|
1
|
Henry R, Vander Heide R, Roy NM. Toxicity of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on oligodendrocytes during embryonic zebrafish development. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2025; 114:104627. [PMID: 39756717 DOI: 10.1016/j.etap.2025.104627] [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: 11/29/2024] [Revised: 01/01/2025] [Accepted: 01/02/2025] [Indexed: 01/07/2025]
Abstract
Polybrominated diphenyl ethers (PBDEs) are flame retardants heavily utilized across plastic, textile and electronic industries. Although these PBDEs are effective in protecting property and human life from fire, their high production volumes have led PBDEs to become pervasive environmental contaminants and pose an ecological and health risk as high levels have been noted in environmental media including water and sediment, wildlife and human tissue. Here we investigate the developmental neurotoxicity of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), one of the more dominant PBDE congeners found in human tissue, on oligodendrocytes in the hindbrain and spinal cord. We utilized the zebrafish vertebrate model system and investigated low (5 µM) and high concentrations (20 µM) of BDE-47. We find that by 6 days post-fertilization, BDE-47 negatively affects oligodendrocyte development in the hindbrain and spinal cord in a concentration dependent manner.
Collapse
Affiliation(s)
- Ryann Henry
- Department of Biology, Sacred Heart University, Fairfield, CT, United States
| | - Reagan Vander Heide
- Department of Biology, Sacred Heart University, Fairfield, CT, United States
| | - Nicole M Roy
- Department of Biology, Sacred Heart University, Fairfield, CT, United States.
| |
Collapse
|
|
2
|
Jiang L, Yang J, Yang H, Kong L, Ma H, Zhu Y, Zhao X, Yang T, Liu W. Advanced understanding of the polybrominated diphenyl ethers (PBDEs): Insights from total environment to intoxication. Toxicology 2024; 509:153959. [PMID: 39341352 DOI: 10.1016/j.tox.2024.153959] [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: 08/20/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/01/2024]
Abstract
Polybrominated diphenyl ethers (PBDEs) are brominated compounds connected by ester bonds between two benzene rings. There are 209 congeners of PBDEs, classified according to the number and position of the bromine atoms. Due to their low cost and superior flame retardant properties, PBDEs have been extensively used as flame retardants in electronic products, plastics, textiles, and other materials since the 1970s. PBDEs are classified as persistent organic pollutants (POPs) under the Stockholm Convention because of their environmental persistence, bioaccumulation, and toxicity to both humans and wildlife. Due to their extensive use and significant quantities, PBDEs have been detected across a range of environments and biological organisms. These compounds are known to cause damage to the metabolic system, exhibit neurotoxicity, and pose reproductive hazards. This review investigates the environmental distribution and human exposure pathways of PBDEs. Using China-a country with significant PBDE use-as an example, it highlights substantial regional and temporal variations in PBDE concentrations and notes that certain environmental levels may pose risks to human health. The article then examines the toxic effects and mechanisms of PBDEs on several major target organs, summarizing recent research and the specific mechanisms underlying these toxic effects from multiple toxicological perspectives. This review enhances our understanding of PBDEs' environmental distribution, exposure pathways, and toxic mechanisms, offering valuable insights for further research and management strategies.
Collapse
Affiliation(s)
- Liujiangshan Jiang
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China
| | - Jing Yang
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China
| | - Huajie Yang
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China
| | - Lingxu Kong
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China
| | - Haonan Ma
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China
| | - Yapei Zhu
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China
| | - Xuan Zhao
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China
| | - Tianyao Yang
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China.
| | - Wei Liu
- Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China.
| |
Collapse
|
|
3
|
Li C, Tian Z, Li X, Sun Y, Tian J, Wu Y, Cai J, He Y, Sanganyado E, Li P, Liang B, Liu W. Toxicogenomic assessment of hydroxylated metabolites of PBDEs on cetaceans: An in vitro study. CHEMOSPHERE 2024; 366:143350. [PMID: 39326706 DOI: 10.1016/j.chemosphere.2024.143350] [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: 05/02/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/28/2024]
Abstract
Despite their ban, polybrominated diphenyl ethers (PBDEs) are frequently detected in various environmental compartments including marine and coastal ecosystems due to their persistence, bio-accumulative, high production volumes, and widespread use. One of the major concerns from PBDEs is the transformation products, such as hydroxylated polybrominated diphenyl ethers (OH-BDEs), which are more bioactive than the parent compounds. For example, 6-hydroxy-2,2',4',4-tetrabromodiphenyl ether (6-OH-BDE-47) is a typical metabolite of PBDEs and cause endocrine system disruption, developmental toxicity, and neurotoxicity in different species. Despite being widely detected in marine environments, investigations on the toxicological mechanisms of 6-OH-BDE-47 in cetaceans remain scarce. High concentrations of PBDEs accumulate in cetaceans due to the long lifespan and large fat reserve. The accumulated PBDEs have become the major source of OH-BDEs in cetaceans. We exposed immortalized fibroblast cell lines from the skin of pygmy killer whales (PKW-LWHT) and Indo-Pacific finless porpoises (FP-LWHT) to 6-OH-BDE-47 and analyzed changes in cellular function using transcriptomic data, along with enzymatic activity. Exposure to the body-relevant body burdens of 6-OH-BDE-47 (250 and 500 ng mL-1) significantly decreased cell viability. Differentially expressed genes in FP-LWHT exposed to 6-OH-BDE-47 were primarily enriched in the pathways associated with steroid metabolism. Total cholesterol was decreased by 6-OH-BDE-47, whereas low-density lipoprotein cholesterol and triglyceride levels were significantly increased in FP-LWHT cells. In contrast, glycolysis was the main enriched function of differentially expressed genes in PKW-LWHT cells exposed to 6-OH-BDE-47, and the enzyme activity of phosphofructokinase and hexokinase was upregulated. Thus, even though the cell viability of both cell lines from these two species was significantly suppressed by 6-OH-BDE-47, the cellular response or affected cellular function was different between the Pygmy killer whale and the Indo-Pacific Finless Porpoise, suggesting a diverse response towards OH-BDEs exposure.
Collapse
Affiliation(s)
- Chengzhang Li
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Ziyao Tian
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Xinying Li
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Yajing Sun
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Jiashen Tian
- Dalian Key Laboratory of Conservation Biology for Endangered Marine Mammals, Liaoning Ocean and Fisheries Science Research Institute, Dalian, Liaoning, 116023, China
| | - Yuqi Wu
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Jingting Cai
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Yijie He
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Edmond Sanganyado
- Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, NE2 4PB, UK
| | - Ping Li
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China
| | - Bo Liang
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China.
| | - Wenhua Liu
- Guangdong Provincial Key Laboratory of Marine Disaster Prediction and Prevention, Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou, 515063, China.
| |
Collapse
|
|
4
|
Yao D, Li S, You M, Chen Y, Yan S, Li B, Wang Y. Developmental exposure to nonylphenol leads to depletion of the neural precursor cell pool in the hippocampal dentate gyrus. Chem Biol Interact 2024; 401:111187. [PMID: 39111523 DOI: 10.1016/j.cbi.2024.111187] [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: 05/15/2024] [Revised: 07/24/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024]
Abstract
Developmental exposure to nonylphenol (NP) results in irreversible impairments of the central nervous system (CNS). The neural precursor cell (NPC) pool located in the subgranular zone (SGZ), a substructure of the hippocampal dentate gyrus, is critical for the development of hippocampal circuits and some hippocampal functions such as learning and memory. However, the effects of developmental exposure to NP on this pool remain unclear. Thus, our aim was to clarify the impacts of developmental exposure to NP on this pool and to explore the potential mechanisms. Animal models of developmental exposure to NP were created by treating Wistar rats with NP during pregnancy and lactation. Our data showed that developmental exposure to NP decreased Sox2-and Ki67-positive cells in the SGZ of offspring. Inhibited activation of Shh signaling and decreased levels of its downstream mediators, E2F1 and cyclins, were also observed in pups developmentally exposed to NP. Moreover, we established the in vitro model in the NE-4C cells, a neural precursor cell line, to further investigate the effect of NP exposure on NPCs and the underlying mechanisms. Purmorphamine, a small purine-derived hedgehog agonist, was used to specifically modulate the Shh signaling. Consistent with the in vivo results, exposure to NP reduced cell proliferation by inhibiting the Shh signaling in NE-4C cells, and purmorphamine alleviated this reduction in cell proliferation by restoring this signaling. Altogether, our findings support the idea that developmental exposure to NP leads to inhibition of the NPC proliferation and the NPC pool depletion in the SGZ located in the dentate gyrus. Furthermore, we also provided the evidence that suppressed activation of Shh signaling may contribute to the effects of developmental exposure to NP on the NPC pool.
