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Mechanism of thorium-nitrate and thorium-dioxide induced cytotoxicity in normal human lung epithelial cells (WI26): Role of oxidative stress, HSPs and DNA damage
2021
Das, Sourav Kumar | Ali, Manjoor | Shetake, Neena G. | Dumpala, Rama Mohan R. | Pandey, Badri N. | Kumar, Amit
Inhalation represents the most prevalent route of exposure with Thorium-232 compounds (Th-nitrate/Th-dioxide)/Th-containing dust in real occupational scenario. The present study investigated the mechanism of Th response in normal human alveolar epithelial cells (WI26), exposed to Th-nitrate or colloidal Th-dioxide (1–100 μg/ml, 24–72 h). Assessment in terms of changes in cell morphology, cell proliferation (cell count), plasma membrane integrity (lactate dehydrogenase leakage) and mitochondrial metabolic activity (MTT reduction) showed that Th-dioxide was quantitatively more deleterious than Th-nitrate to WI26 cells. TEM and immunofluorescence analysis suggested that Th-dioxide followed a clathrin/caveolin-mediated endocytosis, however, membrane perforation/non-endocytosis seemed to be the mode of Th internalization in cells exposed to Th-nitrate. Th-estimation by ICP-MS showed significantly higher uptake of Th in cells treated with Th-dioxide than with Th-nitrate at a given concentration. Both Th-dioxide and nitrate were found to increase the level of reactive oxygen species, which seemed to be responsible for lipid peroxidation, alteration in mitochondrial membrane potential and DNA-damage. Amongst HSPs, the protein levels of HSP70 and HSP90 were affected differentially by Th-nitrate/dioxide. Specific inhibitors of ATM (KU55933) or HSP90 (17AAG) were found to increase the Th- cytotoxicity suggesting prosurvival role of these signaling molecules in rescuing the cells from Th-toxicity.
Show more [+] Less [-]Assessment of the ability of roadside vegetation to remove particulate matter from the urban air
2021
Kończak, B. | Cempa, M. | Pierzchała, Ł | Deska, M.
The development of urbanised areas together with the growing transport infrastructure and traffic volume are the main cause of air quality deterioration due to the increasing concentrations of particulate matter. Dust pollution is a threat to human health. It can cause the development of lung, larynx or circulatory system cancer. Due to the ability to accumulate dust particles on the leaf surface, the contribution of trees in the process of phytoremediation of air pollution has started to be appreciated. An analysis of the elemental composition of particulate matter (PM) stored on the leaves surface was also carried out, which showed high average concentration of: C > O > Si > Fe (above 8wt.%). It was also observed single particles with a high concentration of heavy metals: Ti, Mn, Ba, Zn, Cr, Pb, Sn, Ni and REE (rare earth elements). The major origin of PM are vehicular emissions, soil and re-suspended road dust. This paper presents also a comparison of selected tree, shrub and vine species differing in their ability to accumulate particulate matter. It was experimentally determined the average leaf surface of individual plant species and established the amount of particulate matter with aerodynamic diameter between 10 and 100 μm, 2.5 and 10 μm, and 0.2 and 2.5 μm deposited on the leaf surface and in waxes.Some species of vines (Parthenocissus quinquefolia), shrubs (Forsythia x intermediata) and coniferous trees, such as Betula pendula ‘Youngii’, Quercus rubra, Cratageus monogyna, Acer pseduoplatanus, Tilia cordata Mill. or Platanus orientalis turned out to be the most efficient in the process of phylloremediation.
Show more [+] Less [-]Thioredoxin-albumin fusion protein prevents urban aerosol-induced lung injury via suppressing oxidative stress-related neutrophil extracellular trap formation
2021
Tanaka, Ken-ichiro | Kubota, Maho | Shimoda, Mikako | Hayase, Tomoko | Miyaguchi, Mamika | Kobayashi, Nahoko | Ikeda, Mayumi | Ishima, Yu | Kawahara, Masahiro
The number of deaths from air pollution worldwide is estimated at 8.8 million per year, more than the number of deaths from smoking. Air pollutants, such as PM₂.₅, are known to induce respiratory and cardiovascular diseases by inducing oxidative stress. Thioredoxin (Trx) is a 12-kDa endogenous protein that exerts antioxidant activity by promoting dithiol disulfide exchange reactions. We previously synthesized human serum albumin-fused thioredoxin (HSA-Trx), which has a longer half-life in plasma compared with Trx, and demonstrated its efficacy against various diseases including respiratory diseases. Here, we examined the effect of HSA-Trx on urban aerosol-induced lung injury in mice. Urban aerosols induced lung injury and inflammatory responses in ICR mice, but intravenous administration of HSA-Trx markedly inhibited these responses. We next analyzed reactive oxygen species (ROS) production in murine lungs using an in vivo imaging system. The results show that intratracheal administration of urban aerosols induced ROS production that was inhibited by intravenously administered HSA-Trx. Finally, we found that HSA-Trx inhibited the urban aerosol-induced increase in levels of neutrophilic extracellular trap (NET) indicators (i.e., double-stranded DNA, citrullinated histone H3, and neutrophil elastase) in bronchoalveolar lavage fluid (BALF). Together, these findings suggest that HSA-Trx prevents urban aerosol-induced acute lung injury by suppressing ROS production and neutrophilic inflammation. Thus, HSA-Trx may be a potential candidate drug for preventing the onset or exacerbation of lung injury caused by air pollutants.
