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Sajjad J, Morael J, Melo TG, Foley T, Murphy A, Keane J, Popov J, Stanton C, Dinan TG, Clarke G, Cryan JF, Collins JM, O'Mahony SM. Differential cortical aspartate uptake across the oestrous cycle is associated with changes in gut microbiota in Wistar-Kyoto rats. Neurosci Lett 2025; 847:138096. [PMID: 39716584 DOI: 10.1016/j.neulet.2024.138096] [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: 11/04/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 12/25/2024]
Abstract
Pain and psychological stress are intricately linked, with sex differences evident in disorders associated with both systems. Glutamatergic signalling in the central nervous system is influenced by gonadal hormones via the hypothalamic-pituitary-adrenal axis and is central in pain research. Emerging evidence supports an important role for the gut microbiota in influencing pain signalling. Here, the functional activity of excitatory amino acid transporters (EAATs) in the anterior cingulate cortex (ACC) and lumbosacral spinal cord of male and female Wistar-Kyoto rats, an animal model of comorbid visceral hypersensitivity and enhanced stress responsivity, was investigated across the oestrous cycle. Correlations between the gut microbiota and changes in the functional activity of the central glutamatergic system were also investigated. EAAT function in the lumbosacral spinal cord was similar between males and females across the oestrous cycle. EAAT function was higher in the ACC of dioestrus females compared to proestrus and oestrus females. In males, aspartate uptake in the ACC positively correlated with Bacteroides, while aspartate uptake in the spinal cord positively correlated with the relative abundance of Lachnospiraceae NK4A136. Positive associations with aspartate uptake in the spinal cord were also observed for Alistipes and Bifidobacterium during oestrus, and Eubacterium coprostanoligenes during proestrus. Clostridium sensu stricto1 was negatively associated with aspartate uptake in the ACC in males and dioestrus females. These data indicate that glutamate metabolism in the ACC is oestrous stage-dependent and that short-chain fatty acid-producing bacteria are positively correlated with aspartate uptake in males and during specific oestrous stages in females.
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Affiliation(s)
- Jahangir Sajjad
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Jennifer Morael
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Thieza G Melo
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - Tara Foley
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - Amy Murphy
- Teagasc Food Research Centre, Moorepark, Cork, Ireland
| | - James Keane
- APC Microbiome Ireland, University College Cork, Ireland
| | - Jelena Popov
- APC Microbiome Ireland, University College Cork, Ireland
| | | | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Ireland
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
| | - James M Collins
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland.
| | - Siobhain M O'Mahony
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Ireland, University College Cork, Ireland
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Bone C, Squires EJ. Nuclear Receptor Pathways Mediating the Development of Boar Taint. Metabolites 2022; 12:metabo12090785. [PMID: 36144190 PMCID: PMC9503508 DOI: 10.3390/metabo12090785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022] Open
Abstract
The nuclear receptors PXR, CAR, and FXR are activated by various ligands and function as transcription factors to control the expression of genes that regulate the synthesis and metabolism of androstenone and skatole. These compounds are produced in entire male pigs and accumulate in the fat to cause the development of a meat quality issue known as boar taint. The extent of this accumulation is influenced by the synthesis and hepatic clearance of androstenone and skatole. For this reason, PXR, CAR, and FXR-mediated signaling pathways have garnered interest as potential targets for specialized treatments designed to reduce the development of boar taint. Recent research has also identified several metabolites produced by gut microbes that act as ligands for these nuclear receptors (e.g., tryptophan metabolites, short-chain fatty acids, bile acids); however, the connection between the gut microbiome and boar taint development is not clear. In this review, we describe the nuclear receptor signaling pathways that regulate the synthesis and metabolism of boar taint compounds and outline the genes involved. We also discuss several microbial-derived metabolites and dietary additives that are known or suspected nuclear receptor ligands and suggest how these compounds could be used to develop novel treatments for boar taint.
