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Higuera M, Vargas-Accarino E, Torrens M, Bermúdez-Ramos M, Soriano-Varela A, Salcedo MT, Mínguez B. Impact of zinc on hepatocellular carcinoma cell behavior and metallothionein expression: Insights from preclinical models. Biomed Pharmacother 2025; 185:117918. [PMID: 40048869 DOI: 10.1016/j.biopha.2025.117918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/10/2025] [Accepted: 02/14/2025] [Indexed: 03/23/2025] Open
Abstract
BACKGROUND Zinc (Zn) is an essential trace element involved in a wide variety of cellular processes and is vital for optimal liver function. Our objective was to elucidate the potential therapeutic role of Zn in hepatocellular carcinoma (HCC), the third leading cause of cancer-related death and the first cause of death in patients with cirrhosis. METHODS The impact of Zn supplementation on proliferation, invasion, migration, cell cycle, and apoptosis was conducted on four HCC cell lines as well as in a xenograft mouse model of HCC from which tumor gene expression profiles were also analyzed. Gene deregulation and protein expression were validated in human HCC tissues. Finally, Zn and MT1 (Metallothionein 1) levels were quantified in plasma from patients with HCC. RESULTS Zn supplementation significantly modulated proliferation, invasion, and migration in HCC cell lines and induced apoptosis in a dose-dependent manner. Although Zn did not exhibit a significant increase in survival, Zn supplementation significantly altered the expression of MT genes. Specifically, MT1G and MT1H expression were notably suppressed in HCC tissues from mice and these results were validated in human HCC samples. Overall, gene and protein MTs expression was significantly lower in HCC areas compared to adjacent liver tissue and plasma Zn levels exhibited substantial variation across different stages of the liver disease. CONCLUSION Zn supplementation influences key cellular behaviors in a dose-dependent manner and upregulates the expression of MT family genes, which may have tumor-suppressive properties, in vitro an in vivo models. Future research should investigate the prognostic implications of Zn supplementation as part of a comprehensive therapeutic strategy for HCC patients.
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Affiliation(s)
- Mónica Higuera
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| | - Elena Vargas-Accarino
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - María Torrens
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Liver Unit, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| | - María Bermúdez-Ramos
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Agnès Soriano-Varela
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Liver Unit, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| | - María Teresa Salcedo
- Pathology Department, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Instituto de salud Carlos III, Madrid, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus de la UAB, Plaça Cívica, Bellaterra 08193, Spain.
| | - Beatriz Mínguez
- Liver Cancer Research Group, Liver Diseases, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Hospital Universitario Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus de la UAB, Plaça Cívica, Bellaterra 08193, Spain.
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Ferdigg A, Hopp AK, Wolf G, Superti-Furga G. Membrane transporters modulating the toxicity of arsenic, cadmium, and mercury in human cells. Life Sci Alliance 2025; 8:e202402866. [PMID: 39578074 PMCID: PMC11584324 DOI: 10.26508/lsa.202402866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
Non-essential metals are extremely toxic to living organisms, posing significant health risks, particularly in developing nations where they are a major contributor to illness and death. Although their toxicity is widely acknowledged, the mechanisms by which they are regulated within human cells remain incompletely understood. Specifically, the role of membrane transporters in mediating heavy metal toxicity is not well comprehended. Our study demonstrates how specific transporters can modulate the toxicity of cadmium, mercury, and the metalloid arsenic in human cells. Using CRISPR/Cas9 loss-of-function screens, we found that the multidrug resistance protein MRP1/ABCC1 provided protection against toxicity induced by arsenic and mercury. In addition, we found that SLC39A14 and SLC30A1 increased cellular sensitivity to cadmium. Using a reporter cell line to monitor cellular metal accumulation and performing a cDNA gain-of-function screen, we were able to clarify the function of SLC30A1 in controlling cadmium toxicity through the modulation of intracellular zinc levels. This transporter-wide approach provides new insights into the complex roles of membrane transporters in influencing the toxicity of arsenic, cadmium, and mercury in human cell lines.
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Affiliation(s)
- Andrè Ferdigg
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Ann-Katrin Hopp
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Gernot Wolf
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Giulio Superti-Furga
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Hamzaoui A, Feki A, Eleroui M, Boujhoud Z, Kallel R, Magné C, Deschamps N, Nasri A, Pujo JM, Kallel H, Ben Amara I. Protective effects of polysaccharide extracted from green alga Chaetomorpha linum against zinc and copper-induced testicular toxicity in male mice. Toxicol Mech Methods 2024; 34:897-907. [PMID: 38918930 DOI: 10.1080/15376516.2024.2361070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 06/27/2024]
Abstract
This study aimed to investigate the effects of copper (CuSO4) and zinc (ZnSO4) overload on male reproductive toxicity and the potential of a polysaccharide extracted from green alga Chaetomorpha linum (PS) in mitigating their toxicities. Adult male mice strain of 25 ± 2 g of weight was subdivided into eight groups. Group 1 served as control; group 2 received PS (200 mg/kg), and groups 3 and 4 received intraperitoneally zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), respectively. Group 5 received both zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), group 6 received zinc (60 mg/kg b.w) associated with PS (200 mg/kg), group 7 received copper (33 mg/kg b.w) associated with PS (200 mg/kg), and group 8 received zinc (60 mg/kg b.w) and copper (33 mg/kg b.w) associated with PS (200 mg/kg). Results suggested that ZnSO4 and CuSO4 significantly decreased the functional sperm parameters. Furthermore, extended exposure to these elements increased oxidative stress biomarkers, including malondialdehyde (MDA) as a measure of lipid peroxidation and advanced oxidation protein products (AOPP) indicating protein oxidative damage. This process also reduces the activity of antioxidant enzymes such as glutathione (GSH) and glutathione peroxidase (GPx), which neutralize and catalyze free radicals. Histopathological changes in mice testis were also studied. However, the co-treatments with PS significantly reduced these effects and promoted the reproductive parameters in male mice. In conclusion, PS exhibited protective effects against zinc and copper-induced reproductive toxicity, making it a potential adjuvant treatment for testicular toxicity.
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Affiliation(s)
- Asma Hamzaoui
- Laboratory of Medicinal and Environment Chemistry, Higher Institute of Biotechnology, University of Sfax, Sfax, Tunisia
| | - Amal Feki
- Laboratory of Medicinal and Environment Chemistry, Higher Institute of Biotechnology, University of Sfax, Sfax, Tunisia
| | - Malek Eleroui
- Laboratory of Medicinal and Environment Chemistry, Higher Institute of Biotechnology, University of Sfax, Sfax, Tunisia
| | - Zakaria Boujhoud
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University, Settat, Morocco
| | - Rim Kallel
- Laboratory of Anatomopathology, CHU Habib Bourguiba, University of Sfax, Sfax, Tunisia
| | - Christian Magné
- Laboratory of Géoarchitecture-Torritoires, Urbanisation, Biodiversité, Environnement, UFR Sciences & Techniques, University of Brest, Cedex, France
| | - Nathalie Deschamps
- Neurology Department, Cayenne General Hospital, Cayenne, French Guiana
- Clinical Investigation Center CIC INSERM 142, Cayenne General Hospital Andrée Rosemon, Guiana University, Cayenne, French Guiana
| | - Amina Nasri
- Neurology Department, Cayenne General Hospital, Cayenne, French Guiana
- Clinical Investigation Center CIC INSERM 142, Cayenne General Hospital Andrée Rosemon, Guiana University, Cayenne, French Guiana
| | - Jean Marc Pujo
- Emergency Department, Cayenne General Hospital, Cayenne, French Guiana
| | - Hatem Kallel
- Tropical Biome and Immunopathology CNRS UMR-9017, University of French Guiana, Cayenne, French Guiana
- Intensive Care Unit, Cayenne General Hospital, Cayenne, French Guiana
| | - Ibtissem Ben Amara
- Laboratory of Medicinal and Environment Chemistry, Higher Institute of Biotechnology, University of Sfax, Sfax, Tunisia
- Clinical Investigation Center CIC INSERM 142, Cayenne General Hospital Andrée Rosemon, Guiana University, Cayenne, French Guiana
- Tropical Biome and Immunopathology CNRS UMR-9017, University of French Guiana, Cayenne, French Guiana
- Intensive Care Unit, Cayenne General Hospital, Cayenne, French Guiana
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Zou F, Wu MMH, Tan Z, Lu G, Kwok KWH, Leng Z. Ecotoxicological risk of asphalt pavements to aquatic animals associated with pollutant leaching. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 944:173985. [PMID: 38876354 DOI: 10.1016/j.scitotenv.2024.173985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Contaminants such as heavy metals and polycyclic aromatic hydrocarbons (PAHs) can be released from asphalt pavement and transported through stormwater runoff to nearby water bodies, leading to water pollution and potential harm to living aquatic animals. This study characterizes the heavy metal and PAH leaching from various asphalt paving materials and their potential ecotoxicological effects on zebrafish Danio rerio. Artificial runoffs were prepared in the laboratory concerning the effects of water, temperature, and traffic. The concentrations of heavy metals and PAHs in the leachates were quantified, while the toxicity assessment encompassed mortality, metal stress, PAH toxicity, inflammation, carcinogenicity, and oxidative damage. Gene expressions of related proteins or transcription factors were assessed, including metallothionines, aryl hydrocarbon receptors, interleukin-1β, interleukin-10, nuclear factor-κB, tumor necrosis factor-α, tumor suppressor p53, heat shock protein 70, and reactive oxygen species (ROS). The findings demonstrate that leachates from asphalt pavements containing waste bottom ash, crumb rubber, or specific chemicals could induce notable stress and inflammation responses in zebrafish. In addition, potential carcinogenic effects and the elevation of ROS were identified within certain treatment groups. This study represents the first attempt to assess the ecotoxicity of pavement leachates employing a live fish model, thereby improving the current understanding of the environmental impact of asphalt pavements.
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Affiliation(s)
- Fuliao Zou
- Department of Civil and Environmental Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
| | - Margaret M H Wu
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
| | - Zhifei Tan
- Department of Civil and Environmental Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
| | - Guoyang Lu
- Department of Architecture and Civil Engineering, City University of Hong Kong, Kowloon Tong, Kowloon, Hong Kong
| | - Kevin W H Kwok
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong; Research Institute for Future Food, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
| | - Zhen Leng
- Department of Civil and Environmental Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong; Research Centre for Resources Engineering towards Carbon Neutrality, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
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Van Buren E, Azzara D, Rangel-Moreno J, Garcia-Hernandez MDLL, Murphy SP, Cohen ED, Lewis E, Lin X, Park HR. Single-cell RNA sequencing reveals placental response under environmental stress. Nat Commun 2024; 15:6549. [PMID: 39095385 PMCID: PMC11297347 DOI: 10.1038/s41467-024-50914-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 07/25/2024] [Indexed: 08/04/2024] Open
Abstract
The placenta is crucial for fetal development, yet the impact of environmental stressors such as arsenic exposure remains poorly understood. We apply single-cell RNA sequencing to analyze the response of the mouse placenta to arsenic, revealing cell-type-specific gene expression, function, and pathological changes. Notably, the Prap1 gene, which encodes proline-rich acidic protein 1 (PRAP1), is significantly upregulated in 26 placental cell types including various trophoblast cells. Our study shows a female-biased increase in PRAP1 in response to arsenic and localizes it in the placenta. In vitro and ex vivo experiments confirm PRAP1 upregulation following arsenic treatment and demonstrate that recombinant PRAP1 protein reduces arsenic-induced cytotoxicity and downregulates cell cycle pathways in human trophoblast cells. Moreover, PRAP1 knockdown differentially affects cell cycle processes, proliferation, and cell death depending on the presence of arsenic. Our findings provide insights into the placental response to environmental stress, offering potential preventative and therapeutic approaches for environment-related adverse outcomes in mothers and children.
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Affiliation(s)
- Eric Van Buren
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - David Azzara
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Javier Rangel-Moreno
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester, Rochester, NY, USA
| | | | - Shawn P Murphy
- Department of Obstetrics and Gynecology, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Ethan D Cohen
- Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Ethan Lewis
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA
| | - Xihong Lin
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Statistics, Harvard University, Cambridge, MA, USA
| | - Hae-Ryung Park
- Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA.
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6
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Wang Y, Han J, Ren Q, Liu Z, Zhang X, Wu Z. The Involvement of Lactic Acid Bacteria and Their Exopolysaccharides in the Biosorption and Detoxication of Heavy Metals in the Gut. Biol Trace Elem Res 2024; 202:671-684. [PMID: 37165259 DOI: 10.1007/s12011-023-03693-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 05/01/2023] [Indexed: 05/12/2023]
Abstract
Heavy metal pollution has become one of the most important global environmental issues. The human health risk posed by heavy metals encountered through the food chain and occupational and environmental exposure is increasing, resulting in a series of serious diseases. Ingested heavy metals might disturb the function of the gut barrier and cause toxicity to organs or tissues in other sites of the body. Probiotics, including some lactic acid bacteria (LAB), can be used as an alternative strategy to detoxify heavy metals in the host body due to their safety and effectiveness. Exopolysaccharides (EPS) produced by LAB possess varied chemical structures and functional properties and take part in the adsorption of heavy metals via keeping the producing cells vigorous. The main objective of this paper was to summarize the roles of LAB and their EPS in the adsorption and detoxification of heavy metals in the gut. Accumulated evidence has demonstrated that microbial EPS play a pivotal role in heavy metal biosorption. Specifically, EPS-producing LAB have been reported to show superior absorption, tolerance, and efficient abatement of the toxicity of heavy metals in vitro and/or in vivo to non-EPS-producing species. The mechanisms underlying EPS-metal binding are mainly related to the negatively charged acidic groups and unique steric structure on the surface of EPS. However, whether the enriched heavy metals on the bacterial cell surface increase toxicity to local mammal cells or tissues in the intestine and whether they are released during excretion remain to be elucidated.
