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Bioimaging revealed contrasting organelle-specific transport of copper and zinc and implication for toxicity
2022
Yuan, Liuliang | Wang, Wen-Xiong
Zn and Cu are two of the essential trace elements and it is important to understand the regulation of their distribution on cellular functions. Herein, we for the first time investigated the subcellular fate and behavior of Zn and Cu in zebrafish cells through bioimaging, and demonstrated the completely different behaviors of Zn and Cu. The distribution of Zn²⁺ was concentration-dependent, and Zn²⁺ at low concentration was predominantly located in the lysosomes (76.5%). A further increase of cellular Zn²⁺ resulted in a spillover and more diffusive distribution, with partitioning to mitochondria and other regions. In contrast, the subcellular distribution of Cu⁺ was time-dependent. Upon entering the cells, Cu²⁺ was reduced to Cu⁺, which was first concentrated in the mitochondria (71.4%) followed by transportation to lysosomes (58.6%), and finally removal from the cell. With such differential transportation, Cu²⁺ instead of Zn²⁺ had a negative effect on the mitochondrial membrane potential and glutathione. Correspondingly, the pH of lysosomes was more sensitive to Zn²⁺ exposure and decreased with increasing internalized Zn²⁺, whereas it increased upon Cu²⁺ exposure. The responses of cellular pH showed an opposite pattern from the lysosomal pH. Lysosome was the most critical organelle in response to incoming Zn²⁺ by increasing its number and size, whereas Cu²⁺ reduced the lysosome size. Our study showed that Zn²⁺ and Cu²⁺ had completely different cellular handlings and fates with important implications for understanding of their toxicity.
اظهر المزيد [+] اقل [-]Revealing consensus gene pathways associated with respiratory functions and disrupted by PM2.5 nitrate exposure at bulk tissue and single cell resolution
2021
Zhang, Jushan | Cheng, Haoxiang | Wang, Dongbin | Zhu, Yujie | Yang, Chun | Shen, Yuan | Yu, Jing | Li, Yuanyuan | Xu, Shunqing | Song, Xiaolian | Zhou, Yang | Chen, Jia | Fan, Lihong | Jiang, Jingkun | Wang, Changhui | Hao, Ke
Nitrate is a major pollutant component in ambient PM₂.₅. It is known that chronic exposure to PM₂.₅ NO₃⁻ damages respiratory functions. We aim to explore the underlying toxicological mechanism at single cell resolution.We systematically conducted exposure experiments on forty C57BL/6 mice, assessed respiratory functions, and profiled lung transcriptome. . Afterward, we estimated the cell type compositions from RNA-seq data using deconvolution analysis. The genes and pathways associated with respiratory function and dysregulated by to PM₂.₅ NO₃⁻ exposure were characterized at bulk-tissue and single-cell resolution.PM₂.₅ NO₃⁻ exposure did not significantly modify the cell type composition in lung, but profoundly altered the gene expression within each cell type. At ambient concentration (22 μg/m³), exposure significantly (FDR<10%) altered 95 genes’ expression. Among the genes associated with respiratory functions, a large fraction (74.6–91.7%) were significantly perturbed by PM₂.₅ NO₃⁻ exposure. For example, among the 764 genes associated with peak expiratory flow (PEF), 608 (79.6%) were affected by exposure (p = 1.92e-345). Pathways known to play role in lung disease pathogenesis, including circadian rhythms, sphingolipid metabolism, immune response and lysosome, were found significantly associated with respiratory functions and disrupted by PM₂.₅ NO₃⁻ exposure.This study extended our knowledge of PM₂.₅ NO₃⁻ exposure’s effect to the levels of lung gene expression, pathways, lung cell type composition and cell specific transcriptome. At single cell resolution, we provided insights in toxicological mechanism of PM₂.₅ NO₃⁻ exposure and subsequent pulmonary disease risks.