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Qian XH, Xie RY, Liu XL, Chen SD, Tang HD. Mechanisms of Short-Chain Fatty Acids Derived from Gut Microbiota in Alzheimer's Disease. Aging Dis 2022; 13:1252-1266. [PMID: 35855330 PMCID: PMC9286902 DOI: 10.14336/ad.2021.1215] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
Short-chain fatty acids (SCFAs) are important metabolites derived from the gut microbiota through fermentation of dietary fiber. SCFAs participate a number of physiological and pathological processes in the human body, such as host metabolism, immune regulation, appetite regulation. Recent studies on gut-brain interaction have shown that SCFAs are important mediators of gut-brain interactions and are involved in the occurrence and development of many neurodegenerative diseases, including Alzheimer's disease. This review summarizes the current research on the potential roles and mechanisms of SCFAs in AD. First, we introduce the metabolic distribution, specific receptors and signaling pathways of SCFAs in human body. The concentration levels of SCFAs in AD patient/animal models are then summarized. In addition, we illustrate the effects and mechanisms of SCFAs on the cognitive level, pathological features (Aβ and tau) and neuroinflammation in AD. Finally, we analyze the translational value of SCFAs as potential therapeutic targets for the treatment of AD.
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Affiliation(s)
- Xiao-hang Qian
- Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Ru-yan Xie
- Shanghai Guangci Memorial hospital, Shanghai 200025, China.
| | - Xiao-li Liu
- Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai 201406, China.
| | - Sheng-di Chen
- Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Correspondence should be addressed to: Dr. Sheng-di Chen () and Dr. Hui-dong Tang (), Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hui-dong Tang
- Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Correspondence should be addressed to: Dr. Sheng-di Chen () and Dr. Hui-dong Tang (), Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Kelsey JR. Ethylene oxide derived glycol ethers: A review of the alkyl glycol ethers potential to cause endocrine disruption. Regul Toxicol Pharmacol 2021; 129:105113. [PMID: 34974128 DOI: 10.1016/j.yrtph.2021.105113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 12/15/2021] [Accepted: 12/27/2021] [Indexed: 11/17/2022]
Abstract
The 'ethylene glycol ethers' (EGE) are a broad family of solvents and hydraulic fluids produced through the reaction of ethylene oxide and a monoalcohol. Certain EGE derived from methanol and ethanol are well known to cause toxicity to the testes and fetotoxicity and that this is caused by the common metabolites methoxy and ethoxyacetic acid, respectively. There have been numerous published claims that EGE fall into the category of 'endocrine disruptors' often without substantiated evidence. This review systematically evaluates all of the available and relevant in vitro and in vivo data across this family of substances using an approach based around the EFSA/ECHA 2018 guidance for the identification of endocrine disruptors. The conclusion reached is that there is no significant evidence to show that EGE target any endocrine organs or perturb endocrine pathways and that any toxicity that is seen occurs by non-endocrine modes of action.
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Li S, Qi J, Sun Y, Gao X, Ma J, Zhao S. An integrated RNA-Seq and network study reveals that valproate inhibited progesterone production in human granulosa cells. J Steroid Biochem Mol Biol 2021; 214:105991. [PMID: 34487832 DOI: 10.1016/j.jsbmb.2021.105991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/10/2021] [Accepted: 08/29/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Valproate (VPA) is an antiepileptic drug (AEDs) with an ideal effect against epilepsy as well as other neuropsychiatric diseases. There is considerable evidence that women taking VPA are prone to reproductive endocrine disorders. However, few studies have been published about VPA effects on human ovarian granulosa cells. METHODS By treating human ovarian granulosa cell line KGN with VPA, the cell viability and progesterone production function were evaluated. RNA-sequencing was applied to uncover the global gene expression upon VPA treatment. RESULTS We revealed that VPA dose-dependently repressed the viability of KGN. VPA treatment at 600 μM inhibited the progesterone production. The mRNA and protein expression of CYP11A1 and STAR, two key enzymes in the biosynthesis of progesterone, were both suppressed. Gene set enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the transcriptome revealed classical functions of VPA as a neuromodulator and regulator of histone acetylation modifications. In addition to this, VPA commonly affected many steroid metabolism related genes in follicle cells, such as promoting the expression of vitamin D receptor (VDR). CONCLUSION Our findings suggest that VPA caused steroids metabolism pathways disturbance related with ovarian function and inhibited progesterone biosynthesis by inhibiting the expression of steroidogenesis genes. Our research may provide theoretical basis for the better use of VPA and the possible ways to counteract its side effects.