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Affiliation(s)
- Yitian Wang
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd, Shanghai, 200436, China
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Jin Han
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd, Shanghai, 200436, China
| | - Quanlu Ren
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd, Shanghai, 200436, China
| | - Zhenmin Liu
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd, Shanghai, 200436, China
| | - Xuehong Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Zhengjun Wu
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd, Shanghai, 200436, China.
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Dave A, Joshee L, Barfuss DW, Brownlee R, Surani R, Anis Ali S, Ford IV EG, Pittman EG, Caroland AV, Barkin J, Bridges CC. Proximal tubular transport of Metallothionein-Mercury complexes and protection against nephrotoxicity. Curr Res Toxicol 2023; 5:100132. [PMID: 37885470 PMCID: PMC10598501 DOI: 10.1016/j.crtox.2023.100132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/25/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
Mercury (Hg) is an important environmental toxicant to which humans are exposed on a regular basis. Mercuric ions within biological systems do not exist as free ions. Rather, they are bound to free sulfhydryl groups (thiols) on biological molecules. Metallothionein (MT) is a cysteine-rich, metal-binding protein that has been shown to bind to heavy metals and reduce their toxic effects in target cells and organs. Little is known about the effect of MT on the handing and disposition of Hg. Therefore, the current study was designed to test the hypothesis that overexpression of MT alters the corporal disposition of Hg and reduces its nephrotoxicity. Furthermore, the current study examined the transport of Hg-MT complexes in isolated proximal tubules. Rats were treated with saline or Zn followed by injection with a non-nephrotoxic (0.5 µmol kg-1), moderately nephrotoxic (1.5 µmol kg-1), or significantly nephrotoxic (2.25 µmol kg-1) dose of HgCl2 (containing radioactive Hg). Pretreatment with Zn increased mRNA expression of MT and enhanced accumulation of Hg in the renal cortex of male and female rats. In addition, injection with Zn also protected animals from Hg-induced nephrotoxicity. Studies using isolated proximal tubules from rabbit kidney demonstrated that Hg-MT is taken up rapidly at the apical and basolateral membranes. The current findings suggest that at least part of this uptake occurs through an endocytic process. This study is the first to examine the uptake of Hg-MT complexes in isolated proximal tubules. Overall, the findings of this study suggest that supplementation with Zn may be a viable strategy for reducing the risk of Hg intoxication in at-risk populations.
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Affiliation(s)
- Aditi Dave
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Lucy Joshee
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Delon W. Barfuss
- Department of Biology, Georgia State University, Atlanta, GA, USA
| | - Ryan Brownlee
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Roha Surani
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Sahar Anis Ali
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Earl G. Ford IV
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | - Elizabeth G. Pittman
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
| | | | - Jennifer Barkin
- Department of Community Medicine, Mercer University School of Medicine, Macon, GA, USA
| | - Christy C. Bridges
- Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA, USA
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Vargas DA, Gregory DJ, Koren RN, Zilberstein D, Belew AT, El-Sayed NM, Gómez MA. Macrophage metallothioneins participate in the antileishmanial activity of antimonials. FRONTIERS IN PARASITOLOGY 2023; 2:1242727. [PMID: 38239429 PMCID: PMC10795579 DOI: 10.3389/fpara.2023.1242727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/12/2023] [Indexed: 01/22/2024]
Abstract
Host cell functions that participate in the pharmacokinetics and pharmacodynamics (PK/PD) of drugs against intracellular pathogen infections are critical for drug efficacy. In this study, we investigated whether macrophage mechanisms of xenobiotic detoxification contribute to the elimination of intracellular Leishmania upon exposure to pentavalent antimonials (SbV). Primary macrophages from patients with cutaneous leishmaniasis (CL) (n=6) were exposed ex vivo to L. V. panamensis infection and SbV, and transcriptomes were generated. Seven metallothionein (MT) genes, potent scavengers of heavy metals and central elements of the mammalian cell machinery for xenobiotic detoxification, were within the top 20 up-regulated genes. To functionally validate the participation of MTs in drug-mediated killing of intracellular Leishmania, tandem knockdown (KD) of MT2-A and MT1-E, MT1-F, and MT1-X was performed using a pan-MT shRNA approach in THP-1 cells. Parasite survival was unaffected in tandem-KD cells, as a consequence of strong transcriptional upregulation of MTs by infection and SbV, overcoming the KD effect. Gene silencing of the metal transcription factor-1 (MTF-1) abrogated expression of MT1 and MT2-A genes, but not ZnT-1. Upon exposure to SbV, intracellular survival of Leishmania in MTF-1KD cells was significantly enhanced. Results from this study highlight the participation of macrophage MTs in Sb-dependent parasite killing.
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Affiliation(s)
- Deninson Alejandro Vargas
- Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia
- Universidad Icesi, Cali, Colombia
| | - David J. Gregory
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Roni Nitzan Koren
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Dan Zilberstein
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Ashton Trey Belew
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, United States
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, United States
| | - Najib M. El-Sayed
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, United States
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, United States
| | - María Adelaida Gómez
- Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia
- Universidad Icesi, Cali, Colombia
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Kozlosky D, Lu A, Doherty C, Buckley B, Goedken MJ, Miller RK, Barrett ES, Aleksunes LM. Cadmium reduces growth of male fetuses by impairing development of the placental vasculature and reducing expression of nutrient transporters. Toxicol Appl Pharmacol 2023; 475:116636. [PMID: 37487938 PMCID: PMC10528997 DOI: 10.1016/j.taap.2023.116636] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/12/2023] [Accepted: 07/21/2023] [Indexed: 07/26/2023]
Abstract
In utero exposure to the toxic metal cadmium (Cd) alters fetoplacental growth in rodents and has been inversely associated with birth weight and infant size in some birth cohorts. Moreover, studies suggest that Cd may have differential effects on growth and development according to offspring sex. The purpose of the current study was to evaluate changes in male and female fetoplacental development following a single injection of saline (5 ml/kg ip) or cadmium chloride (CdCl2, 2.5, 5 mg/kg, ip) on gestational day (GD) 9. By GD18, no changes in fetal or placental weights were observed after treatment with 2.5 mg/kg CdCl2. By comparison, the weight and length of male fetuses and their placentas were reduced following treatment with 5 mg/kg CdCl2 whereas no change was observed in females. In addition, the area of maternal and fetal blood vessels as well as the expression of the glucose transporters, Glut1 and Glut3, and the endothelial marker, CD34, were reduced in the placentas of CdCl2-treated male offspring compared to females. Interestingly, the placentas of females accumulated 80% more Cd than males after CdCl2 (5 mg/kg) administration. Female placentas also had higher concentrations of zinc and the zinc transporter Znt1 compared to males which may explain the limited changes in fetal growth observed following CdCl2 treatment. Taken together, disruption of vasculature development and reduced expression of glucose transporters in the placenta provide potential mechanisms underlying reduced fetal growth in male offspring despite the greater accumulation of Cd in female placentas.
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Affiliation(s)
- Danielle Kozlosky
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA
| | - Alexander Lu
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA
| | - Cathleen Doherty
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA..
| | - Brian Buckley
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA..
| | - Michael J Goedken
- Research Pathology Services, Rutgers University, Piscataway, NJ 08854, USA..
| | - Richard K Miller
- School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA..
| | - Emily S Barrett
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.; School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642, USA.; Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ 08854, USA..
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA.; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA..
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10
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Silva SB, Ruiz TFR, Dos Santos FCA, Taboga SR, Vilamaior PSL. Impacts of heavy metal exposure on the prostate of murine models: Mechanisms of toxicity. Reprod Toxicol 2023; 120:108448. [PMID: 37490985 DOI: 10.1016/j.reprotox.2023.108448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/12/2023] [Accepted: 07/21/2023] [Indexed: 07/27/2023]
Abstract
Heavy metals are elements found into the environment mainly due to anthropogenic activities. Naturally occurring and higher released doses cause disorders in the prostate, which depends on appropriate hormonal regulation, and exposure to heavy metals may impair prostate homeostasis. The current work highlighted the main mechanisms of toxicity of different environmental heavy metal contaminants, such as aluminum, arsenic, cadmium, chromium, lead, mercury, and nickel, and their impacts found in the prostate morphophysiology of murine models. The repercussions triggered by heavy metals on the prostate include hormonal imbalance and oxidative damage, leading to morphological alterations, which can vary according to the chemical properties of each element, exposure time and concentration, and age. The information of altered biological pathways and its impacts on the prostate of exposed murines are related to human outcomes being useful in the real context of human exposure.
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Affiliation(s)
- Stella Bicalho Silva
- Department of Biological Sciences, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil
| | - Thalles Fernando Rocha Ruiz
- Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Fernanda Cristina Alcantara Dos Santos
- Department of Histology, Embryology and Cell Biology, Laboratory of Microscopy Applied to Reproduction, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Sebastião Roberto Taboga
- Department of Biological Sciences, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil
| | - Patricia Simone Leite Vilamaior
- Department of Biological Sciences, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
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11
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Li D, Gao Z, Li Q, Liu X, Liu H. Cuproptosis-a potential target for the treatment of osteoporosis. Front Endocrinol (Lausanne) 2023; 14:1135181. [PMID: 37214253 PMCID: PMC10196240 DOI: 10.3389/fendo.2023.1135181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/10/2023] [Indexed: 05/24/2023] Open
Abstract
Osteoporosis is an age-related disease of bone metabolism marked by reduced bone mineral density and impaired bone strength. The disease causes the bones to weaken and break more easily. Osteoclasts participate in bone resorption more than osteoblasts participate in bone formation, disrupting bone homeostasis and leading to osteoporosis. Currently, drug therapy for osteoporosis includes calcium supplements, vitamin D, parathyroid hormone, estrogen, calcitonin, bisphosphates, and other medications. These medications are effective in treating osteoporosis but have side effects. Copper is a necessary trace element in the human body, and studies have shown that it links to the development of osteoporosis. Cuproptosis is a recently proposed new type of cell death. Copper-induced cell death regulates by lipoylated components mediated via mitochondrial ferredoxin 1; that is, copper binds directly to the lipoylated components of the tricarboxylic acid cycle, resulting in lipoylated protein accumulation and subsequent loss of iron-sulfur cluster proteins, leading to proteotoxic stress and eventually cell death. Therapeutic options for tumor disorders include targeting the intracellular toxicity of copper and cuproptosis. The hypoxic environment in bone and the metabolic pathway of glycolysis to provide energy in cells can inhibit cuproptosis, which may promote the survival and proliferation of various cells, including osteoblasts, osteoclasts, effector T cells, and macrophages, thereby mediating the osteoporosis process. As a result, our group tried to explain the relationship between the role of cuproptosis and its essential regulatory genes, as well as the pathological mechanism of osteoporosis and its effects on various cells. This study intends to investigate a new treatment approach for the clinical treatment of osteoporosis that is beneficial to the treatment of osteoporosis.
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Affiliation(s)
- Dinglin Li
- Department of Integrated Traditional Chinese and Western Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhonghua Gao
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Li
- Department of Integrated Traditional Chinese and Western Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangjie Liu
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Liu
- Department of Integrated Traditional Chinese and Western Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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12
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Liu Y, Miao J. An Emerging Role of Defective Copper Metabolism in Heart Disease. Nutrients 2022; 14:nu14030700. [PMID: 35277059 PMCID: PMC8838622 DOI: 10.3390/nu14030700] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 01/02/2023] Open
Abstract
Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.