اظهر المزيد [+] اقل [-]Fluoride induced mitochondrial impairment and PINK1-mediated mitophagy in Leydig cells of mice: In vivo and in vitro studies
2020
Liang, Zhen | Gao, Yan | He, Yuyang | Han, Yongli | Manthari, Ram Kumar | Tikka, Chiranjeevi | Chen, Chenkai | Wang, Jundong | Zhang, Jianhai
It is very important to explore the potential harm and underlying mechanism of fluoride due to the extensive distribution and the significant health risks of fluoride in environment. The objective of this study to investigate whether fluoride can induce mitochondrial impairment and mitophagy in testicular cells. For this, 40 male mice were randomly divided into four groups treated with 0, 0.6, 1.2, 2.4 mM NaF deionized water, respectively, for 90 days continuously. The results showed that mitophagy was triggered by F in testicular tissues, especially in the Leydig cells by transmission electron microscopy and mitophagy receptor PHB2 locations by immunofluorescence. Furthermore, TM3 Leydig cells line was employed and treated with 0, 0.125, 0.25, and 0.5 mM NaF for 24 h. The mitochondrial function indicators and mitophagy maker PHB2, COX IV and regulator PINK1 in transcript and protein levels in Leydig cells were examined by the methods of qRT-PCR, western blotting, and immunofluorescence co-localization. The results showed that fluoride decreased the mitochondrial membrane potential with a concomitant increase in the number of lysosomes. Meanwhile, fluoride exposure also increased the expressions of PINK1 and PHB2 in TM3 Leydig cells. These results revealed that fluoride could induce mitochondrial impairment and excessive PINK1/Parkin-mediated mitophagy in testicular cells, especially in Leydig cells, which could contribute to the elucidation of the mechanisms of F-induced male reproductive toxicity.
اظهر المزيد [+] اقل [-]Modifications of autophagy influenced the Alzheimer-like changes in SH-SY5Y cells promoted by ultrafine black carbon
2019
Shang, Yu | Liu, Mingyuan | Wang, Tiantian | Wang, Lu | He, Huixin | Zhong, Yufang | Qian, Guangren | An, Jing | Zhu, Tong | Qiu, Xinghua | Shang, Jing | Chen, Yingjun
Ambient ultrafine black carbon (uBC) can potentially cross blood-brain barrier, however, very little is currently known about the effects they may have on central nervous system. This study aimed to explore the roles of autophagy in Alzheimer-like pathogenic changes promoted by uBC in SH-SY5Y cells. We firstly found uBC could cause cytotoxicity and oxidative stress in SH-SY5Y cells. Additionally we found uBC initiated progressive development of Alzheimer's disease (AD) associated features, mainly including neuro-inflammation and phosphorylation of tau protein (p-Tau) accumulation. Meanwhile, autophagy process was activated by uBC probably through phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. RNA interference and autophagosome-lysosome fusion inhibitor were applied to block autophagy process at different stages. Autophagy dysfunction at the initial membrane expansion stage could aggravate p-Tau accumulation and other Alzheimer-like changes in SH-SY5Y cells promoted by uBC. However, autophagy inhibition at the final stage could alleviate p-Tau accumulation caused by uBC. This suggested that inhibition of the infusion of autophagosome and lysosome could possibly activate ubiquitination degradation pathway to regulate p-Tau equilibrium in SH-SY5Y cells. Our findings further raise the concerns about the effects of uBC on the risk of AD and indicate potential roles of autophagy in early Alzheimer-like pathogenic changes caused by ambient uBC.
اظهر المزيد [+] اقل [-]Interactions of polymeric drug carriers with DDT reduce their combined cytotoxicity
2018
Zhang, Xuejiao | Lei, Lei | Zhang, Haiyan | Zhang, Siyu | Xing, Weiwei | Wang, Jin | Li, Haibo | Zhao, Qing | Xing, Baoshan
Attention has been paid to the environmental distribution and fate of nanomedicines. However, their effects on the toxicity of environmental pollutants are lack of knowledge. In this study, the negatively charged poly (ethylene glycol)-b-poly (L-lactide-co-glycolide) (mPEG-PLA) and positively charged polyethyleneimine-palmitate (PEI-PA) nanomicelles were synthesized and served as model drug carriers to study the interaction and combined toxicity with dichlorodiphenyltrichloroethane (DDT). DDT exerted limited effect on the biointerfacial behavior of mPEG-PLA nanomicelles, whereas it significantly mitigated the attachment of PEI-PA nanomicelles on the model cell membrane as monitored by quartz crystal microbalance with dissipation (QCM-D). The cytotoxicity of DDT towards NIH 3T3 cells was greatly decreased by either co-treatment or pre-treatment with the nanomicelles according to the results of real-time cell analysis (RTCA). The cell viability of NIH 3T3 exposed to DDT was increased up to 90% by the co-treatment with mPEG-PLA nanomicelles. Three possible reasons were proposed: (1) decreased amount of free DDT in the cell culture medium due to the partitioning of DDT into nanomicelles; (2) mitigated cellular uptake of nanomicelle-DDT complexes due to the complex agglomeration or electrostatic repulsion between complexes and cell membrane; (3) detoxification effect in the lysosome upon endocytosis of nanomicelle-DDT complexes.