Show more [+] Less [-]LncRNA H19-mediated M2 polarization of macrophages promotes myofibroblast differentiation in pulmonary fibrosis induced by arsenic exposure
2021
Xiao, Tian | Zou, Zhonglan | Xue, Junchao | Syed, Binafsha Manzoor | Sun, Jing | Dai, Xiangyu | Shi, Ming | Li, Junjie | Wei, Shaofeng | Tang, Huanwen | Zhang, Aihua | Liu, Qizhan
Arsenic is a potent toxicant, and long-term exposure to inorganic arsenic causes lung damage. M2 macrophages play an important role in the pathogenesis of pulmonary fibrosis. However, the potential connections between arsenic and M2 macrophages in the development of pulmonary fibrosis are elusive. C57BL/6 mice were fed with drinking water containing 0, 10 and 20 ppm arsenite for 12 months. We have found that, in lung tissues of mice, arsenite, a biologically active form of arsenic, elevated H19, c-Myc, and Arg1; decreased let-7a; and caused pulmonary fibrosis. For THP-1 macrophages (THP-M) and bone-marrow-derived macrophages (BMDMs), 8 μM arsenite increased H19, c-Myc, and Arg1; decreased let-7a; and induced M2 polarization of macrophages, which caused secretion of the fibrogenic cytokine, TGF-β1. Down-regulation of H19 or up-regulation of let-7a reversed the arsenite-induced M2 polarization of macrophages. Arsenite-treated THP-M and BMDMs co-cultured with MRC-5 cells or primary lung fibroblasts (PLFs) elevated levels of p-SMAD2/3, SMAD4, α-SMA, and collagen I in lung fibroblasts and resulted in the activation of lung fibroblasts. Knockout of H19 or up-regulation of let-7a in macrophages reversed the effects. The results indicated that H19 functioned as an miRNA sponge for let-7a, which was involved in arsenite-induced M2 polarization of macrophages and induced the myofibroblast differentiation phenotype by regulation of c-Myc. In the sera of arseniasis patients, levels of hydroxyproline and H19 were higher, and levels of let-7a were lower than levels in the controls. These observations elucidate a possible mechanism for arsenic exposure-induced pulmonary fibrosis.
Show more [+] Less [-]Toxicokinetics and systematic responses of differently sized indium tin oxide (ITO) particles in mice via oropharyngeal aspiration exposure
2021
Qu, Jing | Wang, Jianli | Zhang, Haopeng | Wu, Jingying | Ma, Xinmo | Wang, Shile | Zang, Yiteng | Huang, Yuhui | Ma, Ying | Cao, Yuna | Wu, Daming | Zhang, Ting
Indium tin oxide (ITO) is an important semiconductor material, because of increasing commercial products consumption and potentially exposed workers worldwide. So, urgently we need to assess and manage potential health risks of ITO. Although the Occupational Exposure Limit (OEL) has been established for ITO exposure, there is still a lack of distinguishing the risks of exposure to particles of different sizes. Therefore, obtaining toxicological data of small-sized particles will help to improve its risk assessment data. Important questions raised in quantitative risk assessments for ITO particles are whether biodistribution of ITO particles is affected by particle size and to what extent systematic adverse responses is subsequently initiated. In order to determine whether this toxicological paradigm for size is relevant in ITO toxic effect, we performed comparative studies on the toxicokinetics and sub-acute toxicity test of ITO in mice. The results indicate both sized-ITO resided in the lung tissue and slowly excreted from the mice, and the smaller size of ITO being cleared more slowly. Only a little ITO was transferred to other organs, especially with higher blood flow. Two type of ITO which deposit in the lung mainly impacts respiratory system and may injure liver or kidney. After sub-acute exposure to ITO, inflammation featured by neutrophils infiltration and fibrosis with both dose and size effects have been observed. Our findings revealed toxicokinetics and dose-dependent pulmonary toxicity in mice via oropharyngeal aspiration exposure, also replenish in vivo risk assessment of ITO. Collectively, these data indicate that under the current OEL, there are potential toxic effects after exposure to the ITO particles. The observed size-dependent biodistribution patterns and toxic effect might be important for approaching the hazard potential of small-sized ITO in an occupational environment.
