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Cadmium exposure induces osteoporosis through cellular senescence, associated with activation of NF-κB pathway and mitochondrial dysfunction
2021
Luo, Huigen | Gu, Renjie | Ouyang, Huiya | Wang, Lihong | Shi, Shanwei | Ji, Yuna | Bao, Baicheng | Liao, Guiqing | Xu, Baoshan
Cadmium (Cd) is a heavy metal toxicant as a common pollutant derived from many agricultural and industrial sources. The absorption of Cd takes place primarily through Cd-contaminated food and water and, to a significant extent, via inhalation of Cd-contaminated air and cigarette smoking. Epidemiological data suggest that occupational or environmental exposure to Cd increases the health risk for osteoporosis and spontaneous fracture such as itai-itai disease. However, the direct effects and underlying mechanism(s) of Cd exposure on bone damage are largely unknown. We used primary bone marrow-derived mesenchymal stromal cells (BMMSCs) and found that Cd significantly induced BMMSC cellular senescence through over-activation of NF-κB signaling pathway. Increased cell senescence was determined by production of senescence-associated secretory phenotype (SASP), cell cycle arrest and upregulation of p21/p53/p16ᴵᴺᴷ⁴ᵃ protein expression. Additionally, Cd impaired osteogenic differentiation and increased adipogenesis of BMMSCs, and significantly induced cellular senescence-associated defects such as mitochondrial dysfunction and DNA damage. Sprague-Dawley (SD) rats were chronically exposed to Cd to verify that Cd significantly increased adipocyte number, and decreased mineralization tissues of bone marrow in vivo. Interestingly, we observed that Cd exposure remarkably retarded bone repair and regeneration after operation of skull defect. Notably, pretreatment of melatonin is able to partially prevent Cd-induced some senescence-associated defects of BMMSCs including mitochondrial dysfunction and DNA damage. Although Cd activated mammalian target of rapamycin (mTOR) pathway, rapamycin only partially ameliorated Cd-induced cell apoptosis rather than cellular senescence phenotypes of BMMSCs. In addition, a selective NF-κB inhibitor moderately alleviated Cd-caused the senescence-related defects of the BMMSCs. The study shed light on the action and mechanism of Cd on osteoporosis and bone ageing, and may provide a novel option to ameliorate the harmful effects of Cd exposure.
Mostrar más [+] Menos [-]Probiotics inhibit the stunted growth defect of perfluorobutanesulfonate via stress and thyroid axes in zebrafish larvae
2021
Perfluorobutanesulfonate (PFBS) is an emerging pollutant in aquatic environments and potently disrupts the early developmental trajectory of teleosts. Considering the persistent and toxic nature of PFBS, it is necessary to develop in situ protective measures to ameliorate the toxic damage of PFBS. Probiotic supplements are able to mitigate the growth retardation defects of PFBS. However, the interactive mechanisms remain elusive. To this end, this study acutely exposed zebrafish larvae to a concentration gradient of PFBS (0, 1, 3.3 and 10 mg/L) for 4 days, during which probiotic bacteria Lactobacillus rhamnosus were added in the rearing water. After exposure, alterations in gene transcriptions and key hormones along the hypothalamus–pituitary–interrenal (HPI), growth hormone/insulin–like growth factor (GH/IGF) and hypothalamus–pituitary–thyroid (HPT) axes were examined. The results showed that PFBS single exposure significantly increased the cortisol concentrations, suggesting the induction of stress response, while probiotic supplementation effectively decreased the cortisol levels in coexposed larvae in an attempt to relieve the stress of PFBS toxicant. It was unexpected that probiotic additive significantly decreased the larval GH concentrations independent of PFBS, thereby eliminating the contribution of GH/IGF axis to the growth improvement of probiotics. In contrast, probiotic bacteria remarkably increased the concentration of thyroid hormones, particularly the thyroxine (T4), in zebrafish larvae. The pronounced down-regulation of uridinediphosphate glucoronosyltransferases (UDPGT) gene pointed to the blocked elimination process of T4 by probiotics. Furthermore, proteomic fingerprinting found that probiotics were potent to shape the protein expression pattern in PFBS-exposed zebrafish larvae and modulated multiple biological processes that are essential for the growth. In summary, the present findings suggest that HPI and HPT axes may cooperate to enhance the growth of fish larvae under PFBS and probiotic coexposures.
