Meng Tang

Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles.

Previous studies demonstrate that the exposure to titanium dioxide nanoparticles (TiO(2) NPs) damages the central nervous system of mice; however, very little is known about the effects of TiO(2) 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 TiO(2) NPs for consecutive 60 days. Our findings indicate that TiO(2) 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, TiO(2) NPs significantly activated caspase-3 and -9, inhibited Bcl-2, and promoted the levels of Bax and cytochrome c. Furthermore, TiO(2) NPs induced accumulation of reactive oxygen species in the mouse hippocampus. These findings suggest that TiO(2) NP-induced apoptosis in the mouse hippocampus may result from an intrinsic pathway, and workers and consumers should take great caution when handling nanomaterials.

Contributions of altered permeability of intestinal barrier and defecation behavior to toxicity formation from graphene oxide in nematode Caenorhabditis elegans

Graphene oxide (GO) has been extensively studied for potential biomedical applications. Meanwhile, potential GO toxicity arises in both biomedical applications and non-biomedical products where environmental exposures may occur. In the present study, we examined the potential adverse effects of GO and the underlying mechanism using nematode Caenorhabditis elegans as the assay system. We compared the in vivo effects of GO between acute exposure and prolonged exposure, and found that prolonged exposure to 0.5-100 mg L(-1) of GO caused damage on functions of both primary (intestine) and secondary (neuron and reproductive organ) targeted organs. In the intestine, ROS production was significantly correlated with the formation of adverse effects on functions of both primary and secondary targeted organs. GO could be translocated into intestinal cells with loss of microvilli, and distributed to be adjacent to or surrounding mitochondria. Prolonged exposure to GO resulted in a hyper-permeable state of the intestinal barrier, an increase in mean defecation cycle length, and alteration of genes required for intestinal development and defecation behavior. Thus, our data suggest that prolonged exposure to GO may cause potential risk to environmental organisms after release into the environment. GO toxicity may be due to the combinational effects of oxidative stress in the intestinal barrier, enhanced permeability of the biological barrier, and suppressed defecation behavior in C. elegans.

Molecular mechanism of kidney injury of mice caused by exposure to titanium dioxide nanoparticles

Numerous studies have demonstrated that damage of kidney of mice can be caused by exposure to titanium dioxide nanoparticles (TiO(2) NPs). However, the molecular mechanism of TiO(2) NPs-induced nephric injury remains unclear. In this study, the mechanism of nephric injury in mice induced by an intragastric administration of TiO(2) NPs was investigated. The results showed that TiO(2) NPs were accumulated in the kidney, resulting in nephric inflammation, cell necrosis and dysfunction. Nucleic factor-κB was activated by TiO(2) 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 TiO(2) NPs-induced nephric injury of mice might be associated with alteration of inflammatory cytokine expression and reduction of detoxification of TiO(2) NPs.

Chronic Al2O3-nanoparticle exposure causes neurotoxic effects on locomotion behaviors by inducing severe ROS production and disruption of ROS defense mechanisms in nematode Caenorhabditis elegans.

To date, knowledge on mechanisms regarding the chronic nanotoxicity is still largely minimal. In the present study, the effect of chronic (10-day) Al(2)O(3)-nanoparticles (NPs) toxicity on locomotion behavior was investigated in the nematode Caenorhabditis elegans. Exposure to 0.01-23.1 mg/L of Al(2)O(3)-NPs induced a decrease in locomotion behavior, a severe stress response, and a severe oxidative stress; however, these effects were only detected in nematodes exposed to 23.1 mg/L of bulk Al(2)O(3). Formation of significant oxidative stress in nematodes exposed to Al(2)O(3)-NPs was due to both the increase in ROS production and the suppression of ROS defense mechanisms. More pronounced increases in ROS, decreases in SOD activity, and decrease in expression of genes encoding Mn-SODs (sod-2 and sod-3) were detected in nematodes exposed to Al(2)O(3)-NPs compared with bulk Al(2)O(3). Moreover, treatment with antioxidants or SOD-3 overexpression not only suppressed oxidative stress but also prevented adverse effects on locomotion behaviors from Al(2)O(3)-NPs exposure. Thus, chronic exposure to Al(2)O(3)-NPs may have adverse effects on locomotion behaviors by both induction of ROS production and disruption of ROS defense mechanisms. Furthermore, sod-2 and sod-3 mutants were more susceptible than the wild-type to chronic Al(2)O(3)-NPs-induced neurotoxicity inhibition.

Comparison of toxicities from three metal oxide nanoparticles at environmental relevant concentrations in nematode Caenorhabditis elegans

Nematode Caenorhabditis elegans has been developed in a variety of environmental studies to address adverse effects of a wide range of toxicants. In the present study, we compared the toxicities of three metal oxide nanoparticles (NPs) including TiO(2)-NPs, ZnO-NPs, and SiO(2)-NPs with the same nanosize (30 nm) after prolonged exposure from L1-larvae to adult at environmental relevant concentrations. Our data indicated that the adverse effects were detected in nematodes exposed to TiO(2)-NPs and ZnO-NPs at concentrations more than 0.05 μg/L and SiO(2)-NPs at concentrations more than 5 μg/L with locomotion behavior and ROS production as endpoints. With growth, locomotion behavior, reproduction, and ROS production as endpoints, toxicity order for the examined metal oxide NPs was: ZnO-NPs>TiO(2)-NPs>SiO(2)-NPs. In nematodes exposed to the examined metal oxide NPs, ROS production was significantly correlated with lethality, growth, reproduction, and locomotion behavior. Moreover, treatment with antioxidants of ascorbate or NAC effectively inhibited the formation of oxidative stress and retrieved the adverse effects of TiO(2)-NPs, ZnO-NPs, and SiO(2)-NPs on survival, growth, reproduction and locomotion behaviors in nematodes. Our data demonstrated the subtle toxicity differences of different NPs exposure at environmental relevant concentrations in C. elegans.

