Low-dose cadmium telluride quantum dots trigger M1 polarization in macrophages through mTOR-mediated transcription factor EB activation.

The increasing application of quantum dots (QDs) increases interactions with organisms. The inflammatory imbalance is a significant manifestation of immunotoxicity. Macrophages maintain inflammatory homeostasis. Using macrophages differentiated by phorbol 12-myristate 13-acetate-induced THP-1 cells as models, the study found that low-dose (5 µM) cadmium telluride QDs (CdTe-QDs) hindered monocyte-macrophage differentiation. CD11b is a surface marker of macrophage, and the addition of CdTe-QDs during induction resulted in a decrease in CD11b expression. Moreover, exposure of differentiated THP-1 macrophage (dTHP-1) to 5 µM CdTe-QDs led to the initiation of M1 polarization. This was indicated by the increased surface marker CD86 expression, along with elevated level of NF-κB and IL-1ß proteins. The potential mechanisms are being explored. The transcription factor EB (TFEB) plays a significant role in immune regulation and serves as a crucial regulator of the autophagic lysosomal pathway. After exposed to CdTe-QDs, TFEB activation-mediated autophagy and M1 polarization were observed to occur simultaneously in dTHP-1. The mTOR signaling pathway contributed to TFEB activation induced by CdTe-QDs. However, mTOR-independent activation of TFEB failed to promote M1 polarization. These results suggest that mTOR-TFEB is an advantageous target to enhance the biocompatibility of CdTe-QDs.

Influence of silver doping on pro-inflammatory and pro-fibrogenic effects of nano-titanium dioxide in murine lung.

Silver is usually loaded on nano-titanium dioxide (TiO2 ) through photodeposition method to enhance visible-light catalytic functions for environment purification. However, little is known about how the toxicity changes after silver doping and how the physicochemical properties of loaded components affect nanocomposite toxicity. In this study, Ag-TiO2 with different sizes and contents of silver particles were obtained by controlling photodeposition time (PDT) and silver addition amount. Pro-inflammatory and pro-fibrogenic responses of these photocatalysts were evaluated in male C57BL/6J murine lung. As a result, silver was well assembled on TiO2 , promoting visible-light catalytic activity. Notably, the size of silver particles increased with PDT. Meanwhile, toxicity results showed that pure TiO2 (P25) mainly caused neutrophil infiltration, while 2 wt/wt% silver-loaded TiO2 recruited more types of inflammatory cells in the lung. Both of them caused the increase of proinflammatory cytokines while decreasing the anti-inflammatory cytokine in bronchoalveolar lavage fluid. However, 2 wt/wt% silver doping also accelerated the lung pro-fibrogenic response of photocatalysts in the subacute phase from evidence of collagen deposition and hydroxyproline concentrations. Mechanistically, the overactivation of TGFBR2 receptors in TGF-ß/smads pathways by silver-loaded TiO2 rather than pure TiO2 may be the reason why silver-loaded TiO2 can promote pro-fibrogenic effect response. Intriguingly, the increased toxicity caused by silver doping can be rescued by increasing the size of the loaded silver or decreasing the silver amount. These results may be important for the new understanding of the toxicity of TiO2 -based photocatalysts.

Toxicity mechanism of engineered nanomaterials: Focus on mitochondria.

With the rapid development of nanotechnology, engineered nanomaterials (ENMs) are widely used in various fields. This has exacerbated the environmental pollution and human exposure of ENMs. The study of toxicity of ENMs and its mechanism has become a hot research topic in recent years. Mitochondrial damage plays an important role in the toxicity of ENMs. This paper reviews the structural damage, dysfunction, and molecular level perturbations caused by different ENMs to mitochondria, including ZnO NPs, Ag NPs, TiO2 NPs, iron oxide NPs, cadmium-based quantum dots, CuO NPs, silica NPs, carbon-based nanomaterials. Among them, mitochondrial quality control plays an important role in mitochondrial damage. We further summarize the cellular level outcomes caused by mitochondrial damage, mainly including, apoptosis, ferroptosis, pyroptosis and inflammation response. In addition, we concluded that reducing mitochondrial damage at source as well as accelerating recovery from mitochondrial damage through ENMs modification and pharmacological intervention are two feasible strategies. This review further provides new insights into the mitochondrial toxicity mechanisms of ENMs and provides a new foothold for predicting human health and environmental risks of ENMs.

Ag/TiO2 nanohybrids induce fibrosis-related epithelial-mesenchymal transition in lung epithelial cells and the influences of silver content and silver particle size.