Collapse
Affiliation(s)
- Dianqi Yao
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning, PR China; Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China
| | - Siyao Li
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning, PR China; Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China
| | - Mingdan You
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China; School of Public Health, Guizhou Medical University, Guiyang, Guizhou, PR China
| | - Yin Chen
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China
| | - Siyu Yan
- Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China
| | - Bing Li
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning, PR China; Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
| | - Yi Wang
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, Shenyang, Liaoning, PR China; Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
| |
Collapse
|
|
5
|
EFSA Panel on Contaminants in the Food Chain (CONTAM), Schrenk D, Bignami M, Bodin L, Chipman JK, del Mazo J, Grasl‐Kraupp B, Hogstrand C, (Ron) Hoogenboom L, Leblanc J, Nebbia CS, Nielsen E, Ntzani E, Petersen A, Sand S, Schwerdtle T, Wallace H, Benford D, Fürst P, Hart A, Rose M, Schroeder H, Vrijheid M, Ioannidou S, Nikolič M, Bordajandi LR, Vleminckx C. Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food. EFSA J 2024; 22:e8497. [PMID: 38269035 PMCID: PMC10807361 DOI: 10.2903/j.efsa.2024.8497] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2024] Open
Abstract
The European Commission asked EFSA to update its 2011 risk assessment on polybrominated diphenyl ethers (PBDEs) in food, focusing on 10 congeners: BDE-28, -47, -49, -99, -100, -138, -153, -154, -183 and ‑209. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour and reproductive/developmental effects are the critical effects in rodent studies. For four congeners (BDE-47, -99, -153, -209) the Panel derived Reference Points, i.e. benchmark doses and corresponding lower 95% confidence limits (BMDLs), for endpoint-specific benchmark responses. Since repeated exposure to PBDEs results in accumulation of these chemicals in the body, the Panel estimated the body burden at the BMDL in rodents, and the chronic intake that would lead to the same body burden in humans. For the remaining six congeners no studies were available to identify Reference Points. The Panel concluded that there is scientific basis for inclusion of all 10 congeners in a common assessment group and performed a combined risk assessment. The Panel concluded that the combined margin of exposure (MOET) approach was the most appropriate risk metric and applied a tiered approach to the risk characterisation. Over 84,000 analytical results for the 10 congeners in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary Lower Bound exposure to PBDEs were meat and meat products and fish and seafood. Taking into account the uncertainties affecting the assessment, the Panel concluded that it is likely that current dietary exposure to PBDEs in the European population raises a health concern.
Collapse
|
|
6
|
Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery. Cell Biol Toxicol 2021; 38:781-807. [PMID: 33969458 PMCID: PMC9525352 DOI: 10.1007/s10565-021-09603-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/11/2021] [Indexed: 12/12/2022]
Abstract
Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2′,4,4′-tetrabromodiphenylether (BDE-47), 2,2′,4,4′,5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell–based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 μM (5 FRs), 1<10 μM (7 FRs) to the >10 μM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell–based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment.
Collapse
|
|
7
|
Wei J, Xiang L, Cai Z. Emerging environmental pollutants hydroxylated polybrominated diphenyl ethers: From analytical methods to toxicology research. MASS SPECTROMETRY REVIEWS 2021; 40:255-279. [PMID: 32608069 DOI: 10.1002/mas.21640] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/13/2020] [Accepted: 05/23/2020] [Indexed: 06/11/2023]
Abstract
Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are of particular concern due to their ubiquitous distribution and adverse health effects. Significant progress has been made in the characterization of OH-PBDEs by using mass spectrometry (MS). In this review, we summarize applications of MS-based techniques in detection, environmental and biota distribution, and potential health risk effects, hoping to unfold an overall picture on account of current knowledge of OH-PBDEs. The analytical methodologies are discussed from sample pretreatment to MS analysis. The methods including gas chromatography-MS (GC-MS), liquid chromatography-MS (LC-MS), and ion mobility spectrometry-MS (IMS-MS) are discussed. GC-MS is the most frequently adopted method in the analysis of OH-PBDEs due to its excellent chromatographic resolution, high sensitivity, and strong ability for unknown identification. LC-MS has been widely used for its high sensitivity and capability of direct analysis. As a newly developed technique, IMS-MS provides high specificity, which greatly facilitates the identification of isomers. OH-PBDEs pervasively existed in both abiotic and biotic samples, including humans, animals, and environmental matrices. Multiple adverse health effects have been reported, such as thyroid hormone disruption, estrogen effects, and neurotoxicity. The reported potential pathological mechanisms are also reviewed. Additionally, MS-based metabolomics, lipidomics, and proteomics have been shown as promising tools to unveil the molecular mechanisms of the toxicity of OH-PBDEs. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.
Collapse
Affiliation(s)
- Juntong Wei
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China
| | - Li Xiang
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, China
| |
Collapse
|
|
8
|
Deepika D, Sharma RP, Schuhmacher M, Kumar V. An integrative translational framework for chemical induced neurotoxicity – a systematic review. Crit Rev Toxicol 2020; 50:424-438. [DOI: 10.1080/10408444.2020.1763253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Deepika Deepika
- Environmental Engineering Laboratory, Departament d’ Enginyeria Quimica, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Raju Prasad Sharma
- Environmental Engineering Laboratory, Departament d’ Enginyeria Quimica, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Marta Schuhmacher
- Environmental Engineering Laboratory, Departament d’ Enginyeria Quimica, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
| | - Vikas Kumar
- Environmental Engineering Laboratory, Departament d’ Enginyeria Quimica, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
- IISPV, Hospital Universitari Sant Joan de Reus, Universitat Rovira I Virgili, Reus, Spain
| |
Collapse
|
|
9
|
Poston RG, Murphy L, Rejepova A, Ghaninejad-Esfahani M, Segales J, Mulligan K, Saha RN. Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes. J Biol Chem 2020; 295:6120-6137. [PMID: 32229587 PMCID: PMC7196656 DOI: 10.1074/jbc.ra119.011138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 03/23/2020] [Indexed: 12/20/2022] Open
Abstract
The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH-BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH-BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK-ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand-protein docking suggested that 6-OH-BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH-BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH-BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β-lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK-ERK signaling, and axonal guidance.
Collapse
Affiliation(s)
- Robert G Poston
- Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, Merced, California 95343
| | - Lillian Murphy
- Department of Biological Sciences, Center for Interdisciplinary Molecular Biology: Education, Research and Advancement (CIMERA), California State University, Sacramento, California 95819
| | - Ayna Rejepova
- Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, Merced, California 95343
| | - Mina Ghaninejad-Esfahani
- Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, Merced, California 95343
| | - Joshua Segales
- Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, Merced, California 95343
| | - Kimberly Mulligan
- Department of Biological Sciences, Center for Interdisciplinary Molecular Biology: Education, Research and Advancement (CIMERA), California State University, Sacramento, California 95819
| | - Ramendra N Saha
- Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, Merced, California 95343.
| |
Collapse
|
|
10
|
Dunnick JK, Shockley KR, Morgan DL, Travlos G, Gerrish KE, Ton TV, Wilson RE, Brar SS, Brix AE, Waidyanatha S, Mutlu E, Pandiri AR. Hepatic Transcriptomic Patterns in the Neonatal Rat After Pentabromodiphenyl Ether Exposure. Toxicol Pathol 2020; 48:338-349. [PMID: 31826744 PMCID: PMC7596650 DOI: 10.1177/0192623319888433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human exposure to pentabromodiphenyl ether (PBDE) mixture (DE-71) and its PBDE-47 congener can occur both in utero and during lactation. Here, we tested the hypothesis that PBDE-induced neonatal hepatic transcriptomic alterations in Wistar Han rat pups can inform on potential toxicity and carcinogenicity after longer term PBDE exposures. Wistar Han rat dams were exposed to either DE-71 or PBDE-47 daily from gestation day (GD 6) through postnatal day 4 (PND 4). Total plasma thyroxine (T4) was decreased in PND 4 pups. In liver, transcripts for CYPs and conjugation enzymes, Nrf2, and ABC transporters were upregulated. In general, the hepatic transcriptomic alterations after exposure to DE-71 or PBDE-47 were similar and provided early indicators of oxidative stress and metabolic alterations, key characteristics of toxicity processes. The transcriptional benchmark dose lower confidence limits of the most sensitive biological processes were lower for PBDE-47 than for the PBDE mixture. Neonatal rat liver transcriptomic data provide early indicators on molecular pathway alterations that may lead to toxicity and/or carcinogenicity if the exposures continue for longer durations. These early toxicogenomic indicators may be used to help prioritize chemicals for a more complete toxicity and cancer risk evaluation.
Collapse
Affiliation(s)
- J. K. Dunnick
- Toxicology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - K. R. Shockley
- Biostatistics & Computational Biology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - D. L. Morgan
- Toxicology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - G. Travlos
- Cellular & Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - K. E. Gerrish
- Molecular Genomics Core, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - T. V. Ton
- Cellular & Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - R. E. Wilson
- Cellular & Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - S. S. Brar
- Cellular & Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - A. E. Brix
- EPL, Inc., Research Triangle Park, North Carolina
| | - S. Waidyanatha
- Program Operations Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - E. Mutlu
- Program Operations Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - A. R. Pandiri
- Cellular & Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| |
Collapse
|
|
11
|
Dempsey JL, Little M, Cui JY. Gut microbiome: An intermediary to neurotoxicity. Neurotoxicology 2019; 75:41-69. [PMID: 31454513 PMCID: PMC7703666 DOI: 10.1016/j.neuro.2019.08.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 08/04/2019] [Accepted: 08/16/2019] [Indexed: 12/12/2022]
Abstract
There is growing recognition that the gut microbiome is an important regulator for neurological functions. This review provides a summary on the role of gut microbiota in various neurological disorders including neurotoxicity induced by environmental stressors such as drugs, environmental contaminants, and dietary factors. We propose that the gut microbiome remotely senses and regulates CNS signaling through the following mechanisms: 1) intestinal bacteria-mediated biotransformation of neurotoxicants that alters the neuro-reactivity of the parent compounds; 2) altered production of neuro-reactive microbial metabolites following exposure to certain environmental stressors; 3) bi-directional communication within the gut-brain axis to alter the intestinal barrier integrity; and 4) regulation of mucosal immune function. Distinct microbial metabolites may enter systemic circulation and epigenetically reprogram the expression of host genes in the CNS, regulating neuroinflammation, cell survival, or cell death. We will also review the current tools for the study of the gut-brain axis and provide some suggestions to move this field forward in the future.
