toxicity induced by exposure to nano-sized particles is of great concern, but the mechanism of how this toxicity may be incurred has yet to be elucidated. Here, we examined how N-methyl-D-aspartate (NMDA) receptor-mediated postsynaptic signalling cascade may be affected by titanium dioxide particles (TiO2 NPs) exposure for six consecutive months to contribute to the observed neurotoxicity. The results suggest that long-term exposure to TiO2 NPs led to titanium accumulation and iron reduction in the blood and hippocampus tissues, and significant hippocampal injury as well as reduction of learning and memory in mice. The CNS injuries following longterm TiO2 NP exposure were closely associated with significant reductions in NR1, NR2A, NR2B, calcium/calmodulindependent protein kinase II, postsynaptic density protein 95, nuclear activated extracellular-signal regulated kinase (ERK1/2), Dexras1, CAPON, peripheral benzodiazepine receptor-associated protein, and divalent metal transporter as well as elevation of synaptic Ras GTPase- activating protein and neural nitric oxide synthase in the hippocampus. It implies that long-term exposure to TiO2 NPs may induce neurotoxic effects via impairing NMDA receptor-mediated postsynaptic signalling cascade in animals.