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Affiliation(s)
- Yun Liu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China;
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Ji Miao
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Correspondence:
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13
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Yoshioka H, Tominaga S, Suzui M, Shinohara Y, Maeda T, Miura N. Involvement of <i>Npas2</i> and <i>Per2</i> modifications in zinc-induced acute diurnal toxicity in mice. J Toxicol Sci 2022; 47:547-553. [DOI: 10.2131/jts.47.547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Affiliation(s)
| | - Sarah Tominaga
- Department of Neurotoxicology, Nagoya City University Graduate School of Medical Sciences
| | - Masumi Suzui
- Department of Neurotoxicology, Nagoya City University Graduate School of Medical Sciences
| | | | - Tohru Maeda
- Department of Pharmacy, Kinjo Gakuin University
| | - Nobuhiko Miura
- Department of Health Science, Yokohoma University of Pharmacy
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14
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Tian J, Li Y, Fu H, Ren L, He Y, Zhai S, Yang B, Li Q, Liu N, Liu S. Physiological role of CYP17A1-like in cadmium detoxification and its transcriptional regulation in the Pacific oyster, Crassostrea gigas. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 796:149039. [PMID: 34328900 DOI: 10.1016/j.scitotenv.2021.149039] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/09/2021] [Accepted: 07/10/2021] [Indexed: 06/13/2023]
Abstract
Cadmium (Cd) is one of the most harmful heavy metals due to its persistence and bioaccumulation through the food chains, posing health risks to human. Oysters can bioaccumulate and tolerate high concentrations of Cd, providing a great model for studying molecular mechanism of Cd detoxification. In a previous study, we identified two CYP genes, CYP17A1-like and CYP2C50, that were potentially involved in Cd detoxification in the Pacific oyster, Crassostrea gigas. In this work, we performed further investigations on their physiological roles in Cd detoxification through RNA interference (RNAi). After injection of double-stranded RNA (dsRNA) into the adductor muscle of oysters followed by Cd exposure for 7 days, we observed that the expressions of CYP17A1-like and CYP2C50 in interference group were significantly suppressed on day 3 compared with control group injected with PBS. Moreover, the mortality rate and Cd content in the CYP17A1-like dsRNA interference group (dsCYP17A1-like) was significantly higher than those of the control on day 3. Furthermore, the activities of antioxidant enzymes, including SOD, CAT, GST, were significantly increased in dsCYP17A1-like group, while were not changed in dsCYP2C50 group. More significant tissue damage was observed in gill and digestive gland of oysters in RNAi group than control group, demonstrating the critical role of CYP17A1-like in Cd detoxification. Dual luciferase reporter assay revealed three core regulatory elements of MTF-1 within promoter region of CYP17A1-like, suggesting the potential transcriptional regulation of CYP17A1-like by MTF-1 in oysters. This work demonstrated a critical role of CYP17A1-like in Cd detoxification in C. gigas and provided a new perspective toward unravelling detoxification mechanisms of bivalves under heavy metal stress.
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Affiliation(s)
- Jing Tian
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China
| | - Yongjing Li
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China
| | - Huiru Fu
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China
| | - Liting Ren
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China
| | - Yameng He
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China
| | - Shangyu Zhai
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China
| | - Ben Yang
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China
| | - Qi Li
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
| | - Nannan Liu
- Department of Entomology and Plant Pathology, Auburn University, Auburn, AL 36849, USA
| | - Shikai Liu
- Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
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15
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Yang H, Xing R, Liu S, Yu H, Li P. Role of Fucoxanthin towards Cadmium-induced renal impairment with the antioxidant and anti-lipid peroxide activities. Bioengineered 2021; 12:7235-7247. [PMID: 34569908 PMCID: PMC8806766 DOI: 10.1080/21655979.2021.1973875] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Kidney damages caused by cadmium are considered to be one of the most dangerous consequences for the human body. This study aimed to investigate the protective effects of fucoxanthin supplementation on mice models subjected to cadmium-induced kidney damage. The mice treated with cadmium chloride (CdCl2) were observed to have significantly reduced the cross-section area of glomeruli. Cadmium exposure has also caused the damage of the structural integrity of mitochondria and increased blood urea nitrogen (BUN), kidney injury molecule 1 (KIM1), and neutrophil gelatinase associated lipocalin (NGAL) levels. Peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) levels in cadmium-exposed mice were markedly declined. Caspase3, caspase8, and caspase9 gene expressions in association with apoptosis were dramatically elevated in renal tissues. The CdCl2 treated mice were orally administered with 50 mg/kg Shenfukang, 10 mg/kg, 25 mg/kg, and 50 mg/kg fucoxanthin for 14 days. The results revealed that high doses of fucoxanthin administration significantly decreased BUN, KIM1, NGAL levels, increasing POD, SOD, CAT, and ascorbate APX levels. Fucoxanthin administration also promoted recovery of the renal functions, micro-structural organization, and ultra-structural organization in the renal cells. In summary, the ameliorative effects of fucoxanthin supplementation against cadmium-induced kidney damage were mediated via inhibiting oxidative stress and apoptosis, promoting the recovery of structural integrity of mitochondria.
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Affiliation(s)
- Haoyue Yang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Ronge Xing
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Song Liu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Huahua Yu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
| | - Pengcheng Li
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China
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16
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Chen P, Chen B, He M, Hu B. Combined effects of different sizes of ZnO and ZIF-8 nanoparticles co-exposure with Cd 2+ on HepG2 cells. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 786:147402. [PMID: 33975099 DOI: 10.1016/j.scitotenv.2021.147402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/21/2021] [Accepted: 04/23/2021] [Indexed: 06/12/2023]
Abstract
Heavy metal and nanoparticles (NPs) emitted in the environment have attracted worldwide attention. But the combined effect of NPs and heavy metals is still unclear. In this study, the combined effect of zinc-based NPs and Cd2+ on HepG2 cells was investigated by combining biological indicator detection methods with time-resolved inductively coupled plasma mass spectrometry (TRA-ICP-MS) single cell analysis, and the combined effect of Zn2+ and Cd2+ was also investigated for a comparison. High-dose of ZnO or ZIF-8 NPs co-exposure with Cd2+ would reduce the cell viability while low-dose of ZnO or ZIF-8 NPs co-exposure with Cd2+showed antagonism and the particle size has no remarkable effect on the combined toxicity. In the antagonism, Zn2+ would increase cellular Zn amount through increasing the expression of ZIP8 and ZIP14 transporters to manage the ROS generation, but the zinc-based NPs would decrease expression of these transporters to decrease cellular Cd amount to help maintain the cell viability. Thus, we should hold a dialectical thinking about the pollution of NPs emissions in the environment.
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Affiliation(s)
- Pengyu Chen
- Department of Chemistry, Wuhan University, Wuhan 430072, China
| | - Beibei Chen
- Department of Chemistry, Wuhan University, Wuhan 430072, China
| | - Man He
- Department of Chemistry, Wuhan University, Wuhan 430072, China
| | - Bin Hu
- Department of Chemistry, Wuhan University, Wuhan 430072, China.
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17
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Maung MT, Carlson A, Olea-Flores M, Elkhadragy L, Schachtschneider KM, Navarro-Tito N, Padilla-Benavides T. The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB J 2021; 35:e21810. [PMID: 34390520 DOI: 10.1096/fj.202100273rr] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 06/23/2021] [Accepted: 07/07/2021] [Indexed: 12/16/2022]
Abstract
Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.
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Affiliation(s)
- May T Maung
- Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, USA
| | - Alyssa Carlson
- Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, USA
| | - Monserrat Olea-Flores
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Guerrero, Mexico
| | - Lobna Elkhadragy
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Kyle M Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA.,Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.,National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Napoleon Navarro-Tito
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Guerrero, Mexico
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18
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Elgamouz A, Shehadi I, Assal A, Bihi A, Kawde AN. Effect of AgNPs internal solution on the sensing of mercury(II) by an ion-selective electrode based on a thiol coordination from cysteine as ionophore. J Electroanal Chem (Lausanne) 2021. [DOI: 10.1016/j.jelechem.2021.115443] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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19
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Wen X, Kozlosky D, Zhang R, Doherty C, Buckley B, Barrett E, Aleksunes LM. BCRP/ ABCG2 Transporter Regulates Accumulation of Cadmium in Kidney Cells: Role of the Q141K Variant in Modulating Nephrotoxicity. Drug Metab Dispos 2021; 49:629-637. [PMID: 34074729 PMCID: PMC8382159 DOI: 10.1124/dmd.121.000446] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/03/2021] [Indexed: 12/18/2022] Open
Abstract
Exposure to the environmental pollutant cadmium is ubiquitous, as it is present in cigarette smoke and the food supply. Over time, cadmium enters and accumulates in the kidneys, where it causes tubular injury. The breast cancer resistance protein (BCRP, ATP-Binding Cassette G2 ABCG2) is an efflux transporter that mediates the urinary secretion of pharmaceuticals and toxins. The ABCG2 genetic variant Q141K exhibits altered membrane trafficking that results in reduced efflux of BCRP substrates. Here, we sought to 1) evaluate the in vitro and in vivo ability of BCRP to transport cadmium and protect kidney cells from toxicity and 2) determine whether this protection is impaired by the Q141K variant. Cadmium concentrations, cellular stress, and toxicity were quantified in human embryonic kidney 293 cells expressing an empty vector (EV), BCRP wild-type (WT), or variant (Q141K) gene. Treatment with CdCl2 resulted in greater accumulation of cadmium and apoptosis in EV cells relative to WT cells. Exposure to CdCl2 induced expression of stress-related genes and proteins including MT-1A/MT-2A, NAD(P)H quinone dehydrogenase 1, and heme oxygenase-1 to a higher extent in EV cells compared with WT cells. Notably, the Q141K variant protected against CdCl2-induced activation of stress genes and cytotoxicity, but this protection was to a lesser magnitude than observed with WT BCRP. Lastly, concentrations of cadmium in the kidneys of Bcrp knockout mice were 40% higher than in WT mice, confirming that cadmium is an in vivo substrate of BCRP. In conclusion, BCRP prevents the accumulation of cadmium and protects against toxicity, a response that is impaired by the Q141K variant. SIGNIFICANCE STATEMENT: The breast cancer resistance protein transporter lowers cellular accumulation of the toxic heavy metal cadmium. This protective function is partially attenuated by the Q141K genetic variant in the ABCG2 gene.
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Affiliation(s)
- Xia Wen
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Danielle Kozlosky
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Ranran Zhang
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Cathleen Doherty
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Brian Buckley
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Emily Barrett
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
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20
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Capriello T, Félix LM, Monteiro SM, Santos D, Cofone R, Ferrandino I. Exposure to aluminium causes behavioural alterations and oxidative stress in the brain of adult zebrafish. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 85:103636. [PMID: 33741517 DOI: 10.1016/j.etap.2021.103636] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 06/12/2023]
Abstract
Aluminium (Al) water pollution is an increasing environmental problem. Accordingly, this study aimed to find out more about its toxic effects on aquatic organisms. Adult zebrafish were exposed to 11 mg/L of Al and the behavioural responses and its correlation with brain oxidative stress, antioxidant-defences, changes in metabolism and neurotransmission were assessed at 10, 15 and 20 days of exposure. The behavioural and locomotory responses, suggest an increase in the anxiety state, especially observed in animals exposed to Al for 15 days. The reactive oxygen species increased in a time-dependent trend, while the oxidative damage varied over exposure time. The activity of antioxidant enzymes, as superoxide dismutase, glutathione peroxidase and glutathione S-transferases, and the metallothioneins levels increased after short-term exposures and tended to decrease or stabilize at longer times. The results contribute to understand the toxic mechanisms activated by Al highlighting correlations like behavioural disorders and oxidative state.
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Affiliation(s)
- Teresa Capriello
- Department of Biology, University of Naples "Federico II", Naples, Italy
| | - Luis M Félix
- Laboratory Animal Science (LAS), Institute for Research and Innovation in Health (i3S), University of Porto (UP), Porto, Portugal; Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Sandra M Monteiro
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Dércia Santos
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Rita Cofone
- Department of Biology, University of Naples "Federico II", Naples, Italy
| | - Ida Ferrandino
- Department of Biology, University of Naples "Federico II", Naples, Italy; BAT Center - Interuniversity Center for Studies on Bioinspired Agro-Environmental Technology, Portici, NA, Italy.
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21
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Capriello T, Monteiro SM, Félix LM, Donizetti A, Aliperti V, Ferrandino I. Apoptosis, oxidative stress and genotoxicity in developing zebrafish after aluminium exposure. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2021; 236:105872. [PMID: 34052719 DOI: 10.1016/j.aquatox.2021.105872] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/08/2021] [Accepted: 05/13/2021] [Indexed: 06/12/2023]
Abstract
Aluminium is a non-essential metal and potentially toxic to organisms whose environmental concentration increases due to pollution. In our previous studies, the behavioral changes induced by aluminium were already shown on zebrafish, a model organism widely used for ecotoxicology screening. To examine in depth the knowledge about the toxicity mechanism induced by this metal, zebrafish embryos, at 6 hpf, have been exposed to 50, 100 and 200 µM of AlCl3 for 72 h. Phenotypic alterations, apoptosis and oxidative stress responses have been assessed by evaluations of antioxidant defence and changes in metabolism at the end of treatment. The mRNA expression level of c-fos, appa and appb as marker genes of neural development and function were analyzed by qPCR for the highest used concentration. The data showed that aluminium significantly affected the development of zebrafish inducing morphological alterations and cell death. The oxidative state of larvae was altered, although the formation of reactive oxygen species and the levels of metallothioneins, and the activity of some antioxidant enzymes, decreased at the maximum concentration tested. In addition, at this concentration, the expression of the evaluated genes increased. The comprehensive information obtained gives a realistic snapshot of the aluminium toxicity and provides new information on the mechanism of action of this metal.