Collapse
Affiliation(s)
- Joseph L Dempsey
- Department of Environmental and Occupational Health Sciences, University of Washington, United States
| | - Mallory Little
- Department of Environmental and Occupational Health Sciences, University of Washington, United States
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, United States.
| |
Collapse
|
|
12
|
Wang H, Abel GM, Storm DR, Xia Z. Cadmium Exposure Impairs Adult Hippocampal Neurogenesis. Toxicol Sci 2019; 171:501-514. [PMID: 31271426 PMCID: PMC11648796 DOI: 10.1093/toxsci/kfz152] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/07/2019] [Accepted: 06/29/2019] [Indexed: 01/30/2023] Open
Abstract
Cadmium (Cd) is an environmental pollutant of considerable interest throughout the world and potentially a neurotoxicant. Our recent data indicate that Cd exposure induces impairment of hippocampus-dependent learning and memory in mice. However, the underlying mechanisms for this defect are not known. The goal of this study was to determine if Cd inhibits adult neurogenesis and to identify underlying signaling pathways responsible for this impairment. Adult hippocampal neurogenesis is a process in which adult neural progenitor/stem cells (aNPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG) generate functional new neurons in the hippocampus which contributes to hippocampus-dependent learning and memory. However, studies concerning the effects of neurotoxicants on adult hippocampal neurogenesis and the underlying signaling mechanisms are limited. Here, we report that Cd significantly induces apoptosis, inhibits proliferation, and impairs neuronal differentiation in primary cultured aNPCs derived from the SGZ. In addition, the c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase signaling pathways are activated by Cd and contribute to its toxicity. Furthermore, we exposed 8-week-old male C57BL/6 mice to Cd through drinking water for 13 weeks to assess the effects of Cd on adult hippocampal neurogenesis in vivo. Cd treatment reduced the number of 5-week-old adult-born cells in the DG and impaired the differentiation of adult-born hippocampal neurons. These results suggest that Cd exposure impairs adult hippocampal neurogenesis both in vitro and in vivo. This may contribute to Cd-mediated inhibition of hippocampus-dependent learning and memory.
Collapse
Affiliation(s)
- Hao Wang
- Toxicology Program, Department of Environmental and Occupational Health Sciences
| | - Glen M Abel
- Toxicology Program, Department of Environmental and Occupational Health Sciences
| | - Daniel R Storm
- Department of Pharmacology, University of Washington, Seattle, Washington 98195
| | - Zhengui Xia
- Toxicology Program, Department of Environmental and Occupational Health Sciences
| |
Collapse
|
|
13
|
Chen H, Seifikar H, Larocque N, Kim Y, Khatib I, Fernandez CJ, Abello N, Robinson JF. Using a Multi-Stage hESC Model to Characterize BDE-47 Toxicity during Neurogenesis. Toxicol Sci 2019; 171:221-234. [PMID: 31173147 PMCID: PMC6736394 DOI: 10.1093/toxsci/kfz136] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/20/2019] [Accepted: 05/22/2019] [Indexed: 12/20/2022] Open
Abstract
While the ramifications associated with polybrominated diphenyl ethers (PBDE) exposures during human pregnancy have yet to be determined, increasing evidence in humans and animal models suggests that these compounds cause neurodevelopmental toxicity. Human embryonic stem cell models (hESCs) can be used to study the effects of environmental chemicals throughout the successive stages of neuronal development. Here, using a hESC differentiation model, we investigated the effects of common PBDE congeners (BDE-47 or -99) on the successive stages of early neuronal development. First, we determined the points of vulnerability to PBDEs across four stages of in vitro neural development by using assays to assess for cytotoxicity. Differentiated neural progenitors were identified to be more sensitive to PBDEs than their less differentiated counterparts. In follow-up investigations, we observed BDE-47 to inhibit functional processes critical for neurogenesis (e.g., proliferation, expansion) in hESC-derived neural precursor cells (NPCs) at sub-lethal concentrations. Finally, to determine the mechanism(s) underlying PBDE-toxicity, we conducted global transcriptomic and methylomic analyses of BDE-47. We identified 589 genes to be differentially expressed (DE) due to BDE-47 exposure, including molecules involved in oxidative stress mediation, cell cycle, hormone signaling, steroid metabolism, and neurodevelopmental pathways. In parallel analyses, we identified a broad significant increase in CpG methylation. In summary our results suggest, on a cellular level, PBDEs induce human neurodevelopmental toxicity in a concentration-dependent manner and sensitivity to these compounds is dependent on the developmental stage of exposure. Proposed mRNA and methylomic perturbations may underlie toxicity in early embryonic neuronal populations.
Collapse
Affiliation(s)
- Hao Chen
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Helia Seifikar
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Nicholas Larocque
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Yvonne Kim
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Ibrahim Khatib
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Charles J Fernandez
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Nicomedes Abello
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Joshua F Robinson
- Center for Reproductive Sciences and Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco (UCSF), San Francisco, CA, USA
| |
Collapse
|
|
14
|
Dunnick JK, Pandiri AR, Merrick BA, Kissling GE, Cunny H, Mutlu E, Waidyanatha S, Sills R, Hong HL, Ton TV, Maynor T, Recio L, Phillips SL, Devito MJ, Brix A. Carcinogenic activity of pentabrominated diphenyl ether mixture (DE-71) in rats and mice. Toxicol Rep 2018; 5:615-624. [PMID: 29868454 PMCID: PMC5984199 DOI: 10.1016/j.toxrep.2018.05.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 01/19/2023] Open
Abstract
Pentabrominated diphenyl ether (PBDE) mixture was a multispecies carcinogen causing liver tumors in male and female rats and mice. Hras or Ctnnb1 mutations characterized the PBDE-induced liver tumors. PBDE-induced liver tumors increased with increasing PBDE exposure. Pentabrominated diphenyl ether (PBDE) flame retardants have been phased out in Europe and in the United States, but these lipid soluble chemicals persist in the environment and are found human and animal tissues. PBDEs have limited genotoxic activity. However, in a 2-year cancer study of a PBDE mixture (DE-71) (0, 3, 15, or 50 mg/kg (rats); 0, 3, 30, or 100 mg/kg (mice)) there were treatment-related liver tumors in male and female Wistar Han rats [Crl:WI(Han) after in utero/postnatal/adult exposure, and in male and female B6C3F1 mice, after adult exposure. In addition, there was evidence for a treatment-related carcinogenic effect in the thyroid and pituitary gland tumor in male rats, and in the uterus (stromal polyps/stromal sarcomas) in female rats. The treatment-related liver tumors in female rats were unrelated to the AhR genotype status, and occurred in animals with wild, mutant, or heterozygous Ah receptor. The liver tumors in rats and mice had treatment-related Hras and Ctnnb mutations, respectively. The PBDE carcinogenic activity could be related to oxidative damage, disruption of hormone homeostasis, and molecular and epigenetic changes in target tissue. Further work is needed to compare the PBDE toxic effects in rodents and humans.
Collapse
Affiliation(s)
- J K Dunnick
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - A R Pandiri
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - B A Merrick
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - G E Kissling
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - H Cunny
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - E Mutlu
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - S Waidyanatha
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - R Sills
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - H L Hong
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - T V Ton
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - T Maynor
- Integrated Laboratory Systems, Research Triangle Park, NC 27709, USA
| | - L Recio
- Integrated Laboratory Systems, Research Triangle Park, NC 27709, USA
| | - S L Phillips
- Integrated Laboratory Systems, Research Triangle Park, NC 27709, USA
| | - M J Devito
- National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - A Brix
- EPL, Inc., Research Triangle Park, NC 27709, USA
| |
Collapse
|
|
15
|
Saquib Q, Siddiqui MA, Ahmad J, Ansari SM, Al-Wathnani HA, Rensing C. 6-OHBDE-47 induces transcriptomic alterations of CYP1A1, XRCC2, HSPA1A, EGR1 genes and trigger apoptosis in HepG2 cells. Toxicology 2018; 400-401:40-47. [DOI: 10.1016/j.tox.2018.03.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 03/17/2018] [Accepted: 03/26/2018] [Indexed: 12/19/2022]
|
|
16
|
Dingemans MML, Kock M, van den Berg M. Mechanisms of Action Point Towards Combined PBDE/NDL-PCB Risk Assessment. Toxicol Sci 2018; 153:215-24. [PMID: 27672163 DOI: 10.1093/toxsci/kfw129] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
At present, human risk assessment of the structurally similar non-dioxin-like (NDL) PCBs and polybrominated diphenylethers (PBDEs) is done independently for both groups of compounds. There are however obvious similarities between NDL-PCBs and PBDEs with regard to modulation of the intracellular calcium homeostasis (basal calcium levels, voltage-gated calcium channels, calcium uptake, ryanodine receptor) and thyroid hormone (TH) homeostasis (TH levels and transport). which are mechanisms of action related to neurobehavioral effects (spontaneous activity, habituation and learning ability). There also similarities in agonistic interactions with the hepatic nuclear receptors PXR and CAR. Several effects on developmental (reproductive) processes have also been observed, but results were more dispersed and insufficient to compare both groups of compounds. The available mechanistic information is sufficient to warrant a dose addition model for NDL-PCBs and PBDEs, including their hydroxylated metabolites.Although many of the observed effects are similar from a qualitative point of view for both groups, congener or tissue specific differences have also been found. As this is a source of uncertainty in the combined hazard and risk assessment of these compounds, molecular entities involved in the observed mechanisms and adverse outcomes associated with these compounds need to be identified. The systematical generation of (quantitative) structure-activity information for NDL-PCBs and PBDEs on these targets (including potential non-additive effects) will allow a more realistic risk estimation associated with combined exposure to both groups of compounds during early life. Additional validation studies are needed to quantify these uncertainties for risk assessment of NDL-PCBs and PBDEs.