Show more [+] Less [-]The effect of toxic components on metabolomic response of male SD rats exposed to fine particulate matter
2021
Geng, Ningbo | Song, Xiaoyao | Cao, Rong | Luo, Yun | A, Mila | Cai, Zhengang | Yu, Kejie | Gao, Yuan | Ni, Yuwen | Zhang, Haijun | Chen, Jiping
PM₂.₅ pollution was associated with numerous adverse health effects. However, PM₂.₅ induced toxic effects and the relationships with toxic components remain largely unknown. To evaluate the metabolic toxicity of PM₂.₅ at environmentally relevant doses, investigate the seasonal variation of PM₂.₅ induced toxicity and the relationship with toxic components, a combination of general pathophysiological tests and metabolomics analysis was conducted in this study to explore the response of SD rats to PM₂.₅ exposure. The result of general toxicology analysis revealed unconspicuous toxicity of PM₂.₅ under environmental dose, but winter PM₂.₅ at high dose caused severe histopathological damage to lung. Metabolomic analysis highlighted significant metabolic disorder induced by PM₂.₅ even at environmentally relevant doses. Lipid metabolism and GSH metabolism were primarily influenced by PM₂.₅ exposure due to the high levels of heavy metals. In addition, high levels of organic compounds such as PAHs, PCBs and PCDD/Fs in winter PM₂.₅ bring multiple overlaps on the toxic pathways, resulting in larger pulmonary toxicity and metabolic toxicity in rats than summer.
Show more [+] Less [-]A toxicity pathway-oriented approach to develop adverse outcome pathway: AHR activation as a case study
2021
Jin, Yuan | Feng, Meiyao | Ma, Wanli | Wei, Yanhong | Qi, Guangshuai | Luo, Jiao | Xu, Lin | Li, Xinmei | Li, Chuanhai | Wang, Ying | Li, Daochuan | Chen, Jing | Zhao, Yanjie | Hou, Yufei | Zhao, Qianwen | Jiang, Lidan | Xie, Mengyue | Zheng, Yuxin | Yu, Dianke
With numerous new chemicals introduced into the environment everyday, identification of their potential hazards to the environment and human health is a considerable challenge. Developing adverse outcome pathway (AOP) framework is promising in helping to achieve this goal as it can bring In Vitro testing into toxicity measurement and understanding. To explore the toxic mechanism underlying environmental chemicals via the AOP approach, an integration of adequate experimental data with systems biology understanding is preferred. Here, we describe a novel method to develop reliable and sensible AOPs that relies on chemical-gene interactions, toxicity pathways, molecular regulations, phenotypes, and outcomes information obtained from comparative toxicogenomics database (CTD) and Ingenuity Pathway Analysis (IPA). Using Benzo(a)pyrene (BaP), a highly studied chemical as a stressor, we identified the pivotal IPA toxicity pathways, the molecular initiating event (MIE), and candidate key events (KEs) to structure AOPs in the liver and lung, respectively. Further, we used the corresponding CTD information of multiple typical AHR-ligands, including 2,3,7,8-tetrachlorodibenzoparadioxin (TCDD), valproic acid, quercetin, and particulate matter, to validate our AOP networks. Our approach is likely to speed up AOP development as providing a time- and cost-efficient way to collect all fragmented bioinformation in published studies. It also facilitates a better understanding of the toxic mechanism of environmental chemicals, and potentially brings new insights into the screening of critical paths in the AOP network.
Show more [+] Less [-]Biorepositories (biobanks) of human body fluids and materials as archives for tracing early infections of COVID-19
2021
He, Shanshan | Han, Jie
Identifying the individuals and geographical regions witnessing early infections or outbreaks of SARS-CoV-2 and its variants is helpful for studying the early epidemiology or even the origin of the novel coronavirus. Here, we put forward a strategy that can potentially contribute to this goal. Human body fluids and biological materials collected before the COVID-19 pandemic may serve as archives for retrospective testing of early human infections before the recent outbreaks. These have been routinely donated, collected, and archived, creating biorepositories or “biobanks” for clinical or research purposes. SARS-CoV-2 genetic materials and its antibodies have been confirmed in various types of biological samples from COVID-19 patients, including blood, sperm, umbilical cord blood, lung, heart, kidney and so on, making these biological archives as candidates for detecting early COVID-19 infections. Unlike sewage-based epidemiology which only provides information on the geographical aspect, viruses identified in archived human biological samples provide direct links to individuals, from whom a wealth of personal information including their profession, hobbies and activities, travel history, and previous exposure to wildlife can all be retrieved. By analyzing the patterns and links in the behavior of those early infected individuals, it is possible to trace the origin of the virus, for instance, in certain wild animals or local environments.