Mostrar más [+] Menos [-]Responses of the reproduction, population growth and metabolome of the marine rotifer Brachionus plicatilis to tributyl phosphate (TnBP)
2021
Zhang, Xin | Tang, Xuexi | Yang, Yingying | Sun, Zijie | Ma, Wenqian | Tong, Xin | Wang, Chengmin | Zhang, Xinxin
The typical alkyl organophosphorus flame retardant tributyl phosphate (TnBP) can leak from common products into the marine environment, with potential negative effects on marine organisms. However, risk assessments for TnBP regarding zooplankton are lacking. In this study, a marine rotifer, Brachionus plicatilis, was used to analyze the effect of TnBP (0.1 μg/L, environmental concentration; 1 and 6 mg/L) on reproduction, population growth, oxidative stress, mitochondrial function and metabolomics. Mortality increased as the TnBP concentration rose; the 24-h LC₅₀ value was 12.45 mg/L. All tested TnBP concentrations inhibited B. plicatilis population growth, with reproductive toxicity at the higher levels. Microstructural imaging showed ovary injury, the direct cause of reproductive toxicity. Despite elevated glutathione reductase activities, levels of reactive oxygen species and malonyldialdehyde increased under TnBP stress, indicating oxidative imbalance. TnBP induced mitochondrial malformation and activity suppression; the ROS scavenger N-acetylcysteine alleviated this inhibition, suggesting an internal connection. Nontargeted metabolomics revealed 398 and 583 differentially expressed metabolites in the 0.1 μg/L and 6 mg/L treatments relative to control, respectively, which were enriched in the pathways such as biosynthesis of amino acids, purine metabolism, aminoacyl-tRNA biosynthesis. According to metabolic pathway analysis, oxidative stress from purine degradation, mitochondrial dysfunction, disturbed lipid metabolism and elevated protein synthesis were jointly responsible for reproduction and population growth changes. This study echoes the results previously found in rotifer on trade-off among different life processes in response to environmental stress. Our systematic study uncovers the TnBP toxic mode of action.
Mostrar más [+] Menos [-]ABC proteins activity and cytotoxicity in zebrafish hepatocytes exposed to triclosan
2021
Guidony, Nicole Soares | Scaini, João Luís Rheingantz | Oliveira, Matheus William Bandeira | Machado, Karina Santos | Bastos, Cláudio | Escarrone, Ana Laura | Souza, Marta Marques
Chemicals such as triclosan are a concern because of their presence on daily products (soap, deodorant, hand sanitizers …), consequently this compound has an ubiquitous presence in the environment. Little is known about the effect of this bactericide on aquatic life. The aim of this study is to analyze triclosan exposure (24 h) to an in vitro model, zebrafish hepatocytes cell line (ZF-L), if it can be cytotoxic (mitochondrial activity, membrane stability and apoptosis) and if can activate ATP-binding cassette (ABC) proteins (activity, expression and protein/compound affinity). Triclosan was cytotoxic to hepatocytes when exposed to concentrations (1–4 mg/L). The results showed impaired mitochondria function, as well, plasma membrane rupture and an increase of apoptotic cells. We observed an ABC proteins activity inhibition in cells exposed to 0.5 and 1 mg/L. When ABCBs and ABCC2 proteins expression were analyzed, there was an increase of protein expression in both ABC proteins families on cells exposed to 1 mg/L of triclosan. On molecular docking results, triclosan and the fluorescent used as substrate (rhodamine) presented high affinity with all ABC proteins family tested, showing a greater affinity with ABCC2. In conclusion, this study showed that triclosan can be cytotoxic to ZF-L. Molecular docking indicated high affinity between triclosan and the tested pumps.
Mostrar más [+] Menos [-]Exposure of androgen mimicking environmental chemicals enhances proliferation of prostate cancer (LNCaP) cells by inducing AR expression and epigenetic modifications
2021
Singh, Vipendra Kumar | Pal, Rajesh | Srivastava, Priyansh | Misra, Gauri | Shukla, Yogeshwer | Sharma, Pradeep Kumar
Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and β-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and β-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.