Ovarian dysfunction and gene-expressed characteristics of female mice caused by long-term exposure to titanium dioxide nanoparticles.

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.

Acute toxic effects and gender-related biokinetics of silver nanoparticles following an intravenous injection in mice.

This study evaluated the acute toxicity and biokinetics of intravenously administered silver nanoparticles (AgNPs) in mice. Mice were exposed to different dosages of AgNPs (7.5, 30 or 120 mg kg−1). Toxic effects were assessed via general behavior, serum biochemical parameters and histopathological observation of the mice. Biokinetics and tissue distribution of AgNPs were evaluated at a dose of 120 mg kg−1 in both male and female mice. Inductively coupled plasma–mass spectrometry (ICP‐MS) was used to determine silver concentrations in blood and tissue samples collected at predetermined time intervals. After 2 weeks, AgNPs exerted no obvious acute toxicity in the mice. However, inflammatory reactions in lung and liver cells were induced in mice treated at the 120 mg kg−1 dose level. The highest silver levels were observed in the spleen, followed by liver, lungs and kidneys. The elimination half‐lives and clearance of AgNPs were 15.6 h and 1.0 ml h−1 g−1 for male mice and 29.9 h and 0.8 ml h−1 g−1 for female mice. These results indicated that AgNPs could be distributed extensively to various tissues in the body, but primarily in the spleen and liver. Furthermore, there appears to be gender‐related differences in the biokinetic profiles in blood and distribution in lungs and kidneys following an intravenous injection of AgNPs. The data from this study provides information on toxicity and biodistribution of AgNPs following intravenous administration in mice, which represents the worst case scenario of toxicity among all the different administration routes, and may shed light in the future use of products containing AgNPs in humans. Copyright

Carboxylic acid functionalization prevents the translocation of multi-walled carbon nanotubes at predicted environmentally relevant concentrations into targeted organs of nematode Caenorhabditis elegans

Carboxyl (-COOH) surface modified multi-walled carbon nanotubes (MWCNTs-COOH) can be used for targeted delivery of drugs and imaging. However, whether MWCNTs-COOH at environmentally relevant concentrations exert certain toxic effects on multicellular organisms and the underlying mechanisms are still largely unclear. In the present study, we applied the nematode Caenorhabditis elegans to evaluate the properties of MWCNTs-COOH at environmentally relevant concentrations by comparing the effects of MWCNTs and MWCNTs-COOH exposure on C. elegans from L1-larvae to adult at concentrations of 0.001-1000 μg L(-1). Exposure to MWCNTs could potentially damage the intestine (primary targeted organ) at concentrations greater than 0.1 μg L(-1) and functions of neurons and reproductive organ (secondary targeted organs) at concentrations greater than 0.001 μg L(-1). Carboxyl modification prevented the toxicity of MWCNTs on the primary and the secondary targeted organs at concentrations less than 100 μg L(-1), suggesting that carboxyl modification can effectively prevent the adverse effects of MWCNTs at environmentally relevant concentrations. After exposure, MWCNTs-COOH (1 mg L(-1)) were translocated into the spermatheca and embryos in the body through the primary targeted organs. However, MWCNTs-COOH (10 μg L(-1)) were not observed in spermatheca and embryos in the body of nematodes. Moreover, relatively high concentrations of MWCNTs-COOH exposed nematodes might have a hyper-permeable intestinal barrier, whereas MWCNTs-COOH at environmentally relevant concentrations effectively sustained the normally permeable state for the intestinal barrier. Therefore, we elucidated the cellular basis of carboxyl modification to prevent toxicity of MWCNTs at environmentally relevant concentrations. Our data highlights the key role of biological barriers in the primary targeted organs to block toxicity formation from MWCNTs, which will be useful for the design of effective prevention strategies against MWCNTs toxicity.

Gene Expression in Liver Injury Caused by Long-term Exposure to Titanium Dioxide Nanoparticles in Mice

Although liver toxicity induced by titanium dioxide nanoparticles (TiO(2) NPs) has been demonstrated, very little is known about the molecular mechanisms of multiple genes working together underlying this type of liver injury in mice. In this study, we used the whole-genome microarray analysis technique to determine the gene expression profile in the livers of mice exposed to 10 mg/kg body weight TiO(2) NPs for 90 days. The findings showed that long-term exposure to TiO(2) NPs resulted in obvious titanium accumulation in the liver and TiO(2) NP aggregation in hepatocyte nuclei, an inflammatory response, hepatocyte apoptosis, and liver dysfunction. Furthermore, microarray data showed striking changes in the expression of 785 genes related to the immune/inflammatory response, apoptosis, oxidative stress, the metabolic process, response to stress, cell cycle, ion transport, signal transduction, cell proliferation, cytoskeleton, and cell differentiation in TiO(2) NP-exposed livers. In particular, a significant reduction in complement factor D (Cfd) expression following long-term exposure to TiO(2) NPs resulted in autoimmune and inflammatory disease states in mice. Therefore, Cfd may be a potential biomarker of liver toxicity caused by TiO(2) NPs exposure.

Oxidative damage of lung and its protective mechanism in mice caused by long-term exposure to titanium dioxide nanoparticles.

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.