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Affiliation(s)
- Teresa Capriello
- Department of Biology, University of Naples "Federico II", Naples, Italy.
| | - Sandra M Monteiro
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB); Institute for Innovation, Capacity Building and Sustainability of Agri-food Production (Inov4Agro), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.
| | - Luis M Félix
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB); Institute for Innovation, Capacity Building and Sustainability of Agri-food Production (Inov4Agro), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Laboratory Animal Science (LAS), Institute for Research and Innovation in Health (i3S), University of Porto (UP), Porto, Portugal.
| | - Aldo Donizetti
- Department of Biology, University of Naples "Federico II", Naples, Italy.
| | - Vincenza Aliperti
- Department of Biology, University of Naples "Federico II", Naples, Italy.
| | - Ida Ferrandino
- Department of Biology, University of Naples "Federico II", Naples, Italy; BAT Center - Interuniversity Center for Studies on Bioinspired Agro-Environmental Technology, Portici, Italy.
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El Kholy S, Giesy JP, Al Naggar Y. Consequences of a short-term exposure to a sub lethal concentration of CdO nanoparticles on key life history traits in the fruit fly (Drosophila melanogaster). JOURNAL OF HAZARDOUS MATERIALS 2021; 410:124671. [PMID: 33349477 DOI: 10.1016/j.jhazmat.2020.124671] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/27/2020] [Accepted: 11/23/2020] [Indexed: 06/12/2023]
Abstract
Nanoparticles of cadmium oxide (CdO NPs) are among the most common industrial metal oxide nanoparticles. Early adulthood (P1) fruit flies (D. melanogaster) were exposed for 7 days to a sub lethal concentration (0.03 mg CdO NPs/mL, which was 20% of the LC50), spiked into food media to test whether short episodes of CdO NPs exposures early in adult life have long-lasting effects on life history traits such as fecundity well beyond exposure times. All studied life history traits, as well as climbing behavior were adversely affected by exposure to CdO NPs. A blistered wing phenotype was also observed in the non-exposed progeny (F1) of adult flies (P1) and their fecundity was significantly decreased (-50%) compared to the fecundity of non-exposed (control) F1 flies. Expressions of antioxidant enzymes encoding genes; catalase and superoxide dismutase (SOD2) were significantly up regulated in P1 flies compared to control. Expression of metallothionein encoding genes (MTn A-D) were significantly up-regulated in both parent flies (P1) and their progeny (F1) after exposure of P1 flies to CdO NPs compared to non-exposed control flies, suggesting long-term potential effects. Taken together, these findings indicate that short-term exposure to a sub-lethal CdO NP concentration is sufficient to have long-lasting, adverse effects on fruit flies.
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Affiliation(s)
- Samar El Kholy
- Zoology Department, Faculty of Science, Tanta University, 31527 Tanta, Egypt
| | - John P Giesy
- Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B3, Canada; Department of Environmental Sciences, Baylor University, Waco, TX, USA; General Zoology, Institute for Biology, Martin Luther University Halle-Wittenberg, Hoher Weg 8, 06120 Halle (Saale), Germany
| | - Yahya Al Naggar
- Zoology Department, Faculty of Science, Tanta University, 31527 Tanta, Egypt; General Zoology, Institute for Biology, Martin Luther University Halle-Wittenberg, Hoher Weg 8, 06120 Halle (Saale), Germany.
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23
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Qi Z, Wang Q, Wang H, Tan M. Metallothionein Attenuated Arsenic-Induced Cytotoxicity: The Underlying Mechanism Reflected by Metabolomics and Lipidomics. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:5372-5380. [PMID: 33939412 DOI: 10.1021/acs.jafc.1c00724] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Arsenic ions (As3+) have been recognized as a hazard that threatens the health of humans. Metallothionein (MT) rich in cysteine may provide favorable binding sites for chelation of As3+. However, the influence of MT on As3+-induced toxicity and the underlying mechanism are poorly understood, especially at the metabolic level. Herein, the effects of MT on As3+-induced toxicity were evaluated. Cell viability analysis suggested that MT alleviated As3+-induced cytotoxicity. The metabolic response of PC12 cells to As3+ investigated by lipidomics and metabolomics indicated that the presence of As3+ disrupted phospholipids metabolism and induced cell membrane damage. Moreover, energy and amino acid metabolism were perturbed by As3+. The perturbation of As3+ on metabolism was further illustrated by the decrease of the mitochondrial membrane potential and the rise of cellular reactive oxygen species (ROS). On the contrary, MT rescued As3+-induced metabolic disorder and suppressed ROS accumulation. In addition, the binding process between As3+ and MT was characterized. The results proved that the As3+-MT complex was formed and chelated As3+-scavenged ROS, thus alleviating the toxic effects of As3+. These results revealed that MT would be a potential agent to reduce As3+-induced cytotoxicity.
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Affiliation(s)
- Zihe Qi
- Academy of Food Interdisciplinary Sciecne, School of Food Science and Technology, Dalian Polytechnic University, Qinggongyuan 1, Ganjingzi District, Dalian, 116034 Liaoning, China
- National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
| | - Qinghong Wang
- Academy of Food Interdisciplinary Sciecne, School of Food Science and Technology, Dalian Polytechnic University, Qinggongyuan 1, Ganjingzi District, Dalian, 116034 Liaoning, China
- National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
| | - Haitao Wang
- Academy of Food Interdisciplinary Sciecne, School of Food Science and Technology, Dalian Polytechnic University, Qinggongyuan 1, Ganjingzi District, Dalian, 116034 Liaoning, China
- National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
| | - Mingqian Tan
- Academy of Food Interdisciplinary Sciecne, School of Food Science and Technology, Dalian Polytechnic University, Qinggongyuan 1, Ganjingzi District, Dalian, 116034 Liaoning, China
- National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034 Liaoning, China
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Yang H, Xing R, Liu S, Li P. Effect of Fucoxanthin Administration on Thyroid Gland Injury Induced by Cadmium in Mice. Biol Trace Elem Res 2021; 199:1877-1884. [PMID: 32691210 DOI: 10.1007/s12011-020-02291-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/14/2020] [Indexed: 10/23/2022]
Abstract
The intervention effect of fucoxanthin, which is reportedly a powerful antioxidant, on cadmium-induced thyroid damage in mice was evaluated. Animals (N = 120) were divided into control group (given pure water, N = 20) and CdCl2-exposed group (given CdCl2 orally at a dose of 30 mg/kg body weight (bw)/day for 30 days, N = 100). Besides, the CdCl2-exposed group was divided into the following 5 groups (N = 20) to evaluate the intervention effect of fucoxanthin: (1) negative control group (NCG; animals were supplied with pure water); (2) positive control group (PCG; animals were supplied with 50 mg/kg bw/day thyroid tablets. Thyroid tablets are made from the thyroid glands of pigs, cattle, sheep and other food animals (the main components of T4). But because they are extracts of the thyroid glands, they may contain a small amount of T3. The specific amount of T3 is unknown.); (3) low fucoxanthin concentration group (F1; animals were supplied with 10 mg/kg bw/day fucoxanthin); (4) medium fucoxanthin concentration group (F2; animals were supplied with 25 mg/kg bw/day fucoxanthin); (5) high fucoxanthin concentration groups (F3; animals were supplied with 50 mg/kg bw/day fucoxanthin). A 14-day treatment was conducted for these animals. The levels of T4, T3, MDA, ascorbate peroxidase (APX) and catalase were measured, and the expression levels of Bax, Bcl-2, ERK1, ERK2, MEK1, eIf2α, p-eIf2α, GRP78 and GRP94 genes were determined using real-time reverse transcriptase-polymerase chain reactions (RT-PCR). In addition, tissue histopathology and ultrastructure were recorded and analysed. We found that the injection of cadmium chloride (CdCl2) decreased serum T4 and T3 levels to 27.10 ng/ml and 837.74 pg/ml, respectively. In addition, CdCl2 intoxication induced oxidative stress, structural abnormalities and apoptosis in thyroid follicles. Our results showed that the treatment of CaCl-exposed mice with 25-50 mg/kg bw/day fucoxanthin appreciably decreased oxidative stress and apoptosis induced by CdCl2 and restored the microstructural and ultrastructural organisations of the thyroid gland towards normalcy. Compared with the negative control group, fucoxanthin treatment groups showed significant increase in T4 and T3 levels (52.17 ng/ml and 1669.18 ng/ml, respectively; P < 0.05), relieved oxidative stress by decreasing malondialdehyde level and increasing catalase and APX levels and increased apoptosis inhibition through inhibiting the ERK1/2 pathway and preventing endoplasmic reticulum stress in thyroid follicular epithelial cells. Herein, our study provides evidence of the protective effects of fucoxanthin supplementation against thyroid damage and suggests therapeutic potential of this pigment in cases of Cd intoxication and hypothyroidism.
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Affiliation(s)
- Haoyue Yang
- Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, No. 1 Wenhai Road, Qingdao, 266237, China
| | - Ronge Xing
- Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, No. 1 Wenhai Road, Qingdao, 266237, China.
| | - Song Liu
- Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, No. 1 Wenhai Road, Qingdao, 266237, China
| | - Pengcheng Li
- Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, No. 1 Wenhai Road, Qingdao, 266237, China
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Kamińska I, Wosztyl A, Kowalik P, Sikora B, Wojciechowski T, Sobczak K, Minikayev R, Zajdel K, Chojnacki M, Zaleszczyk W, Łysiak K, Paszkowicz W, Szczytko J, Frontczak-Baniewicz M, Stryczniewicz W, Fronc K. Synthesis and characterization of Gd 2O 3: Er 3+, Yb 3+doped with Mg 2+, Li +ions-effect on the photoluminescence and biological applications. NANOTECHNOLOGY 2021; 32:245705. [PMID: 33690193 DOI: 10.1088/1361-6528/abed02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/09/2021] [Indexed: 06/12/2023]
Abstract
Gd2O3:1% Er3+, 18% Yb3+,x% Mg2+(x = 0; 2.5; 4; 5; 6; 8;10; 20; 25; 50) and Gd2O3:1% Er3+, 18% Yb3+, 2,5% Mg2+,y% Li+(y = 0.5-2.5) nanoparticles were synthesized by homogenous precipitation method and calcined at 900 °C for 3 h in air atmosphere. Powder x-ray diffraction, scanning electron microscopy, cathodoluminescence, transmission electron microscopy, energy dispersive x-ray spectroscopy and photoluminescence techniques were employed to characterize the obtained nanoparticles. We observed a 8-fold increase in red luminescence for samples suspended in DMSO solution for 2.5% of Mg2+doping. The x-ray analysis shows that for the concentration of 2.5% Mg, the size of the crystallites in the NPs is the largest, which is mainly responsible for the increase in the intensity of the upconversion luminescence. But the addition of Li+ions did not improve the luminescence of the upconversion due to decreasing of crystallites size of the NPs. Synthesized nanomaterials with very effective upconverting luminescence, can act as luminescent markers inin vivoimaging. The cytotoxicity of the nanoparticles was evaluated on the 4T1 cell line for the first time.
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Affiliation(s)
- Izabela Kamińska
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Aleksandra Wosztyl
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
- Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-093, Poland
| | - Przemysław Kowalik
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Bożena Sikora
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Tomasz Wojciechowski
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
- International Research Centre MagTop, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Kamil Sobczak
- Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, Warsaw 02-089, Poland
| | - Roman Minikayev
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Karolina Zajdel
- Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, Warsaw 02-106, Poland
| | - Michał Chojnacki
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Wojciech Zaleszczyk
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
- International Research Centre MagTop, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Katarzyna Łysiak
- Faculty of Physics, University of Warsaw, Ludwika Pasteura 5, 02-093, Poland
| | - Wojciech Paszkowicz
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
| | - Jacek Szczytko
- Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-093, Poland
| | | | - Wit Stryczniewicz
- Łukasiewicz Research Network-Institute of Aviation, al. Krakowska 110/114, Warsaw 02-256, Poland
| | - Krzysztof Fronc
- Institute of Physics Polish Academy of Sciences, al. Lotników 32/46, Warsaw 02-668, Poland
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26
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Yu HT, Zhen J, Leng JY, Cai L, Ji HL, Keller BB. Zinc as a countermeasure for cadmium toxicity. Acta Pharmacol Sin 2021; 42:340-346. [PMID: 32284539 PMCID: PMC8027184 DOI: 10.1038/s41401-020-0396-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/15/2020] [Indexed: 12/11/2022]
Abstract
Cadmium (Cd) is an important environmental pollutant and long-term Cd exposure is closely related to autoimmune diseases, cancer, cardiovascular diseases (CVD), and hepatic dysfunction. Zinc (Zn) is an essential metal that plays key roles in protein structure, catalysis, and regulation of their function. Numerous studies have shown that Zn can reduce Cd toxicity; however, the underlying mechanisms have not been extensively explored. Preclinical studies have revealed direct competition for sarcolemmal uptake between these two metals. Multiple sarcolemmal transporters participate in Cd uptake, including Zn transporters, calcium channels, and DMT1 (divalent metal transporter 1). Zn also induces several protective mechanisms, including MT (metallothionein) induction and favorable redox homeostasis. This review summarizes current knowledge related to the role of Zn and metal transporters in reducing Cd toxicity and discusses potential future directions of related research.