Collapse
Affiliation(s)
- Milou M L Dingemans
- Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Marjolijn Kock
- Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Martin van den Berg
- Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| |
Collapse
|
|
17
|
Poston RG, Dunn CJ, Sarkar P, Saha RN. Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers. ENVIRONMENTAL EPIGENETICS 2018; 4:dvx020. [PMID: 29765770 PMCID: PMC5941167 DOI: 10.1093/eep/dvx020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 11/08/2017] [Accepted: 11/09/2017] [Indexed: 06/08/2023]
Abstract
Polybrominated diphenyl ethers (PBDEs) are a pervasive class of brominated flame retardants that are present in the environment at particularly high levels, especially in the United States. Their environmental stability, propensity for bioaccumulation, and known potential for neurotoxicity has evoked interest regarding their effects on the developing nervous system. Exposure to PBDEs has been strongly associated with neurodevelopmental disorders. However, the details of their mechanistic roles in such disorders are incompletely understood. Here, we report the effects of one of the most prevalent congeners, BDE-47, and its hydroxylated metabolites on the maturation and function of embryonic rat cortical neurons. Prolonged exposure to 6OH-BDE-47 produces the strongest effects amongst the parent BDE-47 congener and its tested hydroxylated metabolites. These effects include: i) disruption of transcriptional responses to neuronal activity, ii) dysregulation of multiple genes associated with neurodevelopmental disorders, and intriguingly, iii) altered expression of several subunits of the developmentally-relevant BAF (Brg1-associated factors) chromatin remodeling complex, including the key subunit BAF170. Taken together, our data indicate that persistent exposure to 6OH-BDE-47 may interfere with neurodevelopmental chromatin remodeling mechanisms and gene transcription programs, which in turn are likely to interfere with downstream processes such as synapse development and overall functional maturity of neurons. Results from this study have identified a novel aspect of 6OH-BDE-47 toxicity and open new avenues to explore the effects of a ubiquitous environmental toxin on epigenetic regulation of neuronal maturation and function.
Collapse
Affiliation(s)
- Robert G Poston
- Molecular Cell Biology Unit, School of Natural Sciences, University of California, 5200 North Lake Road, Merced, CA 95343, USA
| | - Carissa J Dunn
- Molecular Cell Biology Unit, School of Natural Sciences, University of California, 5200 North Lake Road, Merced, CA 95343, USA
| | - Pushpita Sarkar
- Molecular Cell Biology Unit, School of Natural Sciences, University of California, 5200 North Lake Road, Merced, CA 95343, USA
| | - Ramendra N Saha
- Molecular Cell Biology Unit, School of Natural Sciences, University of California, 5200 North Lake Road, Merced, CA 95343, USA
| |
Collapse
|
|
18
|
Zhang C, Li P, Zhang S, Lei R, Li B, Wu X, Jiang C, Zhang X, Ma R, Yang L, Wang C, Zhang X, Xia T, Wang A. Oxidative stress-elicited autophagosome accumulation contributes to human neuroblastoma SH-SY5Y cell death induced by PBDE-47. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2017; 56:322-328. [PMID: 29096325 DOI: 10.1016/j.etap.2017.10.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 10/10/2017] [Accepted: 10/13/2017] [Indexed: 06/07/2023]
Abstract
Polybrominated diphenyl ethers, a ubiquitous persistent organic pollutant used as brominated flame retardants, is known to damage nervous system, however the underlying mechanism is still elusive. In this study, we used human neuroblastoma SH-SY5Y cells to explore the effects of PBDE-47 on autophagy and investigate the role of autophagy in PBDE-47-induced cell death. Results showed PBDE-47 could increase autophagic level (performation of cell ultrastructure with double membrane formation, MDC-positive cells raised, autophagy-related proteins LC3-II, Beclin1 and P62 increased) after cells exposed to PBDE-47. Then cells were exposed to PBDE-47 (1, 5, 10μmol/L) respectively for 1, 3, 6, 9, 12, 18, 24h, and the results showed that PBDE-47 increased the levels of LC3-II, Beclin1 and P62 in 5, 10μmol/L (9, 12, 18, 24h) PBDE-47 exposed groups. Furthermore, ROS scavenger N-Acetyl-l-cysteine (NAC), autophagic inhibitor 3-methyladenine (3-MA) and 5μmol/L PBDE-47 treated for 9h and 24h were chosen for the follow-up research. Moreover, 3-MA significantly improved cell viability when cells exposed to 5 and 10μmol/L PBDE-47, indicating that PBDE-47-induced autophagic cell death. Importantly, NAC could decrease PBDE-47-induced LC3-II, Beclin1 and P62 expression. We concluded that autophagosome accumulation mediated by oxidative stress may contribute to SH-SY5Y cell death induced by PBDE-47.
Collapse
Affiliation(s)
- Cheng Zhang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China; Wuhan Prevention and Treatment Center for Occupational Diseases, Jianghan North Road 18-20, Wuhan 430015, Hubei, People's Republic of China
| | - Pei Li
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Shun Zhang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Rongrong Lei
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Bei Li
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Xue Wu
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Chunyang Jiang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Xiaofei Zhang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Rulin Ma
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Lu Yang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Chao Wang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Xiao Zhang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Tao Xia
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China
| | - Aiguo Wang
- Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China.
| |
Collapse
|
|
19
|
Huang L, Wang G. The Effects of Different Factors on the Behavior of Neural Stem Cells. Stem Cells Int 2017; 2017:9497325. [PMID: 29358957 PMCID: PMC5735681 DOI: 10.1155/2017/9497325] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/18/2017] [Indexed: 02/07/2023] Open
Abstract
The repair of central nervous system (CNS) injury has been a worldwide problem in the biomedical field. How to reduce the damage to the CNS and promote the reconstruction of the damaged nervous system structure and function recovery has always been the concern of nerve tissue engineering. Multiple differentiation potentials of neural stem cell (NSC) determine the application value for the repair of the CNS injury. Thus, how to regulate the behavior of NSCs becomes the key to treating the CNS injury. So far, a large number of researchers have devoted themselves to searching for a better way to regulate the behavior of NSCs. This paper summarizes the effects of different factors on the behavior of NSCs in the past 10 years, especially on the proliferation and differentiation of NSCs. The final purpose of this review is to provide a more detailed theoretical basis for the clinical repair of the CNS injury by nerve tissue engineering.
Collapse
Affiliation(s)
- Lixiang Huang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China
| | - Gan Wang
- Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan 410073, China
| |
Collapse
|
|
20
|
Petersen K, Hultman MT, Bytingsvik J, Harju M, Evenset A, Tollefsen KE. Characterizing cytotoxic and estrogenic activity of Arctic char tissue extracts in primary Arctic char hepatocytes. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2017; 80:1017-1030. [PMID: 28862540 DOI: 10.1080/15287394.2017.1357277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Contaminants from various anthropogenic activities are detected in the Arctic due to long-range atmospheric transport, ocean currents, and living organisms such as migrating fish or seabirds. Although levels of persistent organic pollutants (POPs) in Arctic fish are generally low, local hot spots of contamination were found in freshwater systems such as Lake Ellasjøen at Bjørnøya (Bear Island, Norway). Higher concentrations of organic halogenated compounds (OHC), and higher levels of cytochrome P450 and DNA-double strand breaks were reported in Arctic char (Salvelinus alpinus) from this lake compared to fish from other lakes on Bjørnøya. Although several of the measured contaminants are potential endocrine disrupters, few studies have investigated potential endocrine disruptive effects of the contaminant cocktail in this fish population. The aim of this study was to compare acutely toxic and estrogenic potency of the cocktail of pollutants as evidenced by cytotoxic and/or estrogenic effects in vitro using extracts of Arctic char livers from contaminated Lake Ellasjøen with those from less contaminated Lake Laksvatn at Bjørnøya. This was performed by in situ sampling and contaminant extraction from liver tissue, followed by chemical analysis and in vitro testing of the following contaminated tissue extracts: F1-nonpolar OHC, F2-polar pesticides and metabolites of OHC, and F3-polar OHC. Contaminant levels were highest in extracts from Ellasjøen fish. The F2 and F3 extracts from Lake Laksvatn and Lake Ellasjøen fish reduced in vitro cell viability at a concentration ratio of 0.03-1 relative to tissue concentration in Arctic char. Only the F3 liver extract from Ellasjøen fish increased in vitro vitellogenin protein expression. Although compounds such as estrogenic OH-PCBs were quantified in Ellasjøen F3 extracts, it remains to be determined which compounds were inducing estrogenic effects.
