Qiuli Wu

Translocation, transfer, and in vivo safety evaluation of engineered nanomaterials in the non-mammalian alternative toxicity assay model of nematode Caenorhabditis elegans

Translocation, transfer, and safety evaluation of engineered nanomaterials in non-mammalian alternative assay model of Caenorhabditis elegans are summarized and discussed. Due to the extensive applications of engineered nanomaterials (ENMs) in industry, agriculture, medicine and public health, environmental exposure of ENMs to human and environmental organisms is inevitable, therefore studies on translocation, transfer, and toxicology of ENMs receive wide interest. Modelling the nematode C. elegans, a widely recognized non-mammalian alternative toxicity assay system has been proven to be valuable in environmental safety evaluation, toxicological study, and examination of translocation and transfer of toxicants. In this review, we summarize and discuss the values and contributions of C. elegans in studies on environmental safety evaluation, toxicology, and translocation and transfer of ENMs. We introduced acute and chronic toxicity assay systems and discussed environmental safety assessment of specific ENMs at predicted environmental relevant concentrations, and influences of chemical properties of ENMs, exposure routes, developmental, genetic or physiological state, and environmental factors on nanotoxicity formation in nematodes. We then discussed the toxicological mechanisms of ENMs mainly with respect to roles of oxidative stress in normal and stress conditions and signaling pathways, reproductive toxicology, neurotoxicology, and translocation, distribution, transfer and metabolism of ENMs in C. elegans. Ways to eliminate or reduce the toxicities of specific ENMs by chemical modification with surface designs were further discussed. Finally, four important challenges have been raised and discussed by surrounding the aspects of environmental safety assessment, toxicological mechanisms, and designs of new safe ENMs.

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.

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.

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.

Evaluation of Environmental Safety Concentrations of DMSA Coated Fe2O3-NPs Using Different Assay Systems in Nematode Caenorhabditis elegans

Dimercaptosuccinic acid (DMSA) coating improves the uptake efficiency presumably by engendering the Fe2O3-NPs. In the present study, we investigated the possible environmental safety concentrations of Fe2O3-NPs using different assay systems in nematode Caenorhabditis elegans with lethality, development, reproduction, locomotion behavior, pharyngeal pumping, defecation, intestinal autofluorescence and reactive oxygen species (ROS) production as the endpoints. After exposure from L4-larvae for 24-hr, DMSA coated Fe2O3-NPs at concentrations more than 50 mg/L exhibited adverse effects on nematodes. After exposure from L1-larvae to adult, DMSA coated Fe2O3-NPs at concentrations more than 500 μg/L had adverse effects on nematodes. After exposure from L1-larvae to day-8 adult, DMSA coated Fe2O3-NPs at concentrations more than 100 μg/L resulted in the adverse effects on nematodes. Accompanied with the alterations of locomotion behaviors, ROS production was pronouncedly induced by exposure to DMSA coated Fe2O3-NPs in the examined three assay systems, and the close associations of ROS production with lethality, growth, reproduction, locomotion behavior, pharyngeal pumping, defecation, or intestinal autofluorescence in nematodes exposed to DMSA coated Fe2O3-NPs were confirmed by the linear regression analysis. Moreover, mutations of sod-2 and sod-3 genes, encoding Mn-SODs, showed more susceptible properties than wild-type when they were used for assessing the DMSA coated Fe2O3-NPs-induced toxicity, and the safety concentrations for DMSA coated Fe2O3-NPs should be defined as concentrations lower than 10 μg/L in sod-2 and sod-3 mutant nematodes.

Molecular Control of TiO2-NPs Toxicity Formation at Predicted Environmental Relevant Concentrations by Mn-SODs Proteins

With growing concerns of the safety of nanotechnology, the in vivo toxicity of nanoparticles (NPs) at environmental relevant concentrations has drawn increasing attentions. We investigated the possible molecular mechanisms of titanium nanoparticles (Ti-NPs) in the induction of toxicity at predicted environmental relevant concentrations. In nematodes, small sizes (4 nm and 10 nm) of TiO2-NPs induced more severe toxicities than large sizes (60 nm and 90 nm) of TiO2-NPs on animals using lethality, growth, reproduction, locomotion behavior, intestinal autofluorescence, and reactive oxygen species (ROS) production as endpoints. Locomotion behaviors could be significantly decreased by exposure to 4-nm and 10-nm TiO2-NPs at concentration of 1 ng/L in nematodes. Among genes required for the control of oxidative stress, only the expression patterns of sod-2 and sod-3 genes encoding Mn-SODs in animals exposed to small sizes of TiO2-NPs were significantly different from those in animals exposed to large sizes of TiO2-NPs. sod-2 and sod-3 gene expressions were closely correlated with lethality, growth, reproduction, locomotion behavior, intestinal autofluorescence, and ROS production in TiO2-NPs-exposed animals. Ectopically expression of human and nematode Mn-SODs genes effectively prevented the induction of ROS production and the development of toxicity of TiO2-NPs. Therefore, the altered expression patterns of Mn-SODs may explain the toxicity formation for different sizes of TiO2-NPs at predicted environmental relevant concentrations. In addition, we demonstrated here a strategy to investigate the toxicological effects of exposure to NPs upon humans by generating transgenic strains in nematodes for specific human genes.