اظهر المزيد [+] اقل [-]Adverse effects induced by ecgonine methyl ester to the zebra mussel: A comparison with the benzoylecgonine
2013
Parolini, Marco | Binelli, Andrea
Cocaine and its metabolites are the prevalent psychotropic substances in aquatic environment. However, to date the knowledge on their adverse effects to non-target organisms is inadequate. The aims of this study were to investigate sub-lethal effects induced by the ecgonine methyl ester (EME) to the freshwater bivalve Dreissena polymorpha and to compare its toxicity to that by benzoylecgonine (BE), the other main cocaine metabolite. EME sub-lethal effects were investigated by 14 days in-vivo exposures and a multi-biomarker approach. Slight variations in biomarker responses were found at 0.15 μg/L treatment. 0.5 μg/L EME treatment induced destabilization of lysosome membranes, an overall inactivation of defense enzymes, increases in lipid peroxidation, protein carbonylation and DNA fragmentation, but no variations in fixed genetic damage. The use of a biomarker response index (BRI) showed that at 0.5 μg/L both cocaine metabolites had the same toxicity to zebra mussels specimens.
اظهر المزيد [+] اقل [-]Canidin-3-glucoside prevents nano-plastics induced toxicity via activating autophagy and promoting discharge
2021
Chen, Wen | Chu, Qiang | Ye, Xiang | Sun, Yuhao | Liu, Yangyang | Jia, Ruoyi | Li, Yonglu | Tu, Pengcheng | Pan, Jijiong | Yu, Ting | Chen, Chuan | Zheng, Xiaodong
Increasing attention has been brought to microplastics pollution recently, while emerging evidences indicate that nano-plastics degraded from microplastics are more of research significance owing to stronger toxicity. However, there is little study focused on the prevention of nano-plastics induced toxicity until now. Canidin-3-glucoside (C3G), a natural anthocyanin proved to possess multiple functions like antioxidant and intestinal tissue protection. Thus, we proposed whether C3G could act as a molecular weapon against nano-plastics induced toxicity. In Caco2 cell and Caenorhabditis elegans (C. elegans) models, we found that polystyrene (PS) nano-plastics exposure resulted in physiological toxicity and oxidative damage, which could be restored by C3G. More significantly in Caco2 cells, we observed that autophagy was activated via Sirt1-Foxo1 signaling pathway to attenuate PS induced toxicity after C3G intervention and further verified by adding autophagy inhibitor 3-Methyladenine (3-MA). Meanwhile, PS co-localization with lysosomes was observed, indicating the encapsulation and degradation of PS. In C. elegans, by detecting LGG-1/LC3 expression in GFP-targeted LGG-1 report gene (LGG-1:GFP) labeled transgenic DA2123 strain, the co-localization of LGG-1:GFP with PS was found as well, means that autophagy is involved in C3G’s beneficial effects. Furthermore, we were surprised to find that C3G could promote the discharge of PS from N2 nematodes, which reduces PS toxicity more directly.
اظهر المزيد [+] اقل [-]Size matters: Zebrafish (Danio rerio) as a model to study toxicity of nanoplastics from cells to the whole organism
2021
Sendra, M. | Pereiro, P. | Yeste, M.P. | Mercado, L. | Figueras, A. | Novoa, B.
The contamination of the aquatic environment by plastic nanoparticles is becoming a major concern due to their potential adverse effects in aquatic biota. Therefore, in-depth knowledge of their uptake, trafficking and effects at cellular and systemic levels is essential to understand their potential impacts for aquatic species. In this work, zebrafish (Danio rerio) was used as a model and our aims were: i) to determine the distribution, uptake, trafficking, degradation and genotoxicity of polystyrene (PS) NPs of different sizes in a zebrafish cell line; ii) to study PS NPs accumulation, migration of immune cells and genotoxicity in larvae exposed to PS NPs; and iii) to assess how PS NPs condition the survival of zebrafish larvae exposed to a pathogen and/or how they impact the resistance of an immunodeficient zebrafish. Our results revealed that the cellular distribution differed depending on the particle size: the 50 nm PS NPs were more homogeneously distributed in the cytoplasm and the 1 μM PS NPs more agglomerated. The main endocytic mechanisms for the uptake of NPs were dynamin-dependent internalization for the 50 nm NPs and phagocytosis for the 1 μm nanoparticles. In both cases, degradation in lysosomes was the main fate of the PS NPs, which generated alkalinisation and modified cathepsin genes expression. These effects at cellular level agree with the results in vivo, since lysosomal alkalization increases oxidative stress and vice versa. Nanoparticles mainly accumulated in the gut, where they triggered reactive oxygen species, decreased expression of the antioxidant gene catalase and induced migration of immune cells. Finally, although PS NPs did not induce mortality in wild-type larvae, immunodeficient and infected larvae had decreased survival upon exposure to PS NPs. This fact could be explained by the mechanical disruption and/or the oxidative damage caused by these NPs that increase their susceptibility to pathogens.