Collapse
Affiliation(s)
- Karina Petersen
- a Section of Ecotoxicology , Norwegian Institute for Water Research (NIVA) , Oslo , Norway
| | - Maria T Hultman
- a Section of Ecotoxicology , Norwegian Institute for Water Research (NIVA) , Oslo , Norway
| | - Jenny Bytingsvik
- c Department of Arctic R&D , Akvaplan-niva, Fram Centre , Tromsø , Norway
| | - Mikael Harju
- b Environmental Chemistry Department , Norwegian Institute for Air Research (NILU) , Tromsø , Norway
| | - Anita Evenset
- c Department of Arctic R&D , Akvaplan-niva, Fram Centre , Tromsø , Norway
- d Department of Arctic and Marine Biology , UiT the Arctic University of Norway , Tromsø , Norway
| | - Knut Erik Tollefsen
- a Section of Ecotoxicology , Norwegian Institute for Water Research (NIVA) , Oslo , Norway
| |
Collapse
|
|
21
|
Ochiai M, Nomiyama K, Isobe T, Yamada TK, Tajima Y, Matsuda A, Shiozaki A, Matsuishi T, Amano M, Iwata H, Tanabe S. Polybrominated diphenyl ethers (PBDEs) and their hydroxylated and methoxylated analogues in the blood of harbor, Dall's and finless porpoises from the Japanese coastal waters. MARINE ENVIRONMENTAL RESEARCH 2017; 128:124-132. [PMID: 27836186 DOI: 10.1016/j.marenvres.2016.11.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 10/27/2016] [Accepted: 11/04/2016] [Indexed: 06/06/2023]
Abstract
This study investigated the accumulation of polybrominated diphenyl ethers (PBDEs) and their hydroxylated and methoxylated analogues (OH-PBDEs and MeO-PBDEs) in the blood of harbor porpoises, Dall's porpoises, and finless porpoises stranded or bycaught in Japanese coastal waters and in the North Pacific Ocean. Moreover, we suggested the origins of these contaminants and the factors affecting their pattern of accumulation. Levels of PBDEs in Dall's porpoises were one order of magnitude greater than those in the other species. OH-PBDE and MeO-PBDE levels were comparable to those of PBDEs. However, no correlation was found between the levels of OH-PBDEs and PBDEs, whereas a strong correlation was found between that of OH-PBDEs and MeO-PBDEs (p < 0.001). 6OH-BDE47, reported compound biosynthesized by marine low-trophic level organisms, was the dominant congener. These results suggest that PBDEs found in these porpoise species derive from flame retardants, but OH-PBDEs and MeO-PBDEs are mainly of natural origins.
Collapse
Affiliation(s)
- Mari Ochiai
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama, Japan
| | - Kei Nomiyama
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama, Japan.
| | - Tomohiko Isobe
- Center for Environmental Health Sciences, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Japan
| | - Tadasu K Yamada
- Department of Zoology, National Museum of Nature and Science, 4-1-1 Amakubo, Tsukuba, Japan
| | - Yuko Tajima
- Department of Zoology, National Museum of Nature and Science, 4-1-1 Amakubo, Tsukuba, Japan
| | - Ayaka Matsuda
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato-cho, Hakodate, Hokkaido, Japan
| | - Akira Shiozaki
- Graduate School of Fisheries Science and Environmental Studies, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, Japan
| | - Takashi Matsuishi
- Faculty of Fisheries Sciences, Hokkaido University, 3-1-1 Minato-cho, Hakodate, Hokkaido, Japan
| | - Masao Amano
- Graduate School of Fisheries Science and Environmental Studies, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, Japan
| | - Hisato Iwata
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama, Japan
| | - Shinsuke Tanabe
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama, Japan
| |
Collapse
|
|
22
|
Extracellular Signal-Regulated Kinase 5 is Required for Low-Concentration H 2O 2-Induced Angiogenesis of Human Umbilical Vein Endothelial Cells. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6895730. [PMID: 28540300 PMCID: PMC5429924 DOI: 10.1155/2017/6895730] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 02/22/2017] [Accepted: 03/09/2017] [Indexed: 01/28/2023]
Abstract
Background. The aim of this study was to assess the effects of low concentrations of H2O2 on angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro and explore the underlying mechanisms. Methods. HUVECs were cultured and stimulated with different concentrations of H2O2. Flow cytometric analysis was used to select an optimal concentration of H2O2 for the following experiments. Cell proliferation, migration, and tubule formation were evaluated by Cell Counting Kit-8 (CCK-8) assays, scratch wound assays, and Matrigel tubule formation assays, respectively. For gain and loss of function studies, constitutively active MEK5 (CA-MEK5) and ERK5 shRNA lentiviruses were used to activate or knock down extracellular signal-regulated kinase 5 (ERK5). Results. We found that low concentrations of H2O2 promoted HUVECs proliferation, migration, and tubule formation. ERK5 in HUVECs was significantly activated by H2O2. Enhanced ERK5 activity significantly amplified the proangiogenic effects of H2O2; in contrast, ERK5 knock-down abrogated the effects of H2O2. Conclusions. Our results confirmed that low concentrations of H2O2 promoted HUVECs angiogenesis in vitro, and ERK5 is an essential mediator of this process. Therefore, ERK5 may be a potential therapeutic target for promoting angiogenesis and improving graft survival.
Collapse
|
|
23
|
Dach K, Bendt F, Huebenthal U, Giersiefer S, Lein PJ, Heuer H, Fritsche E. BDE-99 impairs differentiation of human and mouse NPCs into the oligodendroglial lineage by species-specific modes of action. Sci Rep 2017; 7:44861. [PMID: 28317842 PMCID: PMC5357893 DOI: 10.1038/srep44861] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 02/15/2017] [Indexed: 01/02/2023] Open
Abstract
Polybrominated diphenyl ethers (PBDEs) are bioaccumulating flame retardants causing developmental neurotoxicity (DNT) in humans and rodents. Their DNT effects are suspected to involve thyroid hormone (TH) signaling disruption. Here, we tested the hypothesis whether disturbance of neural progenitor cell (NPC) differentiation into the oligodendrocyte lineage (O4+ cells) by BDE-99 involves disruption of TH action in human and mouse (h,m)NPCs. Therefore, we quantified differentiation of NPCs into O4+ cells and measured their maturation via expression of myelin-associated genes (hMBP, mMog) in presence and absence of TH and/or BDE-99. T3 promoted O4+ cell differentiation in mouse, but not hNPCs, and induced hMBP/mMog gene expression in both species. BDE-99 reduced generation of human and mouse O4+ cells, but there is no indication for BDE-99 interfering with cellular TH signaling during O4+ cell formation. BDE-99 reduced hMBP expression due to oligodendrocyte reduction, but concentrations that did not affect the number of mouse O4+ cells inhibited TH-induced mMog transcription by a yet unknown mechanism. In addition, ascorbic acid antagonized only the BDE-99-dependent loss of human, not mouse, O4+ cells by a mechanism probably independent of reactive oxygen species. These data point to species-specific modes of action of BDE-99 on h/mNPC development into the oligodendrocyte lineage.
Collapse
Affiliation(s)
- Katharina Dach
- IUF- Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Duesseldorf, Germany
| | - Farina Bendt
- IUF- Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Duesseldorf, Germany
| | - Ulrike Huebenthal
- IUF- Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Duesseldorf, Germany
| | - Susanne Giersiefer
- IUF- Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Duesseldorf, Germany
| | - Pamela J Lein
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, United States
| | - Heike Heuer
- IUF- Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Duesseldorf, Germany
| | - Ellen Fritsche
- IUF- Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225, Duesseldorf, Germany
| |
Collapse
|
|
24
|
Human Excretion of Polybrominated Diphenyl Ether Flame Retardants: Blood, Urine, and Sweat Study. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3676089. [PMID: 28373979 PMCID: PMC5360950 DOI: 10.1155/2017/3676089] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 02/26/2017] [Indexed: 01/17/2023]
Abstract
Commonly used as flame retardants, polybrominated diphenyl ethers (PBDEs) are routinely detected in the environment, animals, and humans. Although these persistent organic pollutants are increasingly recognized as having serious health implications, particularly for children, this is the first study, to our knowledge, to investigate an intervention for human elimination of bioaccumulated PBDEs. Objectives. To determine the efficacy of blood, urine, and perspiration as PBDE biomonitoring mediums; assess excretion of five common PBDE congeners (28, 47, 99, 100, and 153) in urine and perspiration; and explore the potential of induced sweating for decreasing bioaccumulated PBDEs. Results. PBDE congeners were not found in urine samples; findings focus on blood and perspiration. 80% of participants tested positive in one or more body fluids for PBDE 28, 100% for PBDE 47, 95% for PBDE 99, and 90% for PBDE 100 and PBDE 153. Induced perspiration facilitated excretion of the five congeners, with different rates of excretion for different congeners. Conclusion. Blood testing provides only a partial understanding of human PBDE bioaccumulation; testing of both blood and perspiration provides a better understanding. This study provides important baseline evidence for regular induced perspiration as a potential means for therapeutic PBDE elimination. Fetotoxic and reproductive effects of PBDE exposure highlight the importance of further detoxification research.