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Affiliation(s)
- Hai-Tao Yu
- The First Hospital of Jilin University, Changchun, 130021, China
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Juan Zhen
- The First Hospital of Jilin University, Changchun, 130021, China
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Ji-Yan Leng
- The First Hospital of Jilin University, Changchun, 130021, China
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Department of Radiation Oncology, University of Louisville School of Medicine, Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA
| | - Hong-Lei Ji
- The First Hospital of Jilin University, Changchun, 130021, China.
| | - Bradley B Keller
- Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA.
- Cincinnati Children's Heart Institute, Greater Louisville and Western Kentucky Practice, Louisville, KY, 40202, USA.
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Udali S, De Santis D, Mazzi F, Moruzzi S, Ruzzenente A, Castagna A, Pattini P, Beschin G, Franceschi A, Guglielmi A, Martinelli N, Pizzolo F, Ambrosani F, Olivieri O, Choi SW, Friso S. Trace Elements Status and Metallothioneins DNA Methylation Influence Human Hepatocellular Carcinoma Survival Rate. Front Oncol 2021; 10:596040. [PMID: 33585212 PMCID: PMC7876470 DOI: 10.3389/fonc.2020.596040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/08/2020] [Indexed: 12/24/2022] Open
Abstract
Background Mechanisms underlying hepatocellular carcinoma (HCC) development are largely unknown. The role of trace elements and proteins regulating metal ions homeostasis, i.e. metallothioneins (MTs), recently gained an increased interest. Object of the study was to investigate the role of promoter DNA methylation in MTs transcriptional regulation and the possible prognostic significance of serum trace elements in HCC. Methods Forty-nine HCC patients were enrolled and clinically characterized. Cu, Se, and Zn contents were measured by Inductively Coupled Plasma Mass Spectrometry in the serum and, for a subset of 27 patients, in HCC and homologous non-neoplastic liver (N) tissues. MT1G and MT1H gene expression in hepatic tissues was assessed by Real-Time RT-PCR and the specific promoter DNA methylation by Bisulfite-Amplicon Sequencing. Results Patients with Cu serum concentration above the 80th percentile had a significantly decreased survival rate (P < 0.001) with a marked increased hazard ratio for mortality (HR 6.88 with 95% CI 2.60-18.23, P < 0.001). Se and Zn levels were significantly lower in HCC as compared to N tissues (P < 0.0001). MT1G and MT1H gene expression was significantly down-regulated in HCC as compared to N tissues (P < 0.05). MTs promoter was hypermethylated in 9 out of the 19 HCC tissues showing MTs down-regulation and methylation levels of three specific CpGs paralleled to an increased mortality rate among the 23 patients analyzed (P = 0.015). Conclusions MT1G and MT1H act as potential tumor suppressor genes regulated through promoter DNA methylation and, together with serum Cu concentrations, be related to survival rate in HCC.
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Affiliation(s)
- Silvia Udali
- Department of Medicine, University of Verona, Verona, Italy
| | | | - Filippo Mazzi
- Department of Medicine, University of Verona, Verona, Italy
| | - Sara Moruzzi
- Department of Medicine, University of Verona, Verona, Italy
| | | | | | | | - Greta Beschin
- Department of Medicine, University of Verona, Verona, Italy
| | - Antonia Franceschi
- Department of Diagnostics and Public Health, University of Verona School of Medicine, Verona, Italy
| | | | | | | | | | | | - Sang-Woon Choi
- Chaum Life Center, CHA University School of Medicine, Seoul, South Korea.,Department of Nutrition, University of Massachusetts School of Public Health and Health Sciences, Amherst, MA, United States
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Seyoum A, Pradhan A, Jass J, Olsson PE. Perfluorinated alkyl substances impede growth, reproduction, lipid metabolism and lifespan in Daphnia magna. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 737:139682. [PMID: 32521362 DOI: 10.1016/j.scitotenv.2020.139682] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 05/18/2020] [Accepted: 05/22/2020] [Indexed: 05/15/2023]
Abstract
Per- and polyfluorinated alkyl substances (PFASs) are synthetic organofluorine compounds with unique stability accompanied with hydrophobic and lipophobic properties. Perfluorooctane sulfonate (PFOS) and Perfluorooctanoic acid (PFOA) are of high concern due to their wide application in consumer and industrial products, extreme persistence, abundant occurrence in the environment and their toxic effect to humans and animals. However, knowledge on the molecular mechanisms of toxicity and the effects on reproduction output remain scarce. In this study, we analyzed the effects of PFOS and PFOA on Daphnia magna. Acute toxicity, development, reproduction, lipid metabolism (lipid-accumulation) and lifespan was investigated, as well as the expression of genes related to these endpoints. Exposure of PFOS and PFOA at 1, 10 and 25 μM did not cause acute lethality. Hatching was reduced following exposure to both compounds, and lifespan was decreased following exposure to 25 μM PFOS. Body length of Daphnia magna was reduced significantly by 25 μM PFOS following 7 days exposure. Lipid staining revealed that all PFAS exposures increased lipid accumulation. qRT-PCR analysis of genes involved in lipid metabolism suggests that the increase in lipid content could be due to inhibition of genes involved on absorption and catabolism of fatty acids. Exposure to both PFOA and PFOS reduced the fecundity significantly. Downregulation of genes involved in development and reproductive process, including vtg2, vasa, EcRA, EcRB, usp, jhe, HR3, ftz-F1, E74 and E75 were observed. The alterations in developmental and reproductive genes as well as the disturbed lipid metabolism provides mechanistic insight into the possible causes for decreased fecundity and lifespan observed following exposure to both PFOS and PFOA.
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Affiliation(s)
- Asmerom Seyoum
- The Life Science Center-Biology, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden
| | - Ajay Pradhan
- The Life Science Center-Biology, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden
| | - Jana Jass
- The Life Science Center-Biology, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden
| | - Per-Erik Olsson
- The Life Science Center-Biology, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
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Gudekar N, Shanbhag V, Wang Y, Ralle M, Weisman GA, Petris MJ. Metallothioneins regulate ATP7A trafficking and control cell viability during copper deficiency and excess. Sci Rep 2020; 10:7856. [PMID: 32398691 PMCID: PMC7217913 DOI: 10.1038/s41598-020-64521-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/16/2020] [Indexed: 11/30/2022] Open
Abstract
Copper (Cu) is an essential, yet potentially toxic nutrient, as illustrated by inherited diseases of copper deficiency and excess. Elevated expression of the ATP7A Cu exporter is known to confer copper tolerance, however, the contribution of metal-binding metallothioneins is less clear. In this study, we investigated the relative contributions of ATP7A and the metallothioneins MT-I and MT-II to cell viability under conditions of Cu excess or deficiency. Although the loss of ATP7A increased sensitivity to low Cu concentrations, the absence of MTs did not significantly affect Cu tolerance. However, the absence of all three proteins caused a synthetic lethal phenotype due to extreme Cu sensitivity, indicating that MTs are critical for Cu tolerance only in the absence of ATP7A. A lack of MTs resulted in the trafficking of ATP7A from the trans-Golgi complex in a Cu-dependent manner, suggesting that MTs regulate the delivery of Cu to ATP7A. Under Cu deficiency conditions, the absence of MTs and / or ATP7A enhanced cell proliferation compared to wild type cells, suggesting that these proteins compete with essential Cu-dependent pathways when Cu is scarce. These studies reveal new roles for ATP7A and metallothioneins under both Cu deficiency and excess.
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Affiliation(s)
- Nikita Gudekar
- The Genetics Area Program, University of Missouri, Columbia, MO, 65211, USA
- The Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA
| | - Vinit Shanbhag
- The Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA
- The Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA
| | - Yanfang Wang
- The Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA
- The Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211, USA
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, People's Republic of China
| | - Martina Ralle
- The Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, 97239, USA
| | - Gary A Weisman
- The Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA
- The Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA
| | - Michael J Petris
- The Genetics Area Program, University of Missouri, Columbia, MO, 65211, USA.
- The Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, 65211, USA.
- The Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA.
- The Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211, USA.
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Yu HT, Zhen J, Xu JX, Cai L, Leng JY, Ji HL, Keller BB. Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms. Acta Pharmacol Sin 2020; 41:638-649. [PMID: 31768045 PMCID: PMC7471469 DOI: 10.1038/s41401-019-0320-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 10/10/2019] [Indexed: 12/19/2022]
Abstract
Cadmium (Cd) is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues (ECTs). In contrast, zinc (Zn) is a potent metallothionein (MT) inducer, which plays an important role in protection against Cd toxicity. In this study, we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms. ECTs were constructed from neonatal ventricular cells of wild-type (WT) mice and mice with global MT gene deletion (MT-KO). In WT-ECTs, Cd (5-20 μM) caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating, apoptosis, and LDH release; Zn (50-200 μM) dose-dependently induced MT expression in ECTs without causing ECT toxicity; co-treatment of ECT with Zn (50 µM) prevented Cd-induced toxicity. In MT-KO ECTs, Cd toxicity was enhanced; but unexpectedly, cotreatment with Zn provided partial protection against Cd toxicity. Furthermore, Cd, but not Zn, significantly activated Nrf2 and its downstream targets, including HO-1; inhibition of HO-1 by a specific HO-1 inhibitor, ZnPP (10 µM), significantly increased Cd-induced toxicity, but did not inhibit Zn protection against Cd injury, suggesting that Nrf2-mediated HO-1 activation was not required for Zn protective effect. Finally, the ability of Zn to reduce Cd uptake provided an additional MT-independent mechanism for reducing Cd toxicity. Thus, Zn exerts protective effects against Cd toxicity for murine ECTs that are partially MT-mediated. Further studies are required to translate these findings towards clinical trials.
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Affiliation(s)
- Hai-Tao Yu
- The Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
- The First Hospital of Jilin University, Changchun, 130021, China
| | - Juan Zhen
- The Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
- The First Hospital of Jilin University, Changchun, 130021, China
| | - Jian-Xiang Xu
- The Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Lu Cai
- The Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA
- Department of Radiation Oncology, The University of Louisville School of Medicine, Louisville, KY, USA
| | - Ji-Yan Leng
- The First Hospital of Jilin University, Changchun, 130021, China
| | - Hong-Lei Ji
- The First Hospital of Jilin University, Changchun, 130021, China.
| | - Bradley B Keller
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA.
- Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY, 40202, USA.
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Yao J, Yang Z, Li H, Qu Y, Qiu B. Effects of waterborne exposure to cadmium on biochemical responses in the freshwater gastropod, Bellamya aeruginosa. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 193:110365. [PMID: 32114244 DOI: 10.1016/j.ecoenv.2020.110365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 06/10/2023]
Abstract
The biochemical responses of Bellamya aeruginosa as a dominant and widespread freshwater gastropod throughout China to waterborne cadmium (Cd) were investigated to explore the impacts of exposure concentration and duration in this potential sentinel species. After the 7 days' test of dosage-mortality relationship, gastropods were exposed for either 7 days at the LC50 (1.7 mg/L), the LC10 (0.7 mg/L) and 0.02 mg/L Cd, or 28 days at 0.02 mg/L Cd. A suite of biochemical indicators including metallothionein-like protein (MTLP), reduced glutathione (GSH), catalase (CAT), contents of tissue metal (Cd, Fe, Mn, Cu, Zn), and the compartments of these metals bound to MTLP were examined. The treatment of 0.02 mg/L Cd led to the increase of Cd bound to MTLP (Cd-MTLP) levels, the decrease of GSH content, and the upregulation of CAT activity, but no induction of MTLP, indicating that the intrinsic MTLP and GSH worked together for the detoxification of Cd at the low exposure. When the exposure concentration increased, GSH was depleted severely and synthesis of MTLP was triggered, leading to a strong and significant relationship between MTLP level and Cd accumulation. At the lethal concentrations (1.7 mg/L), both MTLP induction and CAT activity were inhibited while the proportion of Cd-MTLP to total Cd were increased, suggesting more intrinsic MTLP were utilized to sequester free Cd ions. Therefore, the content of Cd-MTLP in digestive glands of B. aeruginosa was recommended as a reliable biomarker for Cd contamination.