Show more [+] Less [-]Exposure to nanoparticles derived from diesel particulate filter equipped engine increases vulnerability to arrhythmia in rat hearts
2021
Rossi, Stefano | Buccarello, Andrea | Caffarra Malvezzi, Cristina | Pinelli, Silvana | Alinovi, Rossella | Guerrero Gerboles, Amparo | Rozzi, Giacomo | Leonardi, Fabio | Bollati, Valentina | De Palma, Giuseppe | Lagonegro, Paola | Rossi, F. (Francesca) | Lottici, Pier Paolo | Poli, Diana | Statello, Rosario | Macchi, Emilio | Miragoli, Michele
Air pollution is well recognized as a central player in cardiovascular disease. Exhaust particulate from diesel engines (DEP) is rich in nanoparticles and may contribute to the health effects of particulate matter in the environment. Moreover, diesel soot emitted by modern engines denotes defective surfaces alongside chemically-reactive sites increasing soot cytotoxicity. We recently demonstrated that engineered nanoparticles can cross the air/blood barrier and are capable to reach the heart. We hypothesize that DEP nanoparticles are pro-arrhythmogenic by direct interaction with cardiac cells. We evaluated the internalization kinetics and the effects of DEP, collected from Euro III (DEPe3, in the absence of Diesel Particulate Filter, DPF) and Euro IV (DEPe4, in the presence of DPF) engines, on alveolar and cardiac cell lines and on in situ rat hearts following DEP tracheal instillation. We observed significant differences in DEP size, metal and organic compositions derived from both engines. DEPe4 comprised ultrafine particles (<100 nm) and denoted a more pronounced toxicological outcome compared to DEPe3. In cardiomyocytes, particle internalization is fastened for DEPe4 compared to DEPe3. The in-vivo epicardial recording shows significant alteration of EGs parameters in both groups. However, the DEPe4-instilled group showed, compared to DEPe3, a significant increment of the effective refractory period, cardiac conduction velocity, and likelihood of arrhythmic events, with a significant increment of membrane lipid peroxidation but no increment in inflammation biomarkers. Our data suggest that DEPe4, possibly due to ultrafine nanoparticles, is rapidly internalized by cardiomyocytes resulting in an acute susceptibility to cardiac electrical disorder and arrhythmias that could accrue from cellular toxicity. Since the postulated transfer of nanoparticles from the lung to myocardial cells has not been investigated it remains open whether the effects on the cardiovascular function are the result of lung inflammatory reactions or due to particles that have reached the heart.
Show more [+] Less [-]Epigenetic silencing of TET1 mediated hydroxymethylation of base excision repair pathway during lung carcinogenesis
2021
Chen, Hong-qiang | Chen, Dong-jiao | Li, Yan | Yuan, Wen-bo | Fan, Jun | Zhang, Zhe | Han, Fei | Jiang, Xiao | Chen, J. P. (Jian-ping) | Wang, Dan-dan | Cao, Jia | Liu, Jin-yi | Liu, Wen-bin
The methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is an important regulator for the balance of DNA methylation and hydroxymethylation through various pathways. Increasing evidence has suggested that TET1 probably involved in DNA methylation and demethylation dysregulation during chemical carcinogenesis. However, the role and mechanism of TET1 during lung cancer remains unclear. In this study, we found that TET1 expression was significantly down-regulated and the methylation level was significantly up-regulated in 3-methylcholanthrene (3-MCA) induced cell malignant transformation model, rat chemical carcinogenesis model, and human lung cancer tissues. Demethylation experiment further confirmed that DNA methylation negatively regulated TET1 gene expression. TET1 overexpression inhibited cell proliferation, migration and invasion in vitro and in vivo, while knockdown of TET1 resulted in an opposite phenotype. DNA hydroxymethylation level in the promoter region of base excision repair (BER) pathway key genes XRCC1, OGG1, APEX1 significantly decreased and the degree of methylation gradually increased in malignant transformed cells. After differential expression of TET1, the level of hydroxymethylation, methylation and expression of these genes also changed significantly. Furthermore, TET1 binds to XRCC1, OGG1, and APEX1 to maintain them hydroxymethylated. Blockade of BER pathway key gene alone or in combination significantly diminished the effect of TET1. Our study demonstrated for the first time that TET1 expression is regulated by DNA methylation and TET1-mediated hydroxymethylation regulates BER pathway to inhibit the proliferation, migration and invasion during 3-MCA-induced lung carcinogenesis. These results suggested that TET1 gene can be a potential biomarker and therapy target for lung cancer.
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