Collapse
|
|
25
|
Wang H, Engstrom AK, Xia Z. Cadmium impairs the survival and proliferation of cultured adult subventricular neural stem cells through activation of the JNK and p38 MAP kinases. Toxicology 2017; 380:30-37. [PMID: 28163110 DOI: 10.1016/j.tox.2017.01.013] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 01/14/2017] [Accepted: 01/17/2017] [Indexed: 12/13/2022]
Abstract
Cadmium (Cd) is a heavy metal with a long biological half-life in humans and is recognized as a toxic pollutant. Cd is also a potential neurotoxicant and its exposure is associated with olfactory impairment in humans. However, the molecular and cellular mechanisms of Cd neurotoxicity are not well defined. Adult neurogenesis is a process that generates functional neurons from adult neural stem/progenitor cells (aNPCs). It occurs in specific regions of the adult brain including the subventricular zone (SVZ) along the lateral ventricles in mammals, a process that is critical for olfaction. Various external stimuli can modulate adult neurogenesis and the effect of neurotoxicants on adult neurogenesis is just beginning to be elucidated. Since Cd exposure can impair olfaction in humans, the goal of this study is to investigate the effects of Cd on SVZ adult neurogenesis and underlying mechanisms using primary cultured SVZ-aNPCs. In this study, we report that low-level Cd exposure decreases cell number, induces apoptosis, and inhibits cell proliferation in SVZ-aNPCs. Furthermore, Cd exposure significantly increases phosphorylation of c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase in these cells, indicative of JNK and p38 activation. Pharmacological inhibition of JNK or p38 MAPK kinases attenuated Cd-induced cell loss and apoptosis. Cd treatment did not cause cell loss or apoptosis in SVZ-aNPCs prepared from transgenic mice null for the neural-specific JNK3 isoform. These data suggest a critical role for p38 and JNK3 MAP kinases in Cd neurotoxicity. These results are, to our knowledge, the first demonstration that Cd impairs SVZ adult neurogenesis in vitro, which may contribute to its neurotoxicity in olfaction.
Collapse
Affiliation(s)
- Hao Wang
- Toxicology Program in the Department of Environmental and Occupational Health Science, University of Washington, United States
| | - Anna K Engstrom
- Toxicology Program in the Department of Environmental and Occupational Health Science, University of Washington, United States
| | - Zhengui Xia
- Toxicology Program in the Department of Environmental and Occupational Health Science, University of Washington, United States.
| |
Collapse
|
|
26
|
Li J, Zhang Y, Du Z, Peng J, Mao L, Gao S. Biotransformation of OH-PBDEs by pig liver microsomes: Investigating kinetics, identifying metabolites, and examining the role of different CYP isoforms. CHEMOSPHERE 2016; 148:354-360. [PMID: 26820782 DOI: 10.1016/j.chemosphere.2016.01.056] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 01/13/2016] [Accepted: 01/14/2016] [Indexed: 06/05/2023]
Abstract
Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are of great concern due to their potential risk to animal and human health. The biotransformation potential of OH-PBDEs in organisms is important for the understanding of their health risk. In the present study, the biotransformation of 3'-OH-2,4-di-BDE (3'-OH-BDE-7), 4'-OH-2,2',4-tri-BDE (4'-OH-BDE-17) and 3-OH-2,2',4,4'-tetra-BDE (3-OH-BDE-47) by pig liver microsomes was studied. Compared with their precursor PBDEs, the three OH-PBDEs were more readily biotransformed by pig liver microsomes, and the biotransformation rate followed the order: 3'-OH-BDE-7 > 4'-OH-BDE-17 > 3-OH-BDE-47. These results revealed that the biotransformation rate of OH-PBDEs was decreased with an increase in the number of bromine substituents. Cleavage of the diphenyl ether bond was the dominant pathway for biotransformation of the three OH-PBDEs by pig liver microsomes, while debromination and hydroxylation were found to be of less importance. CYP3A4 was suggested to be the specific enzyme responsible for the biotransformation of OH-PBDEs via associated inhibition assay. These findings may enrich our understanding of health risk associated with OH-PBDEs in mammals and human beings.
Collapse
Affiliation(s)
- Jianhua Li
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Ya Zhang
- Nanjing Institute of Environmental Sciences, Ministry of Environmental Protection of the People's Republic of China, Nanjing 210042, PR China
| | - Zhongkun Du
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Jianbiao Peng
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Liang Mao
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China
| | - Shixiang Gao
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
| |
Collapse
|
|
27
|
Singh S, Srivastava A, Kumar V, Pandey A, Kumar D, Rajpurohit CS, Khanna VK, Yadav S, Pant AB. Stem Cells in Neurotoxicology/Developmental Neurotoxicology: Current Scenario and Future Prospects. Mol Neurobiol 2015; 53:6938-6949. [DOI: 10.1007/s12035-015-9615-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 12/03/2015] [Indexed: 12/26/2022]
|
|
28
|
Macaulay LJ, Chen A, Rock KD, Dishaw LV, Dong W, Hinton DE, Stapleton HM. Developmental toxicity of the PBDE metabolite 6-OH-BDE-47 in zebrafish and the potential role of thyroid receptor β. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2015; 168:38-47. [PMID: 26433919 PMCID: PMC4618599 DOI: 10.1016/j.aquatox.2015.09.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 09/14/2015] [Accepted: 09/15/2015] [Indexed: 05/13/2023]
Abstract
6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE-47) is both a polybrominated diphenyl ether (PBDE) flame retardant metabolite and a marine natural product. It has been identified both as a neurotoxicant in cell-based studies and as a developmental toxicant in zebrafish. However, hydroxylated PBDE metabolites are also considered thyroid hormone disruptors due to their structural similarity to endogenous thyroid hormones. The purpose of this study was to evaluate the effects of 6-OH-BDE-47 on a developmental pathway regulated by thyroid hormones in zebrafish. Morphological measurements of development (head trunk angle, otic vesicle length, and eye pigmentation) were recorded in embryos at 30h post fertilization (hpf) and detailed craniofacial morphology was examined in 4 day old larvae using cartilage staining. Exposure to 6-OH-BDE-47 resulted in severe developmental delays. A 100nM concentration resulted in a 26% decrease in head trunk angle, a 54% increase in otic vesicle length, and a 42% decrease in eye pigmentation. Similarly, altered developmental morphology was observed following thyroid receptor β morpholino knockdown, exposure to the thyroid hormone triiodothyronine (T3) or to thyroid disrupting chemicals (TDC; iopanoic acid and propylthiouracil). The threshold for lower jaw deformities and craniofacial cartilage malformations was at doses greater than 50nM. Of interest, these developmental delays and effects were rescued by microinjection of TRβ mRNA during the 1-2 cell stage. These data indicate that OH-BDEs can adversely affect early life development of zebrafish and suggest they may be impacting thyroid hormone regulation in vivo through downregulation of the thyroid hormone receptor.
Collapse
Affiliation(s)
- Laura J Macaulay
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
| | - Albert Chen
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
| | - Kylie D Rock
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
| | - Laura V Dishaw
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
| | - Wu Dong
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
| | - David E Hinton
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
| | | |
Collapse
|
|
29
|
Hendriks HS, Westerink RH. Neurotoxicity and risk assessment of brominated and alternative flame retardants. Neurotoxicol Teratol 2015; 52:248-69. [DOI: 10.1016/j.ntt.2015.09.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 09/01/2015] [Accepted: 09/01/2015] [Indexed: 11/29/2022]
|
|
30
|
Inducible activation of ERK5 MAP kinase enhances adult neurogenesis in the olfactory bulb and improves olfactory function. J Neurosci 2015; 35:7833-49. [PMID: 25995470 DOI: 10.1523/jneurosci.3745-14.2015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury.
Collapse
|
|
31
|
Bradford AB, McNutt PM. Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons. World J Stem Cells 2015; 7:899-921. [PMID: 26240679 PMCID: PMC4515435 DOI: 10.4252/wjsc.v7.i6.899] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/28/2015] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments.
Collapse
|
|
32
|
Lu J, Shao J, Liu H, Wang Z, Huang Q. Formation of Halogenated Polyaromatic Compounds by Laccase Catalyzed Transformation of Halophenols. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2015; 49:8550-8557. [PMID: 26147794 DOI: 10.1021/acs.est.5b02399] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Laccases are a type of extracellular enzyme produced by fungi, bacteria, and plants. Laccase can catalyze one-electron oxidation of a variety of phenolic compounds using molecular oxygen as the electron acceptor. In this study, transformation of halophenols (XPs) in laccase-catalyzed oxidation processes was explored. We first examined the intrinsic reaction kinetics and found that the transformation of XPs appeared first order to the concentrations of both XPs and laccase. A numerical model was developed to describe the role of humic acid (HA) in this process. It was demonstrated that HA could reverse the oxidation of XPs by acting as the inner filtrator of XP radical intermediates formed upon reactions between the substrates and laccase. The extent of such reversion was proportional to HA concentration. MS analysis in combination with quantum chemistry computation suggested that coupling products were generated. XPs coupled to each via C-C or C-O-C pathways, generating hydroxyl polyhalogenated biphenyl ethers (OH-PCDEs) and hydroxyl polyhalogenated biphenyls, respectively. Many of these polyhalogenated products are known to be hazardous to the ecosystem and human health, but they are not synthetic chemicals. This study shed light on their genesis in the environmental media.