اظهر المزيد [+] اقل [-]Transcriptome, bioaccumulation and toxicity analyses of earthworms (Eisenia fetida) affected by trifloxystrobin and trifloxystrobin acid
2020
Liu, Tong | Liu, Yalei | Fang, Kuan | Zhang, Xiaolian | Wang, Xiuguo
As a promising fungicide, the potential environmental risk of trifloxystrobin (TFS) and its main metabolism trifloxystrobin acid (TFSA) in soil environment should be given special attention. The present study investigated the potential risks of TFS and TFSA in soil environment to earthworms (Eisenia fetida) through measuring several biomarkers. Residual analysis showed that TFSA was more stable than TFS in artificial soil with half-lives ranging from 138.6 to 231.0 d and 20.4–24.7 d, respectively. Additionally, the accumulation of TFS in earthworms increased in the beginning and then decreased from day 14, while that of TFSA continuously increased. At concentrations of 4.0 mg/kg and 10.0 mg/kg, the weight and lysosomal membrane stability of earthworms were reduced; however, the superoxide dismutase (SOD) activity, glutathione-S-transferase (GST) activity and malondialdehyde (MDA) content in earthworms were enhanced by TFS and TFSA. Moreover, the growth inhibition effect and the oxidative damage level induced by TFSA to earthworms were higher than those induced by TFS. The transcriptome analysis date indicated that the differentially expressed genes (DEGs) in both TFS and TFSA treatments were mainly enriched in ribosome pathway and lysosome pathway, finally affecting the protein synthesis and proteolysis in earthworms. The findings of the present study indicated that TFSA may pose a higher risk in the soil environment than TFS.
اظهر المزيد [+] اقل [-]Roles of hemocyte subpopulations in silver nanoparticle transformation and toxicity in the oysters Crassostrea hongkongensis
2022
Luo, Yali | Wang, Wen-Xiong
Hemocytes are the main immune cells in bivalve mollusks and one of the sensitive targets for nanoparticle toxicity. Bivalve hemocytes consist of multiple functional heterogeneous cell types, but their different roles in immune system against foreign particles remain largely unknown. In order to clarify the different immune responses of hemocyte subpopulations to silver nanoparticles (AgNPs) and Ag ions, in this study, the Hong Kong oyster (Crassostrea hongkongensis) hemocytes were employed and separated into three subpopulations based on their cell size and granularity, including agranulocytes (R1), semigranulocytes (R2), and granulocytes (R3). We first demonstrated that AgNPs could rapidly enter into the oyster hemocytes within 3 h by phagocytosis process and resulted in different immune responses in hemocyte subpopulations. The most affected cell subtype by AgNPs was the granulocytes, followed by semigranulocytes, whereas agranulocytes were not affected following exposure to AgNPs. Interestingly, AgNPs induced the granule formation in semigranulocytes and further increased the proportion of granulocytes, whereas their ionic counterparts had no such effects on hemocyte composition, indicating the different detoxification mechanisms for nanoparticulate and ionic form. Following AgNP exposure, the dissolved Ag ions were accumulated in lysosomes and caused lysosomal dysfunction, indicating that lysosomes were the main targets for AgNP toxicity and the dissolved Ag ions were the main contributor of AgNP toxicity. Furthermore, AgNP exposure induced reactive oxygen production and impeded the lysosome function and phagocytosis in granulocytes, with impaired immunity system in oysters. Our study identified the different immune responses of oyster hemocyte subpopulations to AgNPs based on the in vitro short-term exposure assays, which may be applied to rapidly evaluate the ecotoxicological risks of different nanoparticles in aquatic systems.
اظهر المزيد [+] اقل [-]