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Affiliation(s)
- Jie Yao
- Center for Environment and Water Resource, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
| | - Zhaoguang Yang
- Center for Environment and Water Resource, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
| | - Haipu Li
- Center for Environment and Water Resource, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
| | - Yaobaixue Qu
- Center for Environment and Water Resource, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
| | - Bo Qiu
- Center for Environment and Water Resource, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
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Shaw JR, Colbourne JK, Glaholt SP, Turner E, Folt CL, Chen CY. Dynamics of Cadmium Acclimation in Daphnia pulex: Linking Fitness Costs, Cross-Tolerance, and Hyper-Induction of Metallothionein. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2019; 53:14670-14678. [PMID: 31738529 DOI: 10.1021/acs.est.9b05006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Acclimation increases tolerance to stress in individuals but is assumed to contribute fitness costs when the stressor is absent, though data supporting this widely held claim are sparse. Therefore, using clonal (i.e., genetically identical) cultures of Daphnia pulex, we isolated the contributions of acclimation to the regulation of the metal response gene, metallothionein 1 (MT1), and defined the reproductive benefits and costs of cadmium (Cd)-acclimation. Daphnia pulex were exposed for 50 parthenogenetic generations to environmentally realistic levels (1 μg Cd/L), and tolerance to Cd and other metals assessed during this period via standard toxicity tests. These tests revealed (1) increased tolerance to Cd compared to genetically identical nonacclimated cultures, (2) fitness costs in Cd-acclimated Daphnia when Cd was removed, and (3) cross-tolerance of Cd-acclimated Daphnia to zinc and silver, but not arsenic, thereby defining a functional role for metallothionein. Indeed, Cd-acclimated clones had significantly higher expression of MT1 mRNA than nonacclimated clones, when Cd exposed. Both the enhanced induction of MT1 and tolerant phenotype were rapidly lost when Cd was removed (1-2 generations), which is further evidence of acclimation costs. These findings provide evidence for the widely held view that acclimation is costly and are important for investigating evolutionary principles of genetic assimilation and the survival mechanisms of natural populations that face changing environments.
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Affiliation(s)
- Joseph R Shaw
- O'Neill School of Public and Environmental Affairs , Indiana University , Bloomington , Indiana 47405 , United States
- Department of Biology , Dartmouth College , Hanover , New Hampshire 03755 , United States
- Center for Environmental Health Sciences , Dartmouth Medical School , Hanover , New Hampshire 03755 , United States
| | - John K Colbourne
- School of Biosciences , University of Birmingham , Birmingham B15 2TT , U.K
| | - Stephen P Glaholt
- O'Neill School of Public and Environmental Affairs , Indiana University , Bloomington , Indiana 47405 , United States
- Department of Biology , Dartmouth College , Hanover , New Hampshire 03755 , United States
| | - Elizabeth Turner
- O'Neill School of Public and Environmental Affairs , Indiana University , Bloomington , Indiana 47405 , United States
| | - Carol L Folt
- Department of Biology , Dartmouth College , Hanover , New Hampshire 03755 , United States
- Center for Environmental Health Sciences , Dartmouth Medical School , Hanover , New Hampshire 03755 , United States
- USC Office of the President , University of Southern California , Los Angeles , California 90089 , United States
| | - Celia Y Chen
- Department of Biology , Dartmouth College , Hanover , New Hampshire 03755 , United States
- Center for Environmental Health Sciences , Dartmouth Medical School , Hanover , New Hampshire 03755 , United States
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Tavera-Montañez C, Hainer SJ, Cangussu D, Gordon SJV, Xiao Y, Reyes-Gutierrez P, Imbalzano AN, Navea JG, Fazzio TG, Padilla-Benavides T. The classic metal-sensing transcription factor MTF1 promotes myogenesis in response to copper. FASEB J 2019; 33:14556-14574. [PMID: 31690123 PMCID: PMC6894080 DOI: 10.1096/fj.201901606r] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 09/23/2019] [Indexed: 12/15/2022]
Abstract
Metal-regulatory transcription factor 1 (MTF1) is a conserved metal-binding transcription factor in eukaryotes that binds to conserved DNA sequence motifs, termed metal response elements. MTF1 responds to both metal excess and deprivation, protects cells from oxidative and hypoxic stresses, and is required for embryonic development in vertebrates. To examine the role for MTF1 in cell differentiation, we use multiple experimental strategies [including gene knockdown (KD) mediated by small hairpin RNA and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), immunofluorescence, chromatin immunopreciptation sequencing, subcellular fractionation, and atomic absorbance spectroscopy] and report a previously unappreciated role for MTF1 and copper (Cu) in cell differentiation. Upon initiation of myogenesis from primary myoblasts, both MTF1 expression and nuclear localization increased. Mtf1 KD impaired differentiation, whereas addition of nontoxic concentrations of Cu+-enhanced MTF1 expression and promoted myogenesis. Furthermore, we observed that Cu+ binds stoichiometrically to a C terminus tetra-cysteine of MTF1. MTF1 bound to chromatin at the promoter regions of myogenic genes, and Cu addition stimulated this binding. Of note, MTF1 formed a complex with myogenic differentiation (MYOD)1, the master transcriptional regulator of the myogenic lineage, at myogenic promoters. These findings uncover unexpected mechanisms by which Cu and MTF1 regulate gene expression during myoblast differentiation.-Tavera-Montañez, C., Hainer, S. J., Cangussu, D., Gordon, S. J. V., Xiao, Y., Reyes-Gutierrez, P., Imbalzano, A. N., Navea, J. G., Fazzio, T. G., Padilla-Benavides, T. The classic metal-sensing transcription factor MTF1 promotes myogenesis in response to copper.
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Affiliation(s)
- Cristina Tavera-Montañez
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Sarah J. Hainer
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA; and
| | - Daniella Cangussu
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Shellaina J. V. Gordon
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Yao Xiao
- Department of Chemistry, Skidmore College, Saratoga Springs, New York, USA
| | - Pablo Reyes-Gutierrez
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Anthony N. Imbalzano
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Juan G. Navea
- Department of Chemistry, Skidmore College, Saratoga Springs, New York, USA
| | - Thomas G. Fazzio
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA; and
| | - Teresita Padilla-Benavides
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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Cheng D, Li H, Zhou J, Wang S. Chlorogenic acid relieves lead-induced cognitive impairments and hepato-renal damage via regulating the dysbiosis of the gut microbiota in mice. Food Funct 2019; 10:681-690. [PMID: 30657151 DOI: 10.1039/c8fo01755g] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Lead (Pb), a heavy metal which is widely recognized as an environmental toxicant, is transported from the earth's crust into the human body to a significant extent. To control and reduce the hazard of Pb burdens in the human body, chlorogenic acid (CGA) has been used to antagonize Pb-induced cognitive impairments, and hepatic and renal toxicity in the present study. Seven-week-old male Kunming mice were treated with PbCl2 (1.34 g L-1 in drinking water) and/or CGA (30 mg per kg mouse per day) by gavage administration for 8 weeks. In this study, we evaluated behavior tests, serum biochemical parameters, biomarkers of oxidative stress, and community structure of gut microbiota in mice to explore the potential mechanism of the protective effect. Based on our results, CGA appreciably prevented memory impairment, the release of serum biomarkers, and oxidative stress caused by Pb intake. CGA significantly inhibited Pb-induced increase of cytoplasmic NF-κB, Bax, cytochrome C, and caspase-9 protein expressions. Furthermore, Pb + CGA treatment had a remarkable reversion effect of the gut microbiota composition change induced by Pb, for example increasing the ratio of Helicobacter from 2.95% (Pb) to 11.24% (Pb + CGA) and decreasing the ratio of the Lachnospiraceae_NK4A136_ group from 7.09% (Pb) to 2.68% (Pb + CGA), which suggests that CGA is a superior natural product to eliminate Pb-induced nephrotoxicity and hepatotoxicity.
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Affiliation(s)
- Dai Cheng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology & Business University (BTBU), Beijing 100048, China.
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35
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Zoidis E, Papadomichelakis G, Pappas AC, Theodorou G, Fegeros K. Effects of Selenium and Cadmium on Breast Muscle Fatty-Acid Composition and Gene Expression of Liver Antioxidant Proteins in Broilers. Antioxidants (Basel) 2019; 8:antiox8050147. [PMID: 31137881 PMCID: PMC6562737 DOI: 10.3390/antiox8050147] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/15/2019] [Accepted: 05/23/2019] [Indexed: 12/20/2022] Open
Abstract
The present work was part of a project intended to evaluate whether organic selenium (Se) has the potential to protect against toxic effects exerted by cadmium (Cd). For this reason, 300 as-hatched, one-day-old broiler chickens were randomly allocated in four dietary treatments with five replicate pens per treatment. Chickens in T1 treatment, were offered a diet supplemented with 0.3 ppm Se (as Se-yeast), without added Cd; in T2 treatment, they were offered a diet with 0.3 ppm Se and 10 ppm Cd; in T3 treatment, they were offered a diet with 0.3 ppm Se and 100 ppm Cd; in T4 treatment, chickens were offered a diet supplemented with 3 ppm Se and 100 ppm Cd. Cadmium was added to the diets in T2, T3, and T4 as CdCl2. On the fourth and sixth weeks, liver and breast samples were obtained from two broilers per replicate pen. Relative gene expression levels of catalase (CAT), superoxide dismutase 1 (SOD1) and 2 (SOD2), methionine sulfoxide reductase A (MSRA) and B3 (MSRB3), iodothyronine deiodinase 1 (DIO1), 2 (DIO2), and 3 (DIO3), glutathione peroxidase 1 (GPX1) and 4 (GPX4), thioredoxin reductase 1 (TXNRD1) and 3 (TXNRD3), and metallothionein 3 (MT3) were analyzed by real-time quantitative PCR in liver, whereas the fatty-acid (FA) profile of breast muscle was determined by gas chromatography. Broilers supplemented with 0.3 ppm Se could tolerate low levels of Cd present in the diets, as there were no significant changes in the breast muscle FA profile, whereas excess Cd led to decreased polyunsaturated fatty acids (PUFAs), and in particular n-6 PUFA. Furthermore, treatments mainly affected the messenger RNA (mRNA) expression of SOD2, TXNRD3, and MT3, while age affected CAT, MSRB3, DIO2, DIO3, GPX4, TXNRD1, and MT3. In conclusion, dietary Se may help against the negative effects of Cd, but cannot be effective when Cd is present at excessive amounts in the diet.
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Affiliation(s)
- Evangelos Zoidis
- Department of Nutritional Physiology and Feeding, Faculty of Animal Science, Agricultural University of Athens, 11855 Athens, Greece.
| | - George Papadomichelakis
- Department of Nutritional Physiology and Feeding, Faculty of Animal Science, Agricultural University of Athens, 11855 Athens, Greece.
| | - Athanasios C Pappas
- Department of Nutritional Physiology and Feeding, Faculty of Animal Science, Agricultural University of Athens, 11855 Athens, Greece.
| | - Georgios Theodorou
- Department of Animal Breeding and Husbandry, Faculty of Animal Science, Agricultural University of Athens, 11855 Athens, Greece.
| | - Kostas Fegeros
- Department of Nutritional Physiology and Feeding, Faculty of Animal Science, Agricultural University of Athens, 11855 Athens, Greece.
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The footprints of mitochondrial impairment and cellular energy crisis in the pathogenesis of xenobiotics-induced nephrotoxicity, serum electrolytes imbalance, and Fanconi's syndrome: A comprehensive review. Toxicology 2019; 423:1-31. [PMID: 31095988 DOI: 10.1016/j.tox.2019.05.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 04/29/2019] [Accepted: 05/09/2019] [Indexed: 12/19/2022]
Abstract
Fanconi's Syndrome (FS) is a disorder characterized by impaired renal proximal tubule function. FS is associated with a vast defect in the renal reabsorption of several chemicals. Inherited and/or acquired conditions seem to be connected with FS. Several xenobiotics including many pharmaceuticals are capable of inducing FS and nephrotoxicity. Although the pathological state of FS is well described, the exact underlying etiology and cellular mechanism(s) of xenobiotics-induced nephrotoxicity, serum electrolytes imbalance, and FS are not elucidated. Constant and high dependence of the renal reabsorption process to energy (ATP) makes mitochondrial dysfunction as a pivotal mechanism which could be involved in the pathogenesis of FS. The current review focuses on the footprints of mitochondrial impairment in the etiology of xenobiotics-induced FS. Moreover, the importance of mitochondria protecting agents and their preventive/therapeutic capability against FS is highlighted. The information collected in this review may provide significant clues to new therapeutic interventions aimed at minimizing xenobiotics-induced renal injury, serum electrolytes imbalance, and FS.
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Ljubojević M, Orct T, Micek V, Karaica D, Jurasović J, Breljak D, Madunić IV, Rašić D, Jovanović IN, Peraica M, Gerić M, Gajski G, Oguić SK, Rogić D, Nanić L, Rubelj I, Sabolić I. Sex-dependent expression of metallothioneins MT1 and MT2 and concentrations of trace elements in rat liver and kidney tissues: Effect of gonadectomy. J Trace Elem Med Biol 2019; 53:98-108. [PMID: 30910215 DOI: 10.1016/j.jtemb.2019.02.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 02/20/2019] [Accepted: 02/22/2019] [Indexed: 02/02/2023]
Abstract
Metallothioneins (MTs) exhibit binding affinity for several essential and toxic trace elements. Previous studies in rodents indicated sex differences in the hepatic and renal expression of MTs and concentrations of various elements. The mechanism responsible for these differences has not been resolved. Here, in the liver and kidney tissues of sham-operated and gonadectomized male and female rats we determined the expression of MT1 and MT2 (MT1&2) mRNA by RT-PCR, abundance of MT1&2 proteins by Western blotting and immunocytochemistry, concentrations of essential (Fe, Zn, Cu, Co) and toxic (Cd, Hg, Pb) elements by ICP-MS, and oxidative status parameters (SOD, GPx, MDA, GSH) by biochemical methods. In both organs, the expression of MT1&2 mRNA and MT1&2 proteins was female-dominant, upregulated by castration, and downregulated by ovariectomy. Concentrations of Fe in the liver and Co in the kidneys followed the same pattern. Most other elements (Zn, Cu, Cd, Hg) exhibited female- or male-dominant sex differences, affected by gonadectomy in one or both organs. Pb was sex- and gonadectomy-unaffected. GPx and MDA were elevated and associated with the highest concentrations of Fe only in the female liver. We conclude that the sex-dependent expression of MT1&2 mRNA and proteins in the rat liver and kidneys may include different mechanisms. In the liver, the female-dominant tissue concentrations of Fe may generate oxidative stress which is a potent enhancer of MTs production, whereas in kidneys, the female-dominant expression of MTs may be unrelated to Fe-mediated oxidative stress.