The controlled synthesis of silver nanoparticles (AgNPs) decorated TiO2 nanohybrids (Ag/TiO2) for photocatalysis has received considerable attention. These photocatalysts are widely used in environment and energy, resulting in human exposure through inhalation. Pure TiO2 is generally considered a low-toxic nanomaterial. However, little is known about the toxicity after AgNPs loading. In this study, silver-decorated TiO2 nanohybrids were controllably synthesized by the photodeposition method, and their toxic effects on murine lung and human lung epithelial cells were explored. As a result, silver loading significantly enhanced the effect of TiO2 photocatalyst on EMT in lung epithelial cells, potentially acting as a pro-fibrogenic effect in murine lung. Meanwhile, the increase in autophagy vacuoles, LC3-II marker, stub-RFP-sens-GFP-LC3 fluorescence assay, and LC3 turnover assay showed that silver loading also significantly increased autophagy flux. Furthermore, analysis of autophagy inhibition by 3-Methyladenine indicated that the promotion of EMT by silver loading was related to the increased autophagy flux. Intriguingly, the autophagy and EMT biological effects could be alleviated when the silver loading amount was reduced or silver particle size was increased, and the enhanced pro-fibrogenic effect was mitigated at the same time. This study supplemented safety information of Ag-decorated TiO2 nanohybrids and provided methods of controlled synthesis for reducing toxicity.

The DNA damage potential of quantum dots: Toxicity, mechanism and challenge.

Quantum dots (QDs) are semiconductor nanoparticles (1-10 nm) with excellent optical and electrical properties. As QDs show great promise for applications in fields such as biomedicine, their biosafety is widely emphasized. Therefore, studies on the potential 'nanotoxicity' of QDs in genetic material are warranted. This review summarizes and discusses recent reports derived from different cell lines or animal models concerning the effects of QDs on genetic material. QDs could induce many types of genetic material damage, which subsequently triggers a series of cellular adverse outcomes, including apoptosis, cell cycle arrest and senescence. However, the individual biological and ecological significance of the genotoxicity of QDs is not yet clear. In terms of mechanisms of genotoxicity, QDs can damage DNA either through their own nanomorphology or through the released metal ions. It also includes the reactive oxygen species generation, inflammation and failure of DNA damage repair. Notably, apoptosis may lead to false positive results in genotoxicity tests. Finally, given the different uses of QDs and the interference of the physicochemical properties of QDs on the test method, genotoxicity testing of QDs should be different from traditional toxic compounds, which requires further research.

CdTe quantum dots trigger oxidative stress and endoplasmic reticulum stress-induced apoptosis and autophagy in rat Schwann cell line RSC96.

In the current study, the cytotoxicity and mechanisms of cadmium telluride quantum dots (CdTe QDs) on RSC96 cells were evaluated by exposing different doses of CdTe QDs for 24 h. Two types of cell death, including apoptosis and autophagy, as well as two important organelles, mitochondria and endoplasmic reticulum, were focused after CdTe QDs exposure. The results showed that CdTe QDs induced apoptosis in RSC96 cells in a concentration-dependent manner; promoted the accumulation of intracellular reactive oxygen species; decreased the mitochondrial membrane potential; caused the release of cytochrome c; and also increased the expression of Bcl-2 associated X protein, caspase-3, and cytochrome c proteins and decreased the expression of Bcl-2 protein. Further results also confirmed that CdTe QDs could be internalized by RSC96 cells, and the exposure and internalization of CdTe QDs could induce excessive endoplasmic reticulum stress in the cells, and the expression levels of binding immunoglobulin protein, C/EBP homologous protein, and caspase12 proteins were increased in a concentration-dependent manner. Moreover, autophagy-related proteins LC3II, Beclin1, and P62 all increased after CdTe QDs exposure, suggesting that CdTe QDs exposure both promoted autophagosome formation and inhibited autophagosome degradation, and that CdTe QDs affected the autophagic flow in RSC96 cells. In conclusion, CdTe QDs are able to cause apoptosis and autophagy in RSC96 cells through mitochondrial and endoplasmic reticulum stress pathways, and the possible neurotoxicity of CdTe QDs should be further investigated.

Adverse reproductive and developmental consequences of quantum dots.

Quantum dots (QDs), with a size of 1-10 nm, are luminescent semiconductor nanocrystals characterized by a shell-core structure. Notably, QDs have potential application in bioimaging owing to their higher fluorescence performance than conventional fluorescent dyes. To date, QDs has been widely used in photovoltaic devices, supercapacitors, electrocatalysis, photocatalysis. In recent years, scientists have focused on whether the use of QDs can interfere with the reproductive and developmental processes of organisms, resulting in serious population and community problems. In this study, we first analyze the possible reproductive and development toxicity of QDs. Next, we summarize the possible mechanisms underlying QDs' interference with reproduction and development, including oxidative stress, altered gametogenesis and fetal development gene expression, autophagy and apoptosis, and release of metal ions. Thereafter, we highlight some potential aspects that can be used to eliminate or reduce QDs toxicity. Based on QDs' unique physical and chemical properties, a comprehensive range of toxicity test data is urgently needed to build structure-activity relationship to quickly evaluate the ecological safety of each kind of QDs.

A critical review of advances in reproductive toxicity of common nanomaterials to Caenorhabditis elegans and influencing factors.