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Affiliation(s)
- Shumin Li
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
| | - Junfeng Qi
- Department of Plastic Surgery, Shandong Provincial Maternal and Child Health Care Hospital, Jinan, Shandong, 250012, China
| | - Yu Sun
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
| | - Xueying Gao
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China; Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinlong Ma
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
| | - Shigang Zhao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China.
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Acevedo N, Alashkar Alhamwe B, Caraballo L, Ding M, Ferrante A, Garn H, Garssen J, Hii CS, Irvine J, Llinás-Caballero K, López JF, Miethe S, Perveen K, Pogge von Strandmann E, Sokolowska M, Potaczek DP, van Esch BCAM. Perinatal and Early-Life Nutrition, Epigenetics, and Allergy. Nutrients 2021; 13:724. [PMID: 33668787 PMCID: PMC7996340 DOI: 10.3390/nu13030724] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/08/2021] [Accepted: 02/12/2021] [Indexed: 02/08/2023] Open
Abstract
Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.
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Affiliation(s)
- Nathalie Acevedo
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Bilal Alashkar Alhamwe
- Institute of Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany; (B.A.A.); (E.P.v.S.)
- College of Pharmacy, International University for Science and Technology (IUST), Daraa 15, Syria
| | - Luis Caraballo
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Mei Ding
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (M.D.); (M.S.)
- Christine Kühne-Center for Allergy Research and Education, 7265 Davos, Switzerland
- Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Antonio Ferrante
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
- School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia
| | - Holger Garn
- Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Philipps University Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center, 35043 Marburg, Germany; (H.G.); (S.M.)
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands;
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
| | - Charles S. Hii
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
| | - James Irvine
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
| | - Kevin Llinás-Caballero
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Juan Felipe López
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Sarah Miethe
- Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Philipps University Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center, 35043 Marburg, Germany; (H.G.); (S.M.)
| | - Khalida Perveen
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
| | - Elke Pogge von Strandmann
- Institute of Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany; (B.A.A.); (E.P.v.S.)
| | - Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (M.D.); (M.S.)
- Christine Kühne-Center for Allergy Research and Education, 7265 Davos, Switzerland
| | - Daniel P. Potaczek
- Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Philipps University Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center, 35043 Marburg, Germany; (H.G.); (S.M.)
| | - Betty C. A. M. van Esch
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands;
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
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Li J, Cao H, Feng H, Xue Q, Zhang A, Fu J. Evaluation of the Estrogenic/Antiestrogenic Activities of Perfluoroalkyl Substances and Their Interactions with the Human Estrogen Receptor by Combining In Vitro Assays and In Silico Modeling. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2020; 54:14514-14524. [PMID: 33111528 DOI: 10.1021/acs.est.0c03468] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
The potential estrogenic activities of perfluoroalkyl substances (PFASs) are controversial. Here, we investigated the estrogenic/antiestrogenic activities of PFASs and explored the corresponding interaction mode of PFASs with the estrogen receptor (ER) by combining in vitro assays and in silico modeling. We found that three PFASs (perfluorobutanoic acid, perfluorobutane sulfonate, and perfluoropentanoic acid) exerted antiestrogenic effects by inhibiting luciferase activity, whereas perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) exerted estrogenic effects by inducing luciferase activity. When coexposed to 17β-estradiol (E2), all tested PFASs attenuated the E2-stimulated luciferase activity; unexpectedly, each PFAS could further attenuate the luciferase activity generated by the cotreatment with ICI 182,780 and E2, with a minimal effective concentration comparable to that found in human serum. PFHxS and PFOS significantly induced the gene expression of TFF1; additionally, all PFASs inhibited the E2-induced gene expression of TFF1 and EGR3. Furthermore, the results of the blind docking analyses suggested that the interaction with the coactivator-binding region on the ER surface should be included as a pathway through which PFASs exert estrogenic and antiestrogenic activities. Finally, we revealed the critical molecular property of the zero-order molecular connectivity index (MCI) (0χ) that affects the antiestrogenic activity of PFASs.