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Affiliation(s)
- Marija Ljubojević
- Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Tatjana Orct
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Vedran Micek
- Animal Breeding Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Dean Karaica
- Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Jasna Jurasović
- Analytical Toxicology and Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Davorka Breljak
- Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Ivana Vrhovac Madunić
- Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Dubravka Rašić
- Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Ivana Novak Jovanović
- Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Maja Peraica
- Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Marko Gerić
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Goran Gajski
- Mutagenesis Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia
| | - Saša Kralik Oguić
- Clinical Institute of Laboratory Diagnostics, Clinical Hospital Center, Zagreb, Croatia
| | - Dunja Rogić
- Clinical Institute of Laboratory Diagnostics, Clinical Hospital Center, Zagreb, Croatia
| | - Lucia Nanić
- Laboratory for Molecular and Cellular Biology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Ivica Rubelj
- Laboratory for Molecular and Cellular Biology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Ivan Sabolić
- Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Zagreb, Croatia.
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Zhang D, Zhang T, Liu J, Chen J, Li Y, Ning G, Huo N, Tian W, Ma H. Zn Supplement-Antagonized Cadmium-Induced Cytotoxicity in Macrophages In Vitro: Involvement of Cadmium Bioaccumulation and Metallothioneins Regulation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:4611-4622. [PMID: 30942077 DOI: 10.1021/acs.jafc.9b00232] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Cadmium (Cd) is a toxic metal leading to multiple forms of organ damage. Zinc (Zn) was reported as a potential antagonist against Cd toxicity. The present study investigates the antagonistic effect of Zn (20 μM) on Cd (20 or 50 μM) cytotoxicity in macrophages in vitro. The results shows that Cd exposure caused dose-dependent morphologic and ultrastructural alterations in RAW 264.7 macrophages. Zn supplement significantly inhibited Cd cytotoxicity in RAW 264.7 or HD-11 macrophages by mitigating cell apoptosis, excessive ROS output, and mitochondrial membrane depolarization. Notably, Zn supplement for 12 h remarkably prevented intracellular Cd2+ accumulation in 20 μM (95.99 ± 9.93 vs 29.64 ± 5.08 ng/106 cells; P = 0.0008) or 50 μM Cd (179.78 ± 28.66 vs 141.62 ± 22.15 ng/106 cells; P = 0.003) exposed RAW 264.7 cells. Further investigation found that Cd promoted metallothioneins (MTs) and metal regulatory transcription factor 1 (MTF-1) expression in RAW 264.7 macrophages. Twenty μM Zn supplement dramatically enhanced MTs and MTF-1 levels in Cd-exposed RAW 264.7 macrophages. Intracellular Zn2+ chelation or MTF-1 gene silencing inhibited MTs synthesis in Cd-exposed RAW 264.7 macrophages, which was accompanied by the declined expression of MTF-1, indicating that regulation of Zn on MTs was partially achieved by MTF-1 mobilization. In conclusion, this study demonstrates the antagonism of Zn against Cd cytotoxicity in macrophages and reveals its antagonistic mechanism by preventing Cd2+ bioaccumulation and promoting MTs expression.
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Affiliation(s)
- Ding Zhang
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
| | - Ting Zhang
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
| | - Jingying Liu
- Function Laboratory , Shanxi Medical University , Taiyuan 030001 , P. R. China
| | - Jianshan Chen
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
| | - Ying Li
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
| | - Guanbao Ning
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
| | - Nairui Huo
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
| | - Wenxia Tian
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
| | - Haili Ma
- College of Animal Science and Veterinary Medicine , Shanxi Agricultural University , Taigu 030800 , P. R. China
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Huang X, Feng Y, Fan W, Duan J, Duan Y, Xiong G, Wang K, Deng Y, Geng Y, Ouyang P, Chen D, Yang S. Potential ability for metallothionein and vitamin E protection against cadmium immunotoxicity in head kidney and spleen of grass carp (Ctenopharyngodon idellus). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 170:246-252. [PMID: 30529919 DOI: 10.1016/j.ecoenv.2018.11.134] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 11/27/2018] [Accepted: 11/29/2018] [Indexed: 06/09/2023]
Abstract
Cadmium (Cd) pollution is an important issue affecting the food safety of aquatic products. Cd can impair the immune system and cause irreversible damage to fish and other aquatic organisms. The immunoprotection activities of exogenous metallothionein (MT) and vitamin E (VE) were investigated in Cd poisoned grass carp, Ctenopharyngodon idellus, in the present study. C. idellus were divided into three groups: Cd+phosphate-buffered saline (PBS) group; Cd+MT; and Cd+VE. All fish were injected with cadmium chloride (CdCl2) on the first day and then treated with PBS, MT or VE four days post-injection. Fish not injected with Cd were used as a negative control. Cd exposure caused severe head-kidney and splenic injury in C. idellus, mainly expressed as an increase in Cd content, histological damage, percentage of head-kidney and splenic cells apoptosis and decreases in immune-related gene mRNA transcript expression. However, MT and VE treatments protected against Cd-induced immunotoxicity in C. idellus by decreasing Cd contents, lessening histological damage, reducing the percentage of apoptosis and recovering immune-related mRNA transcript expression. Our results demonstrate that MT and VE can alleviate Cd-induced immunotoxicity and that MT has a more powerful effect than VE, indicating that MT could be a potential antidote in cases of Cd poisoning.
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Affiliation(s)
- Xiaoli Huang
- Department of Aquaculture, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China.
| | - Yang Feng
- Department of Aquaculture, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Wei Fan
- NeiJiang Academy of Agricultural Sciences, Neijiang, Sichuan 641000, China
| | - Jing Duan
- Department of Aquaculture, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Yajiao Duan
- Department of Aquaculture, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Guanqing Xiong
- Department of Aquaculture, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Kaiyu Wang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Yongqiang Deng
- Sichuan Provincial Agricultural Department, Chengdu, Sichuan 610000, China
| | - Yi Geng
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Ping Ouyang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Defang Chen
- Department of Aquaculture, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
| | - Shiyong Yang
- Department of Aquaculture, Sichuan Agricultural University, Wenjiang, Sichuan 611130, China
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Hertika AMS, Kusriani K, Indrayani E, Yona D, Putra RBDS. Metallothionein expression on oysters ( Crassostrea cuculata and Crassostrea glomerata) from the southern coastal region of East Java. F1000Res 2019; 8:56. [PMID: 32477493 PMCID: PMC7217233 DOI: 10.12688/f1000research.17381.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/24/2020] [Indexed: 11/20/2022] Open
Abstract
Background: This study aimed to analyse levels of heavy metals (Pb, Hg and Cd) in the aquatic body, gills and stomach of the oysters Crassostrea cuculata and Crassostrea glomerata, the metallothionein (MT) level in the gills and stomach of both oysters, and relationships between heavy metals level (Pb, Hg and Cd) in the gills and stomach to MT level in both species of oysters. Methods: The research method utilized was a descriptive method. The oyster samples were taken from three stations: Sendang Biru, Popoh and Prigi beaches. MT values were assessed using confocal laser scanning microscopy. The heavy metal levels were assessed using atomic absorption spectrophotometry method. Results: Both oyster heavy metal content obtained in the southern coastal waters exceeded the safe limit set by the State Minister of Environment No. 51 of 2004. In general, the expression of MT was found to be higher in stomach tissue compared to gill tissue. Conclusions: The levels of the heavy metals Pb, Hg, and has a strong relationship with MT levels in the gills and stomach in both types of oysters.
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Affiliation(s)
| | - Kusriani Kusriani
- Faculty of Fisheries and Marine Science, University of Brawijaya, Malang, East Java, 65165, Indonesia
| | - Erlinda Indrayani
- Faculty of Fisheries and Marine Science, University of Brawijaya, Malang, East Java, 65165, Indonesia
| | - Defri Yona
- Faculty of Fisheries and Marine Science, University of Brawijaya, Malang, East Java, 65165, Indonesia
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Hertika AMS, Kusriani K, Indrayani E, Yona D, Putra RBDS. Metallothionein expression on oysters ( Crassostrea cuculata and Crassostrea glomerata) from the southern coastal region of East Java. F1000Res 2019; 8:56. [PMID: 32477493 PMCID: PMC7217233 DOI: 10.12688/f1000research.17381.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/07/2019] [Indexed: 03/29/2024] Open
Abstract
Background: This study aimed to analyse levels of heavy metals (Pb, Hg and Cd) in the aquatic body, gills and stomach of the oysters Crassostrea cuculata and Crassostrea glomerata, the metallothionein (MT) level in the gills and stomach of both oysters, and relationships between heavy metals level (Pb, Hg and Cd) in the gills and stomach to MT level in both types of oysters. Methods: The research method utilized was a descriptive method. The oyster samples were taken from three stations: Sendang Biru, Popoh and Prigi beaches. MT values were assessed using confocal laser scanning microscopy. The heavy metal levels were assessed using atomic absorption spectrophotometry method. Results: Both oyster heavy metal content obtained in the southern coastal waters exceeded the safe limit set by the State Minister of Environment No. 51 of 2004. In general, the expression of MT was found to be higher in gastric tissue compared to gill tissue. Conclusions: The relationship between levels of the heavy metals Pb, Hg, and Cd in oyster gills and stomach has a strong relationship with MT levels in the gills and stomach in both types of oysters.
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Affiliation(s)
| | - Kusriani Kusriani
- Faculty of Fisheries and Marine Science, University of Brawijaya, Malang, East Java, 65165, Indonesia
| | - Erlinda Indrayani
- Faculty of Fisheries and Marine Science, University of Brawijaya, Malang, East Java, 65165, Indonesia
| | - Defri Yona
- Faculty of Fisheries and Marine Science, University of Brawijaya, Malang, East Java, 65165, Indonesia
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Application of Microbial Cleaning Technology for Removal of Surface Contamination. DEVELOPMENTS IN SURFACE CONTAMINATION AND CLEANING: APPLICATIONS OF CLEANING TECHNIQUES 2019. [PMCID: PMC7149890 DOI: 10.1016/b978-0-12-815577-6.00015-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Microbial cleaning takes advantage of naturally-occurring microbes to remove a wide variety of contaminants from various surfaces. The method is based on the affinity of microbes for hydrocarbons that are digested, producing harmless carbon dioxide, water, and soluble fatty acids. The microbes are nonpathogenic and are safe to handle and dispose. The process is environmentally-friendly and is less expensive than solvent cleaning, but it is not applicable to high precision cleaning applications. Typical applications include parts washing; oil and grease removal from concrete and other floor surfaces, and from drains and grease traps; cleaning and disinfection in healthcare facilities; cleaning of historical artworks and structures; and household and institutional cleaning applications.
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Verma N, Bal S, Gupta R, Aggarwal N, Yadav A. Antioxidative Effects of Piperine against Cadmium-Induced Oxidative Stress in Cultured Human Peripheral Blood Lymphocytes. J Diet Suppl 2018; 17:41-52. [DOI: 10.1080/19390211.2018.1481485] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Neha Verma
- Biotechnology Department, Kurukshetra University, Kurukshetra, India
| | - Surbhi Bal
- Biotechnology Department, Kurukshetra University, Kurukshetra, India
| | - Ranjan Gupta
- Biochemistry Department, Kurukshetra University, Kurukshetra, India
| | - Neeraj Aggarwal
- Microbiology Department, Kurukshetra University, Kurukshetra, India
| | - Anita Yadav
- Biotechnology Department, Kurukshetra University, Kurukshetra, India
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Yu M, Cao T, Yu D, Huang F. Association Study Between Metallothionein-3 Protein Polymorphisms and Autism. Neurotox Res 2018. [DOI: 10.1007/s12640-017-9858-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Yoshioka H, Nonogaki T, Shinohara Y, Suzui M, Mori Y, Hwang GW, Ohtani K, Miura N. Lethal chronotoxicity induced by seven metal compounds in mice. J Toxicol Sci 2018; 43:129-134. [PMID: 29479034 DOI: 10.2131/jts.43.129] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The aim of the present study is to investigate the "chronotoxicity" of seven metal compounds (Hg, Pb, Ni, Cr, Cu, Zn, or Fe) by assessing how their toxicity varies with circadian periodicity. Male ICR mice were injected with each metal compound intraperitoneally at 6 different time points over the course of a day (zeitgeber time [ZT]: ZT2, ZT6, ZT10, ZT14, ZT18 and ZT22). Mortality was then monitored until 14 days after the injection. Our investigation demonstrated that mice were tolerant against Ni toxicity during dark phase, on the other hand, they were tolerant against Cr toxicity during light phase. The chronotoxicity of Hg and Pb seemed to be biphasic. Further, mice were susceptible to toxicities against Cu and Zn in the time zone during which light and dark were reversed. Interestingly, no significant differences were observed for Fe exposure at any time of the day. Our results propose that the chronotoxicology may provide valuable information regarding the importance of injection timing for not only toxicity evaluation tests but also the reproducibility of animal experiments. Furthermore, our data suggests that chronotoxicology may be an important consideration when evaluating the quality of risk assessments for night shift workers who may be exposed to toxic substances at various times of the day.