Mostrar más [+] Menos [-]In vitro renal toxicity evaluation of copper-based metal–organic framework HKUST-1 on human embryonic kidney cells
2021
Chen, Yi-Chun | Andrew Lin, Kun-Yi | Chen, Ku-Fan | Jiang, Xin-Yu | Lin, Chia-Hua
HKUST-1 is currently studied for a very diverse range of applications. Despite its exciting potential, significant concerns remain regarding the safety of HKUST-1. Therefore, human embryonic kidney 293 (HEK293) cells were used to verify the renal toxicity of HKUST-1. In this study, HKUST-1 induced concentration-dependent cytotoxic effects in HEK293 cells. The depolarization of mitochondrial membrane potential and formation of apoptotic bodies and autophagic vesicles were observed in HKUST-1–treated HEK293 cells. Oxidative (oxidative stress and haem oxygenase-1 activation) and inflammatory responses (NF-κB and NLRP3 activation) in HEK293 cells were induced by HKUST-1 exposure. In addition, the observed reduction in NAD(P)H levels in HKUST-1–treated HEK293 cells may be attributable to PARP-1 activation following DNA single- and double-strand breaks. The HKUST-1–induced depletion of zonula occludens proteins in HEK293 cells might lead to altered renal barrier integrity. The variations of α1-antitrypsin, oxidised α1-antitrypsin and NLRP3 protein expression in HEK293 cells suggested that HKUST-1 increases the risk of chronic kidney diseases. However, most of these adverse effects were significantly induced only by high HKUST-1 concentration (100 μg/mL), which do not reflect the actual exposure. Thus, the toxic risk of HKUST-1 appears to be negligible.
Mostrar más [+] Menos [-]Gene expression response of the alga Fucus virsoides (Fucales, Ochrophyta) to glyphosate solution exposure
2020
Gerdol, Marco | Visintin, Andrea | Kaleb, Sara | Spazzali, Francesca | Pallavicini, Alberto | Falace, Annalisa
Fucus virsoides is an ecologically important canopy-forming brown algae endemic to the Adriatic Sea. Once widespread in marine coastal areas, this species underwent a rapid population decline and is now confined to small residual areas. Although the reasons behind this progressive disappearance are still a matter of debate, F. virsoides may suffer, like other macroalgae, from the potential toxic effects of glyphosate-based herbicides.Here, through a transcriptomic approach, we investigate the molecular basis of the high susceptibility of this species to glyphosate solution, previously observed at the morphological and eco-physiological levels. By simulating runoff event in a factorial experiment, we exposed F. virsoides to glyphosate (Roundup® 2.0), either alone or in association with nutrient enrichment, highlighting significant alterations of gene expression profiles that were already visible after three days of exposure. In particular, glyphosate exposure determined the near-complete expression shutdown of several genes involved in photosynthesis, protein synthesis and stress response molecular pathways. Curiously, these detrimental effects were partially mitigated by nutrient supplementation, which may explain the survival of relict population in confined areas with high nutrient inputs.
Mostrar más [+] Menos [-]Proteomic analysis revealed gender-specific responses of mussels (Mytilus galloprovincialis) to trichloropropyl phosphate (TCPP) exposure
2020
Zhong, Mingyu | Wu, Huifeng | Li, Fei | Shan, Xiujuan | Ji, Chenglong
Trichloropropyl phosphate (TCPP) is a halogenated organophosphate ester that is widely used as flame retardants and plasticizers. In this study, gender-specific accumulation and responses in mussel Mytilus galloprovincialis to TCPP exposure were focused and highlighted. After TCPP (100 nmol L⁻¹) exposure for 42 days, male mussels showed similar average bioaccumulation (37.14 ± 6.09 nmol g⁻¹ fat weight (fw)) of TCPP with that in female mussels (32.28 ± 4.49 nmol g⁻¹ fw). Proteomic analysis identified 219 differentially expressed proteins (DEPs) between male and female mussels in control group. There were 52 and 54 DEPs induced by TCPP in male and female mussels, respectively. Interestingly, gender-specific DEPs included 37 and 41 DEPs induced by TCPP in male and female mussels, respectively. The proteomic differences between male and female mussels were related to protein synthesis and degradation, energy metabolism, and functions of cytoskeleton and motor proteins. TCPP influenced protein synthesis, energy metabolism, cytoskeleton functions, immunity, and reproduction in both male and female mussels. Protein-protein interaction (PPI) networks indicated that protein synthesis and energy metabolism were the main biological processes influenced by TCPP. However, DEPs involved in these processes and their interaction patterns were quite different between male and female mussels. Basically, twelve ribosome DEPs which directly or indirectly interacted were found in protein synthesis in TCPP-exposed male mussels, while only 3 ribosome DEPs (not interacted) in TCPP-exposed female mussels. In energy metabolism, only 4 DEPs (with the relatively simple interaction pattern) mainly resided in fatty acid metabolism, butanoate/propanoate metabolism and glucose metabolism were discovered in TCPP-exposed male mussels, and more DEPs (with multiple interactions) functioned in TCA cycle and pyruvate/glyoxylate/dicarboxylate metabolism were found in TCCP-exposed female mussels. Taken together, TCPP induced gender-specific toxicological effects in mussels, which may shed new lights on further understanding the toxicological mechanisms of TCPP in aquatic organisms.