Collapse
Affiliation(s)
- Junhe Lu
- †College of Resources and Environmental Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Juan Shao
- †College of Resources and Environmental Science, Nanjing Agricultural University, Nanjing 210095, China
| | - Hui Liu
- ‡School of Environment, Nanjing University, Nanjing 210093, China
| | - Zunyao Wang
- ‡School of Environment, Nanjing University, Nanjing 210093, China
| | - Qingguo Huang
- §Department of Crop and Soil Sciences, University of Georgia, Griffin, 30223, United States
| |
Collapse
|
|
33
|
Macaulay LJ, Bailey JM, Levin ED, Stapleton HM. Persisting effects of a PBDE metabolite, 6-OH-BDE-47, on larval and juvenile zebrafish swimming behavior. Neurotoxicol Teratol 2015; 52:119-26. [PMID: 25979796 DOI: 10.1016/j.ntt.2015.05.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 04/30/2015] [Accepted: 05/04/2015] [Indexed: 12/09/2022]
Abstract
Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants that are widely detected in the environment, biota, and humans. In mammals, PBDEs can be oxidatively metabolized to form hydroxylated polybrominated diphenyl ethers (OH-BDEs). While studies have examined behavioral deficits or alterations induced by exposure to PBDEs in both rodents and fish, no study to date has explored behavioral effects from exposure to OH-BDEs, which have been shown to have greater endocrine disrupting potential compared to PBDEs. In the present study, zebrafish (Danio rerio) were exposed during embryonic and larval development (0-6 days post fertilization, dpf) to a PBDE metabolite, 6-hydroxy, 2,2',4,4' tetrabromodiphenyl ether (10-50 nM) and then examined for short and long-term behavioral effects. Exposed zebrafish tested as larvae (6 dpf) showed an altered swimming response to light-dark transitions, exhibiting hypoactivity in light periods compared to control fish. When fish exposed from 0-6 dpf were tested as juveniles (45 dpf), they showed an increased fear response and hyperactivity in response to tests of novel environment exploration and habituation learning. These results demonstrate that early life exposure to a PBDE metabolite can have immediate or later life (more than a month after exposure) effects on activity levels, habituation, and fear/anxiety.
Collapse
Affiliation(s)
- Laura J Macaulay
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
| | - Jordan M Bailey
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
| | - Edward D Levin
- Nicholas School of the Environment, Duke University, Durham, NC 27708, USA; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA
| | | |
Collapse
|
|
34
|
Engstrom A, Wang H, Xia Z. Lead decreases cell survival, proliferation, and neuronal differentiation of primary cultured adult neural precursor cells through activation of the JNK and p38 MAP kinases. Toxicol In Vitro 2015; 29:1146-55. [PMID: 25967738 DOI: 10.1016/j.tiv.2015.05.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 05/01/2015] [Accepted: 05/03/2015] [Indexed: 12/23/2022]
Abstract
Adult hippocampal neurogenesis is the process whereby adult neural precursor cells (aNPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG) generate adult-born, functional neurons in the hippocampus. This process is modulated by various extracellular and intracellular stimuli, and the adult-born neurons have been implicated in hippocampus-dependent learning and memory. However, studies on how neurotoxic agents affect this process and the underlying mechanisms are limited. The goal of this study was to determine whether lead, a heavy metal, directly impairs critical processes in adult neurogenesis and to characterize the underlying signaling pathways using primary cultured SGZ-aNPCs isolated from adult mice. We report here that lead significantly increases apoptosis and inhibits proliferation in SGZ-aNPCs. In addition, lead significantly impairs spontaneous neuronal differentiation and maturation. Furthermore, we found that activation of the c-Jun NH2-terminal kinase (JNK) and p38 mitogen activated protein (MAP) kinase signaling pathways are important for lead cytotoxicity. Our data suggest that lead can directly act on adult neural stem cells and impair critical processes in adult hippocampal neurogenesis, which may contribute to its neurotoxicity and adverse effects on cognition in adults.
Collapse
Affiliation(s)
- Anna Engstrom
- Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
| | - Hao Wang
- Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
| | - Zhengui Xia
- Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
| |
Collapse
|
|
35
|
Gross MS, Butryn DM, McGarrigle BP, Aga DS, Olson JR. Primary role of cytochrome P450 2B6 in the oxidative metabolism of 2,2',4,4',6-pentabromodiphenyl ether (BDE-100) to hydroxylated BDEs. Chem Res Toxicol 2015; 28:672-81. [PMID: 25629761 DOI: 10.1021/tx500446c] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Human exposure to polybrominated diphenyl ethers (PBDEs) through various routes poses deleterious health effects. PBDEs are biotransformed into hydroxylated metabolites (OH-BDEs) via cytochrome P450s (P450s), which may add to their neurotoxic effects. This study characterizes the in vitro metabolism of 2,2',4,4',6-pentabromodiphenyl ether (BDE-100), one of the most abundant PBDE congeners found in humans, by recombinant human P450s and pooled human liver microsomes (HLMs). Ten recombinant P450s were individually incubated with BDE-100 to monitor P450-specific metabolism. P450 2B6 was found to be the predominant enzyme responsible for nearly all formation of six mono-OH-pentaBDE and two di-OH-pentaBDE metabolites. Four metabolites were identified as 3-hydroxy-2,2',4,4',6-pentabromodiphenyl ether (3-OH-BDE-100), 5'-hydroxy-2,2',4,4',6-pentabromodiphenyl ether (5'-OH-BDE-100), 6'-hydroxy-2,2',4,4',6-pentabromodiphenyl ether (6'-OH-BDE-100), and 4'-hydroxy-2,2',4,5',6-pentabromodiphenyl ether (4'-OH-BDE-103) through use of reference standards. The two remaining mono-OH-pentaBDE metabolites were hypothesized using mass spectral fragmentation characteristics of derivatized OH-BDEs, which allowed prediction of an ortho-OH-pentaBDE and a para-OH-pentaBDE positional isomer. Additional information based on theoretical boiling point calculations using COnductor-like Screening MOdel for Realistic Solvents (COSMO-RS) and experimental chromatographic retention times were used to identify the hypothesized metabolites as 2'-hydroxy-2,3',4,4',6-pentabromodiphenyl ether (2'-OH-BDE-119) and 4-hydroxy-2,2',4',5,6-pentabromodiphenyl ether (4-OH-BDE-91), respectively. Kinetic studies of BDE-100 metabolism using P450 2B6 and HLMs revealed Km values ranging from 4.9 to 7.0 μM and 6-10 μM, respectively, suggesting a high affinity toward the formation of OH-BDEs. Compared to the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) reported in previous studies, BDE-100 appears to be more slowly metabolized by P450s due to the presence of a third ortho-substituted bromine atom.
Collapse
Affiliation(s)
- Michael S Gross
- †Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
| | - Deena M Butryn
- †Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
| | - Barbara P McGarrigle
- ‡Department of Pharmacology and Toxicology and Department of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| | - Diana S Aga
- †Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
| | - James R Olson
- ‡Department of Pharmacology and Toxicology and Department of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States
| |
Collapse
|
|
36
|
Simpson S, Gross MS, Olson JR, Zurek E, Aga DS. Identification of polybrominated diphenyl ether metabolites based on calculated boiling points from COSMO-RS, experimental retention times, and mass spectral fragmentation patterns. Anal Chem 2015; 87:2299-305. [PMID: 25565148 DOI: 10.1021/ac504107b] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The COnductor-like Screening MOdel for Realistic Solvents (COSMO-RS) was used to predict the boiling points of several polybrominated diphenyl ethers (PBDEs) and methylated derivatives (MeO-BDEs) of monohydroxylated BDE (OH-BDE) metabolites. The linear correlation obtained by plotting theoretical boiling points calculated by COSMO-RS against experimentally determined retention times from gas chromatography-mass spectrometry facilitated the identification of PBDEs and OH-BDEs. This paper demonstrates the applicability of COSMO-RS in identifying unknown PBDE metabolites of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',6-pentabromodiphenyl ether (BDE-100). Metabolites of BDE-47 and BDE-100 were formed through individual incubations of each PBDE with recombinant cytochrome P450 2B6. Using calculated boiling points and characteristic mass spectral fragmentation patterns of the MeO-BDE positional isomers, the identities of the unknown monohydroxylated metabolites were proposed to be 2'-hydroxy-2,3',4,4'-tetrabromodiphenyl ether (2'-OH-BDE-66) from BDE-47, and 2'-hydroxy-2,3',4,4',6-pentabromodiphenyl ether (2'-OH-BDE-119) and 4-hydroxy-2,2',3,4',6-pentabromodiphenyl ether (4-OH-BDE-91) from BDE-100. The collective use of boiling points predicted with COSMO-RS, and characteristic mass spectral fragmentation patterns provided a valuable tool toward the identification of isobaric compounds.