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Affiliation(s)
- Hiroki Yoshioka
- College of Pharmacy, Kinjo Gakuin University.,Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences
| | | | | | - Masumi Suzui
- Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences
| | - Yurie Mori
- College of Pharmacy, Kinjo Gakuin University
| | - Gi-Wook Hwang
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Katsumi Ohtani
- Division of Hazard Evaluation and Epidemiology Research, Japan National Institute of Occupational Safety and Health
| | - Nobuhiko Miura
- Division of Health Effects Research, Japan National Institute of Occupational Safety and Health
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Krasnići N, Dragun Z, Erk M, Ramani S, Jordanova M, Rebok K, Kostov V. Size-exclusion HPLC analysis of trace element distributions in hepatic and gill cytosol of Vardar chub (Squalius vardarensis Karaman) from mining impacted rivers in north-eastern Macedonia. THE SCIENCE OF THE TOTAL ENVIRONMENT 2018; 613-614:1055-1068. [PMID: 28950668 DOI: 10.1016/j.scitotenv.2017.09.160] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/14/2017] [Accepted: 09/16/2017] [Indexed: 06/07/2023]
Abstract
Many bioindicators have not yet been well characterized regarding their tendency to bind trace elements by different cytosolic biomolecules in response to trace element exposure. Accordingly, our principal aim was to define the cytosolic distributions of Cd, Co, Cu, Fe, Mn, Mo, Se, and Zn among the biomolecules of different molecular masses in liver and gills of Vardar chub (Squalius vardarensis Karaman), a representative fish species of Macedonian rivers, and to determine distribution changes which occur as a consequence of increased exposure to specific trace elements. Additionally, we aimed to confirm the presence of heat-stable biomolecules in chub hepatic and gill cytosols. Distribution profiles were obtained by separation of cytosols and heat-treated cytosols using size-exclusion high performance-liquid chromatography, and by offline determination of trace element concentrations using high resolution inductively coupled plasma-mass spectrometry. Distribution profiles of trace elements were mainly characterized by several peaks encompassing different ranges of molecular masses, as a sign of incorporation of trace elements in various biomolecules within hepatic and gill cytosols. Especially interesting finding was probable binding of Fe to ferritin, which was especially pronounced in the liver, as a sign of important liver function in Fe storage. Furthermore, association with heat-stable proteins, metallothioneins (MT), was indicated for Cd, Cu, and Zn in the hepatic cytosol, as well as for Cd in the gill cytosol, whereas a sign of Zn-MT association was not observed in the gills. The presence of Mo- and Se-binding heat-stable compounds of very low molecular masses (<10kDa) in the cytosol was determined for both liver and the gills. Trace elements under all studied conditions were found associated to the same biomolecules, and only their proportions associated to specific cytosolic compounds have changed as a consequence of their increased bioaccumulation in the liver and gills of Vardar chub.
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Affiliation(s)
- Nesrete Krasnići
- Ruđer Bošković Institute, Division for Marine and Environmental Research, Laboratory for Biological Effects of Metals, P.O. Box 180, 10002 Zagreb, Croatia
| | - Zrinka Dragun
- Ruđer Bošković Institute, Division for Marine and Environmental Research, Laboratory for Biological Effects of Metals, P.O. Box 180, 10002 Zagreb, Croatia.
| | - Marijana Erk
- Ruđer Bošković Institute, Division for Marine and Environmental Research, Laboratory for Biological Effects of Metals, P.O. Box 180, 10002 Zagreb, Croatia
| | - Sheriban Ramani
- Hydrometeorological Service of Macedonia, Department for Water Analysis, Skupi 28, 1000 Skopje, Macedonia
| | - Maja Jordanova
- Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Arhimedova 3, 1000 Skopje, Macedonia
| | - Katerina Rebok
- Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University in Skopje, Arhimedova 3, 1000 Skopje, Macedonia
| | - Vasil Kostov
- Institute of Animal Sciences, Ile Ilievski 92a, 1000 Skopje, Macedonia
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Bjørklund G, Dadar M, Mutter J, Aaseth J. The toxicology of mercury: Current research and emerging trends. ENVIRONMENTAL RESEARCH 2017; 159:545-554. [PMID: 28889024 DOI: 10.1016/j.envres.2017.08.051] [Citation(s) in RCA: 277] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 08/27/2017] [Accepted: 08/30/2017] [Indexed: 05/16/2023]
Abstract
Mercury (Hg) is a persistent bio-accumulative toxic metal with unique physicochemical properties of public health concern since their natural and anthropogenic diffusions still induce high risk to human and environmental health. The goal of this review was to analyze scientific literature evaluating the role of global concerns over Hg exposure due to human exposure to ingestion of contaminated seafood (methyl-Hg) as well as elemental Hg levels of dental amalgam fillings (metallic Hg), vaccines (ethyl-Hg) and contaminated water and air (Hg chloride). Mercury has been recognized as a neurotoxicant as well as immunotoxic and designated by the World Health Organization as one of the ten most dangerous chemicals to public health. It has been shown that the half-life of inorganic Hg in human brains is several years to several decades. Mercury occurs in the environment under different chemical forms as elemental Hg (metallic), inorganic and organic Hg. Despite the raising understanding of the Hg toxicokinetics, there is still fully justified to further explore the emerging theories about its bioavailability and adverse effects in humans. In this review, we describe current research and emerging trends in Hg toxicity with the purpose of providing up-to-date information for a better understanding of the kinetics of this metal, presenting comprehensive knowledge on published data analyzing its metabolism, interaction with other metals, distribution, internal doses and targets, and reservoir organs.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Toften 24, 8610 Mo i Rana, Norway.
| | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | | | - Jan Aaseth
- Innlandet Hospital Trust and Inland Norway University of Applied Sciences, Elverum, Norway
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Li SW, He Y, Zhao HJ, Wang Y, Liu JJ, Shao YZ, Li JL, Sun X, Zhang LN, Xing MW. Assessment of 28 trace elements and 17 amino acid levels in muscular tissues of broiler chicken (Gallus gallus) suffering from arsenic trioxide. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2017; 144:430-437. [PMID: 28666216 DOI: 10.1016/j.ecoenv.2017.06.061] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 06/21/2017] [Accepted: 06/22/2017] [Indexed: 06/07/2023]
Abstract
The contents of 28 trace elements, 17 amino acid were evaluated in muscular tissues (wings, crureus and pectoralis) of chickens in response to arsenic trioxide (As2O3). A total of 200 one-day-old male Hy-line chickens were fed either a commercial diet (C-group) or an As2O3 supplement diet containing 7.5mg/kg (L-group), 15mg/kg (M-group) or 30mg/kg (H-group) As2O3 for 90 days. The elements content was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Under As2O3 exposure, the concentration of As were elevated 8.87-15.76 fold, 7.93-15.63 fold and 5.94-12.45 fold in wings, crureus and pectoralis compared to the corresponding C-group, respectively. 19 element levels (lithium (Li), magnesium (Mg), aluminum (Al), silicon (Si), kalium (K), vanadium (V), chromium (Cr), manganese (Mn), nickel (Ni), copper (Cu), selenium (Se), strontium (Sr), molybdenum (Mo), cadmium (Cd), tin (Sn), antimony (Sb), barium (Ba), mercury (Hg) and lead (Pb), 9 element levels (K, Co, Ni, Cu, As, Se, Sr, Sn, Ba and Hg) and 4 element levels (Mn, cobalt (Co), As, Sr and Ba) were significantly increased (P < 0.05) in wing, crureus and pectoralis, respectively. 2 element levels (sodium (Na) and zinc (Zn)), 5 element levels (Li, Na, Si, titanium (Ti and Cr), 13 element levels (Li, Na, Mg, K, V, Cr, iron (Fe), Cu, Zn, Mo, Sn, Hg and Pb) were significantly decreased (P < 0.05) in wing muscle, crureus and pectoralis, respectively. Additionally, in crureus and pectoralis, the content of total amino acids (TAA) was no significant alterations in L and M-group and then increased approximately 10.2% and 7.6% in H-group, respectively (P < 0.05). In wings, the level of total amino acids increased approximately 10% in L-group, whereas it showed unchanged in M and H-group compared to the corresponding C-group. We also observed that significantly increased levels of proline, cysteine, aspartic acid, methionine along with decrease in the tyrosine levels in muscular tissues compared to the corresponding C-group. In conclusion, the residual of As in the muscular tissues of chickens were dose-dependent and disrupts trace element homeostasis, amino acids level in muscular tissues of chickens under As2O3 exposure. Additionally, the response (trace elements and amino acids) were different in wing, thigh and pectoral of chick under As2O3 exposure. This study provided references for further study of heavy metal poisoning and may be helpful to understanding the toxicological mechanism of As2O3 exposure in muscular tissues of chickens.
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Affiliation(s)
- Si-Wen Li
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Ying He
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Hong-Jing Zhao
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Yu Wang
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Juan-Juan Liu
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Yi-Zhi Shao
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Jing-Lun Li
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Xiao Sun
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China
| | - Li-Na Zhang
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China.
| | - Ming-Wei Xing
- College of Wildlife Resources, Northeast Forestry University, Harbin 150040, People's Republic of China.
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Ghiasi F, Mirzargar SS, Ashrafihellan J. Histological Effects of Cadmium on Hepatopancreas and Gill in Cyprinus carpio. IRANIAN JOURNAL OF TOXICOLOGY 2017. [DOI: 10.29252/arakmu.11.5.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Chin WC, Lin KH, Liu CC, Tsuge K, Huang CC. Improved n-butanol production via co-expression of membrane-targeted tilapia metallothionein and the clostridial metabolic pathway in Escherichia coli. BMC Biotechnol 2017; 17:36. [PMID: 28399854 PMCID: PMC5387206 DOI: 10.1186/s12896-017-0356-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 03/22/2017] [Indexed: 11/10/2022] Open
Abstract
Background N-Butanol has favorable characteristics for use as either an alternative fuel or platform chemical. Bio-based n-butanol production using microbes is an emerging technology that requires further development. Although bio-industrial microbes such as Escherichia coli have been engineered to produce n-butanol, reactive oxygen species (ROS)-mediated toxicity may limit productivity. Previously, we show that outer-membrane-targeted tilapia metallothionein (OmpC-TMT) is more effective as an ROS scavenger than human and mouse metallothioneins to reduce oxidative stress in the host cell. Results The host strain (BUT1-DE) containing the clostridial n-butanol pathway displayed a decreased growth rate and limited n-butanol productivity, likely due to ROS accumulation. The clostridial n-butanol pathway was co-engineered with inducible OmpC-TMT in E. coli (BUT3-DE) for simultaneous ROS removal, and its effect on n-butanol productivity was examined. The ROS scavenging ability of cells overexpressing OmpC-TMT was examined and showed an approximately twofold increase in capacity. The modified strain improved n-butanol productivity to 320 mg/L, whereas the control strain produced only 95.1 mg/L. Transcriptomic analysis revealed three major KEGG pathways that were significantly differentially expressed in the BUT3-DE strain compared with their expression in the BUT1-DE strain, including genes involved in oxidative phosphorylation, fructose and mannose metabolism and glycolysis/gluconeogenesis. Conclusions These results indicate that OmpC-TMT can increase n-butanol production by scavenging ROS. The transcriptomic analysis suggested that n-butanol causes quinone malfunction, resulting in oxidative-phosphorylation-related nuo operon downregulation, which would diminish the ability to convert NADH to NAD+ and generate proton motive force. However, fructose and mannose metabolism-related genes (fucA, srlE and srlA) were upregulated, and glycolysis/gluconeogenesis-related genes (pfkB, pgm) were downregulated, which further assisted in regulating NADH/NAD+ redox and preventing additional ATP depletion. These results indicated that more NADH and ATP were required in the n-butanol synthetic pathway. Our study demonstrates a potential approach to increase the robustness of microorganisms and the production of toxic chemicals through the ability to reduce oxidative stress. Electronic supplementary material The online version of this article (doi:10.1186/s12896-017-0356-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei-Chih Chin
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Kuo-Hsing Lin
- Center of Cold Chain Logistics Certification, College of Management, National Kaohsiung First University of Science and Technology, Kaohsiung, Taiwan
| | - Chun-Chi Liu
- Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan
| | - Kenji Tsuge
- Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan
| | - Chieh-Chen Huang
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
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