Mostrar más [+] Menos [-]β-catenin mediates fluoride-induced aberrant osteoblasts activity and osteogenesis
2020
Chu, Yanru | Gao, Yanhui | Yang, Yanmei | Liu, Yang | Guo, Zining | Wang, Limei | Huang, Wei | Wu, Liaowei | Sun, Dianjun | Gu, Weikuan
Excess fluoride in drinking water is an environmental issue of increasing worldwide concern, because of its adverse effect on human health. Skeletal fluorosis caused by chronic exposure to excessive fluoride is a metabolic bone disease characterized by accelerated bone turnover accompanied by aberrant activation of osteoblasts. It is not clear whether Wnt/β-catenin signaling, an important signaling pathway regulating the function of osteoblasts, mediates the pathogenesis of skeletal fluorosis. A cross-sectional case-control study was conducted in Tongyu County, Jilin Province, China showed that fluoride stimulated the levels of OCN and OPG, resulting in accelerated bone turnover in patients with skeletal fluorosis. To investigate the influence of fluoride on Wnt/β-catenin signaling pathway, 64 male BALB/c mice were allotted randomly to four groups and treated with deionized water containing 0, 55, 110 and 221 mg/L NaF for 3 months, respectively. The results demonstrated that fluoride significantly increased mouse cancellous bone formation and the protein expression of Wnt3a, phospho-GSK3β (ser 9) and Runx2. Moreover, partial correlation analysis indicated that there was no significant correlation between fluoride exposure and Runx2 protein levels, after adjusting for β-catenin, suggesting that β-catenin might play a crucial role in fluoride-induced aberrant osteogenesis. In vivo, viability of SaoS2 cells was significantly facilitated by 4 mg/L NaF, and fluoride could induce the abnormal activation of Wnt/β-catenin signaling, the expression of its target gene Runx2 and significantly increased Tcf/Lef reporter activity. Importantly, inhibition of β-catenin suppressed fluoride-induced Runx2 protein expression and the osteogenic phenotypes. Taken together, the present study provided in vivo and in vitro evidence reveals a potential mechanism for fluoride-induced aberrant osteoblast activation and indicates that β-catenin is the pivot molecule mediating viability and differentiation of osteoblasts and might be a therapeutic target for skeletal fluorosis.
Mostrar más [+] Menos [-]Investigation of the effects of dichlorvos poisoning on AMPK signaling pathway in chicken brain tissues
2020
Xiao, Yanyu | Zheng, Xibang | Li, Guyue | Zhou, Changming | Wu, Cong | Xu, Zheng | Hu, Guoliang | Guo, Xiaoquan | Li, Lin | Cao, Huabin | Latigo, Vincent | Liu, Ping
Dichlorvos is a common crop insecticide widely used by people which causes extensive and serious environmental pollution. However, it has been shown that organophosphorus poisoning causes energy metabolism and neural disorders. The overall purpose of this study was to investigate the damage to brain tissue and the changes in AMPK signaling pathway-related gene expression after dichlorvos poisoning in chickens. White-feathered broiler chickens, as the research subjects of this experiment, were divided into three groups: control group, low-dose group (77.5% dichlorvos at 1.13 mg/kg dose) and high-dose group (77.5% dichlorvos at 10.2 mg/kg dose). Clinical symptoms were observed after modeling, and an integrative analysis was conducted using HE staining microscopy, immune-histochemical microscopy, electron microscopy and PCR arrays. The results showed that the high-dose group had more obvious dyspnea, salivation, convulsion and other neurological phenomena. Pathological sections showed that nuclear disintegration of neurons was most obvious in the low-dose group, and apoptosis of brain cells was most obvious in the high-dose group, and the mitochondrial structure was destroyed in the two poisoned group, i.e. low-dose group and high-dose group. PCR arrays showed that AMPK signaling pathway was inhibited and the expressions of genes involved in energy metabolism (ACACA and PRKAA1) were significantly changed. Furthermore, genes associated with protein synthesis (EIF4EBP1) were significantly upregulated. FASN and HMGCR expressions were significantly increased. There were significant changes in the expressions of cell cycle-related genes (STK11, TP53 and FOXO3). Organophosphate poisoning can cause a lot of nuclear disintegration of brain neurons, increases cell apoptosis, disrupts the energy metabolism of mitochondrial structure, and inhibits the AMPK signaling pathway. These results provide a certain idea and basis for studying the mechanism of AMPK signaling after organophosphorus poisoning and provide a research basis for the prevention and treatment of organophosphorus poisoning.
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