Collapse
Affiliation(s)
- Scott Simpson
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY) , Buffalo, New York 14260, United States
| | | | | | | | | |
Collapse
|
|
37
|
Qu BL, Yu W, Huang YR, Cai BN, Du LH, Liu F. 6-OH-BDE-47 promotes human lung cancer cells epithelial mesenchymal transition via the AKT/Snail signal pathway. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2015; 39:271-279. [PMID: 25531265 DOI: 10.1016/j.etap.2014.11.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 11/27/2014] [Accepted: 11/29/2014] [Indexed: 06/04/2023]
Abstract
Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been detected in the various human tissues. The OH-PBDEs are suggested to be stronger endocrine-disrupting compounds than PBDEs, therefore the toxicological effects of OH-PBDEs had received lots of attention. However, there is no study about the carcinogenic effect of OH-PBDEs and their estrogen potencies on the tumorigenesis and development of cancer. In the present study, we found that 6-hydroxy-2,2',4',4'-tetrabromodiphenyl ether (6-OH-BDE-47), the most abundant OH-PBDE congeners in human serum, promoted the in vitro migration of lung cancer A549 and H358 cells by induction of epithelial to mesenchymal transition (EMT). This was confirmed by that 6-OH-BDE-47 significantly down regulated the expression of epithelial markers E-cadherin (E-Cad) and zona occludin-1 (ZO-1) while up regulated the mesenchymal markers vimentin (Vim) and N-cadherin (N-Cad). 6-OH-BDE-47 up regulated the protein while not mRNA levels of Snail, which was the key transcription factor of EMT. Silencing of Snail by use of siRNA attenuated the 6-OH-BDE-47 induced EMT. This suggested that the stabilization of Snail was essential for 6-OH-BDE-47 induced EMT. Further, the treatment of 6-OH-BDE-47 increased the phosphorylation of AKT and ERK in A549 cells. Only PI3K/AKT inhibitor (LY294002), but not ERK inhibitor (PD98059), completely blocked the 6-OH-BDE-47 induced up regulation of Snail and down regulation of E-Cad, suggesting that PI3K/AKT pathway is important for 6-OH-BDE-47-mediated Snail stabilization and EMT in A549 cells. Generally, our results revealed for the first time that 6-OH-BDE-47 promoted the EMT of lung cancer cells via AKT/Snail signals. This suggested that more attention should be paid to the effects of OH-PBDEs on tumorigenesis and development of lung cancer.
Collapse
Affiliation(s)
- Bao-Lin Qu
- Department of Radiation Oncology, PLA General Hospital, Beijing 100853, China.
| | - Wei Yu
- Department of Radiation Oncology, PLA General Hospital, Beijing 100853, China
| | - Yu-Rong Huang
- Department of Radiation Oncology, PLA General Hospital, Beijing 100853, China
| | - Bo-Ning Cai
- Department of Radiation Oncology, PLA General Hospital, Beijing 100853, China
| | - Le-Hui Du
- Department of Radiation Oncology, PLA General Hospital, Beijing 100853, China
| | - Fang Liu
- Department of Radiation Oncology, PLA General Hospital, Beijing 100853, China
| |
Collapse
|
|
38
|
Dong W, Macaulay LJ, Kwok KW, Hinton DE, Ferguson PL, Stapleton HM. The PBDE metabolite 6-OH-BDE 47 affects melanin pigmentation and THRβ MRNA expression in the eye of zebrafish embryos. ACTA ACUST UNITED AC 2014; 2. [PMID: 25767823 PMCID: PMC4354867 DOI: 10.4161/23273739.2014.969072] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Polybrominated diphenyl ethers and their hydroxyl-metabolites (OH-BDEs) are commonly detected contaminants in human serum in the US population. They are also considered to be endocrine disruptors, and are specifically known to affect thyroid hormone regulation. In this study, we investigated and compared the effects of a PBDE and its OH-BDE metabolite on developmental pathways regulated by thyroid hormones using zebrafish as a model. Exposure to 6-OHBDE 47 (10–100 nM), but not BDE 47 (1–50 μM), led to decreased melanin pigmentation and increased apoptosis in the retina of zebrafish embryos in a concentration-dependent manner in short-term exposures (4 – 30 hours). Six-OH-BDE 47 exposure also significantly decreased thyroid hormone receptor β (THRβ) mRNA expression, which was confirmed using both RT-PCR and in situ hybridization (whole mount and paraffin- section). Interestingly, exposure to the native thyroid hormone, triiodothyronine (T3) also led to similar responses: decreased THRβ mRNA expression, decreased melanin pigmentation and increased apoptosis, suggesting that 6-OH-BDE 47 may be acting as a T3 mimic. To further investigate short-term effects that may be regulated by THRβ, experiments using a morpholino gene knock down and THRβ mRNA over expression were conducted. Knock down of THRβ led to decreases in melanin pigmentation and increases in apoptotic cells in the eye of zebrafish embryos, similar to exposure to T3 and 6-OH-BDE 47, but THRβ mRNA overexpression rescued these effects. Histological analysis of eyes at 22 hpf from each group revealed that exposure to T3 or to 6-OH-BDE 47 was associated with a decrease of melanin and diminished proliferation of cells in layers of retina near the choroid. This study suggests that 6-OH-BDE 47 disrupts the activity of THRβ in early life stages of zebrafish, and warrants further studies on effects in developing humans.
Collapse
Affiliation(s)
- Wu Dong
- Nicholas School of the Environment; Duke University; Durham, NC USA
| | - Laura J Macaulay
- Nicholas School of the Environment; Duke University; Durham, NC USA
| | - Kevin Wh Kwok
- Nicholas School of the Environment; Duke University; Durham, NC USA
| | - David E Hinton
- Nicholas School of the Environment; Duke University; Durham, NC USA
| | - P Lee Ferguson
- Nicholas School of the Environment; Duke University; Durham, NC USA
| | | |
Collapse
|
|
39
|
Li T, Wang G. Computer-aided targeting of the PI3K/Akt/mTOR pathway: toxicity reduction and therapeutic opportunities. Int J Mol Sci 2014; 15:18856-91. [PMID: 25334061 PMCID: PMC4227251 DOI: 10.3390/ijms151018856] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 09/21/2014] [Accepted: 10/08/2014] [Indexed: 12/14/2022] Open
Abstract
The PI3K/Akt/mTOR pathway plays an essential role in a wide range of biological functions, including metabolism, macromolecular synthesis, cell growth, proliferation and survival. Its versatility, however, makes it a conspicuous target of many pathogens; and the consequential deregulations of this pathway often lead to complications, such as tumorigenesis, type 2 diabetes and cardiovascular diseases. Molecular targeted therapy, aimed at modulating the deregulated pathway, holds great promise for controlling these diseases, though side effects may be inevitable, given the ubiquity of the pathway in cell functions. Here, we review a variety of factors found to modulate the PI3K/Akt/mTOR pathway, including gene mutations, certain metabolites, inflammatory factors, chemical toxicants, drugs found to rectify the pathway, as well as viruses that hijack the pathway for their own synthetic purposes. Furthermore, this evidence of PI3K/Akt/mTOR pathway alteration and related pathogenesis has inspired the exploration of computer-aided targeting of this pathway to optimize therapeutic strategies. Herein, we discuss several possible options, using computer-aided targeting, to reduce the toxicity of molecularly-targeted therapy, including mathematical modeling, to reveal system-level control mechanisms and to confer a low-dosage combination therapy, the potential of PP2A as a therapeutic target, the formulation of parameters to identify patients who would most benefit from specific targeted therapies and molecular dynamics simulations and docking studies to discover drugs that are isoform specific or mutation selective so as to avoid undesired broad inhibitions. We hope this review will stimulate novel ideas for pharmaceutical discovery and deepen our understanding of curability and toxicity by targeting the PI3K/Akt/mTOR pathway.
Collapse
Affiliation(s)
- Tan Li
- Department of Biology, South University of Science and Technology of China, 1088 Xueyuan Rd., Shenzhen 518055, China.
| | - Guanyu Wang
- Department of Biology, South University of Science and Technology of China, 1088 Xueyuan Rd., Shenzhen 518055, China.
| |
Collapse
|
|
40
|
Costa LG, de Laat R, Tagliaferri S, Pellacani C. A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity. Toxicol Lett 2014; 230:282-94. [PMID: 24270005 PMCID: PMC4028440 DOI: 10.1016/j.toxlet.2013.11.011] [Citation(s) in RCA: 197] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 11/12/2013] [Indexed: 01/01/2023]
Abstract
Polybrominated diphenyl ethers (PBDEs), extensively used in the past few decades as flame retardants in a variety of consumer products, have become world-wide persistent environmental pollutants. Levels in North America are usually higher than those in Europe and Asia, and body burden is 3-to-9-fold higher in infants and toddlers than in adults. The latter has raised concern for potential developmental toxicity and neurotoxicity of PBDEs. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or post-natal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. The mechanisms underlying the developmental neurotoxic effects of PBDEs are not known, though several hypotheses have been put forward. One general mode of action relates to the ability of PBDEs to impair thyroid hormone homeostasis, thus indirectly affecting the developing brain. An alternative or additional mode of action involves a direct effect of PBDEs on nervous system cells; PBDEs can cause oxidative stress-related damage (DNA damage, mitochondrial dysfunction, apoptosis), and interfere with signal transduction (particularly calcium signaling), and with neurotransmitter systems. Important issues such as bioavailability and metabolism of PBDEs, extrapolation of results to low level of exposures, and the potential effects of interactions among PBDE congeners and between PBDEs and other contaminants also need to be taken into account.
Collapse
Affiliation(s)
- Lucio G Costa
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Department of Neuroscience, University of Parma, Parma, Italy.
| | - Rian de Laat
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | | | | |
Collapse
|
|
41
|
|