The in vivo underlying mechanism for recovery response formation in nano-titanium dioxide exposed Caenorhabditis elegans after transfer to the normal condition

UNLABELLED So far, we still know little about mechanism for recovery response of engineered nanomaterials (ENMs). Here we used Caenorhabditis elegans to investigate recovery responses of titanium dioxide nanoparticles (TiO2-NPs) exposed animals and the underlying mechanism. After acute exposure to TiO2-NPs (100mg/L), endpoints including defecation and permeable state of intestinal barrier of exposed nematodes returned to control levels; however, after prolonged exposure to TiO2-NPs (100μg/L), endpoints of exposed nematodes could not be recovered to control levels under the normal condition. After prolonged exposure to TiO2-NPs, nematodes exhibited severe deficits in development of intestinal barrier and AVL and DVB neurons controlling defecation; however, after acute exposure to TiO2-NPs, nematodes had normal developmental state of intestinal barrier and AVL and DVB neurons. Our results imply that developmental states of intestinal barrier and AVL and DVB neurons may serve as a pivotal determinant for recovery response in TiO2-NPs exposed nematodes. FROM THE CLINICAL EDITOR This basic science study investigates the recovery response to TiO2 nanoparticles in a nematode model, and concludes that developmental states of the intestinal barrier and AVL and DVB neurons likely serve as determinants for recovery following TiO2-NP exposure.

Transmissions of serotonin, dopamine, and glutamate are required for the formation of neurotoxicity from Al2O3-NPs in nematode Caenorhabditis elegans

Abstract In this study, we investigated genetic mechanisms of neurotransmitters in regulating the formation of adverse effects on locomotion behavior in Al2O3 nanoparticles (NPs)-exposed Caenorhabditis elegans. Al2O3-NPs exposure caused the decrease of locomotion behavior with head thrash and body bend as endpoints. Interestingly, the neurotransmitters of glutamate, serotonin, and dopamine were required for the adverse effects of Al2O3-NPs on locomotion behavior in nematodes. Glutamate transporter EAT-4, serotonin transporter MOD-5, and dopamine transporter DAT-1 might serve as the molecular targets of Al2O3-NPs for neurotoxicity formation. Moreover, the behavioral response of nematodes to Al2O3-NPs exposure was primarily mediated by non-NMDA glutamate receptors GLR-2 and GLR-6, ionotropic serotonin receptor MOD-1, and D1-like dopamine receptor DOP-1. Therefore, Al2O3-NPs exposure influences locomotion behavior of nematodes primarily by impinging on their glutamatergic, serotoninergic, and dopaminergic systems. Our data will shed light on questions surrounding the involvement of neurotransmitters in mediating the adverse behavioral effects from Al2O3-NPs.

Biosafety assessment of titanium dioxide nanoparticles in acutely exposed nematode Caenorhabditis elegans with mutations of genes required for oxidative stress or stress response

We used Caenorhabditis elegans to investigate whether acute exposure to TiO2-NPs at the concentration of 20 μg L(-1) reflecting predicted environmental relevant concentration and 25 mg L(-1) reflecting concentration in food can cause toxicity on nematodes with mutations of susceptible genes. Among examined mutants associated with oxidative stress and stress response, we found that genes of sod-2, sod-3, mtl-2, and hsp-16.48 might be susceptible for TiO2-NPs toxicity. Mutations of these genes altered functions of both possible primary and secondary targeted organs in nematodes exposed to 25 mg L(-1) of TiO2-NPs for 24-h. Mutations of these genes caused similar expression patterns of genes required for oxidative stress in TiO2-NPs exposed mutant nematodes, implying their similar mechanisms to form the susceptible property. Nevertheless, acute exposure to 20 μg L(-1) of TiO2-NPs for 24-h and 25 mg L(-1) of TiO2-NPs for 0.48-h or 5.71-h did not influence functions of both possible primary and secondary targeted organs in sod-2, sod-3, mtl-2, and hsp-16.48 mutants. Therefore, our results suggest the relatively safe property of acute exposure to TiO2-NPs with certain durations at predicted environmental relevant concentrations or concentrations comparable to those in food in nematodes with mutations of some susceptible genes.

Small sizes of TiO2-NPs exhibit adverse effects at predicted environmental relevant concentrations on nematodes in a modified chronic toxicity assay system.

In Caenorhabditis elegans, although acute toxicity of TiO(2) nanoparticles (TiO(2)-NPs) at high concentrations has been investigated, we still know little about chronic toxicity of TiO(2)-NPs. Our data here showed that acute TiO(2)-NPs exposure in the range of μg/L had no obviously adverse effects on nematodes, but the chronic toxicities of large sizes (60 nm and 90 nm) of TiO(2)-NPs in the range of μg/L were detected in nematodes in a modified chronic toxicity assay system. Moreover, chronic toxicities of small sizes (4 nm and 10nm) of TiO(2)-NPs in the range of ng/L were observed in nematodes with locomotion behavior and ROS production as endpoints. In nematodes chronically exposed to small sizes of TiO(2)-NPs at predicted environmental relevant concentrations, locomotion behavior was significantly (P<0.01) correlated with ROS production. Furthermore, treatment with antioxidants (ascorbate and N-acetyl-l-cysteine) inhibited both the induction of ROS production and the decrease of locomotion behaviors observed in nematodes chronically exposed to small sizes of TiO(2)-NPs at predicted environmental relevant concentrations. Therefore, chronic exposure to small sizes of TiO(2)-NPs at predicted environmental relevant concentrations can cause adverse effects on nematodes, and formation of such adverse effects may be largely due to the induction of oxidative stress.