In recent decades, nanotechnology has rapidly developed. Therefore, there is growing concern about the potential environmental risks of nanoparticles (NPs). Caenorhabditis elegans (C. elegans) has been used as a powerful tool for studying the potential ecotoxicological impacts of nanomaterials from the whole animal level to single cell level, especially in the area of reproduction. In this review, we discuss the reproductive toxicity of common nanomaterials in C. elegans, such as metal-based nanomaterial (silver nanoparticles (NPs), gold NPs, zinc oxide NPs, copper oxide NPs), carbon-based nanomaterial (graphene oxide, multi-walled carbon nanotubes, fullerene nanoparticles), polymeric NPs, silica NPs, quantum dots, and the potential mechanisms involved. This insights into the toxic effects of existing nanomaterials on the human reproductive system. In addition, we summarize how the physicochemical properties (e.g., size, charge, surface modification, shape) of nanomaterials influence their reproductive toxicity. Overall, using C. elegans as a platform to develop rapid detection techniques and prediction methods for nanomaterial reproductive toxicity is expected to reduce the gap between biosafety evaluation of nanomaterials and their application.

Advances in endocrine toxicity of nanomaterials and mechanism in hormone secretion disorders.

The size of nanoparticles is about 1-100 nm. People are exposed to nanoparticles in environmental pollutants from ancient times to the present. With the maturity of nanotechnology in the past two decades, the production of manufactured nanomaterials is rapidly increasing and they are used in a wide range of aerospace, medicine, food, and industrial applications. However, both natural and manufactured nanomaterials have been proved to pose a threat to diverse organs and systems. The endocrine system is critical to maintaining homeostasis. Endocrine disorders are associated with many diseases, including cancer, reduced fertility, and metabolic diseases. Therefore, we review the literatures dealing with the endocrine toxicity of nanomaterial. This review provides an exhaustive description of toxic effects of several common nanomaterials in the endocrine system; more involved are reproductive endocrinology. Then physicochemical factors that determine the endocrine toxicity of nanomaterials are discussed. Furthermore, oxidative stress, changes in steroid production and metabolic enzymes, organelle disruption, and alterations in signal pathways are introduced as potential mechanisms that may cause changes in hormone levels. Finally, we suggest that a risk assessment of endocrine toxicity based on standard procedures and consideration of endocrine disrupting effects of nanomaterials in the field and its environmental and population effects could be future research directions for endocrine toxicity of nanomaterials.

Ambient particulate matter triggers defective autophagy and hijacks endothelial cell renewal through oxidative stress-independent lysosomal impairment.

Ambient particulate matter (APM) has been authenticated to exert hazards on human vascular endothelial cells, including abnormal autophagy. However, the potential reasons for autophagosome accumulation are still obscure. Since autophagy is a dynamic process, it is imperative to systemically consider the autophagic induction combined with its degradation to reflect realistic scenarios. Therefore, in the current study, different exposure durations were initially employed for the detection of autophagic marker proteins to assess the dynamic autophagic state preliminarily. Additionally, LC3 turn-over and autophagic flux assays were used to determine the specific cause of LC3II upregulation in EA.hy926 human vascular endothelial cells by a type of standard urban particulate matter, PM SRM1648a. As a result, PM SRM1648a stimulates excess autophagic vacuoles in EA. hy926 cells, in which the underlying causes are probably different at varying incubation endpoints. Intriguingly, LC3II upregulation was due to the intensifying autophagic initiation after 6 h of exposure, whereas as exposure period was extended to 24 h, overloaded autophagic vacuoles were attributed to the defective autophagy. Mechanistically, PM SRM1648a damages EA. hy926 cells by inducing lysosomal disequilibrium and resultant autophagic malfunction which are not directly mediated by oxidative stress. These data indicate that appropriate maintenance of lysosomal function and autophagic flux is probably a protective measure against APM-induced endothelial cell damage.

The involvement of DRP1-mediated caspase-1 activation in inflammatory response by urban particulate matter in EA.hy926 human vascular endothelial cells.

Atmospheric particulate matter (PM) has been reported to be closely related to cardiovascular adverse events. However, the underlying mode of action remains to be elucidated. Previous studies have documented that PM induces mitochondrial damage and inflammation, the relation between these two biological outcomes is still unclear though. In this study, we used EA.hy926 human vascular endothelial cells and a standard PM, PM SRM1648a to study the potential effects of mitochondrial dysfunction on endothelial inflammatory responses. As a result, PM SRM1648a changes mitochondrial morphology and interrupts mitochondrial dynamics with a persistent tendency of fission in a dose-dependent manner. Additionally, the caspase-1/IL-1ß axis is involved in inflammatory responses but not cell pyroptosis in EA.hy926 cells following the exposure to PM SRM1648a. The activation of caspase-1 has implications in inflammation but not pyroptosis, because caspase-1-dependent pyroptosis is not the main modality of cell death in PM SRM1648a-treated EA.hy926 cells. With regard to the association between mitochondrial damage and inflammation in the case of particle stimulation, DRP1-mediated mitochondrial fission is responsible for inflammatory responses as a result of caspase-1 activation. The current study showed that PM SRM1648a has the ability to disturb mitochondrial dynamics, and trigger endothelial inflammation via DRP1/caspase-1/IL-1ß regulatory pathway. In a conclusion, mitochondrial fission enables EA.hy926 cells to facilitate caspase-1 activation in response to PM SRM1648a, which is a crucial step for inflammatory reaction in vascular endothelial cells.