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Affiliation(s)
- Juan Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China
- School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Huiming Cao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China
- Institute of Environment and Health, Jianghan University, Wuhan 430056, China
| | - Hongru Feng
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China
| | - Qiao Xue
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China
| | - Aiqian Zhang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China
- College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100190, China
| | - Jianjie Fu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China
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Increment of Lysosomal Biogenesis by Combined Extracts of Gum Arabic, Parsley, and Corn Silk: A Reparative Mechanism in Mice Renal Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:8631258. [PMID: 32733590 PMCID: PMC7369655 DOI: 10.1155/2020/8631258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 06/02/2020] [Indexed: 01/22/2023]
Abstract
Gum Arabic (GA), parsley, and corn silk have been traditionally used for renal failure patients worldwide. This study aimed at probing the mechanism of the combined extracts, namely, GA (3 g/kg/day), parsley (1 g/kg/day), and corn silk (200 mg/kg/day), as nephroprotective agents in mice after amikacin (1.2 g/kg) single dose through exploration of their action on G-protein coupled receptors (GPR) 41 and 43 and the ensuing lysosomal biogenesis. Western blotting was employed for renal levels of bcl-2-associated X protein (BAX) and cytosolic cathepsin D; cell death markers, nuclear transcription factor EB (TFEB), and lysosomal associated membrane protein-1 (LAMP-1); and lysosomal biogenesis indicators. Liquid chromatography–mass spectrometry (LC-MS) and docking were also employed. After amikacin treatment, BAX and cathepsin D levels were upregulated while LAMP-1 and nuclear TFEB levels were inhibited. The combined extracts inhibited BAX and cytosolic cathepsin D but upregulated LAMP-1 and nuclear TFEB levels. Docking confirmed GPR modulatory signaling. The combined extracts showed GPR signal modulatory properties that triggered lysosome synthesis and contributed to reversing the adverse effects of amikacin on renal tissues.
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Li ASW, Marikawa Y. Methoxyacetic acid inhibits histone deacetylase and impairs axial elongation morphogenesis of mouse gastruloids in a retinoic acid signaling-dependent manner. Birth Defects Res 2020; 112:1043-1056. [PMID: 32496642 DOI: 10.1002/bdr2.1712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Teratogenic potential has been linked to various industrial compounds. Methoxyacetic acid (MAA) is a primary metabolite of the widely used organic solvent and plasticizer, methoxyethanol and dimethoxyethyl phthalate, respectively. Studies using model animals have shown that MAA acts as the proximate teratogen that causes various malformations in developing embryos. Nonetheless, the molecular mechanisms by which MAA exerts its teratogenic effects are not fully understood. METHODS Gastruloids of mouse P19C5 pluripotent stem cells, which recapitulate axial elongation morphogenesis of gastrulation-stage embryos, were explored as an in vitro model to investigate the teratogenic action of MAA. Morphometric parameters of gastruloids were measured to evaluate the morphogenetic effect, and transcript levels of various developmental regulator genes were examined to assess the impact on gene expression patterns. The effects of MAA on the level of retinoic acid (RA) signaling and histone deacetylase activity were also measured. RESULTS MAA reduced axial elongation of gastruloids at concentrations comparable to the teratogenic plasma level (5 mM) in vivo. MAA at 4 mM significantly altered the expression profiles of developmental regulator genes. In particular, it upregulated the RA signaling target genes. The concomitant suppression of RA signaling using a pharmacological agent alleviated the morphogenetic effect of MAA. MAA at 4 mM also significantly reduced the activity of purified histone deacetylase protein. CONCLUSIONS MAA impaired axial elongation morphogenesis in a RA signaling-dependent manner in mouse gastruloids, possibly through the inhibition of histone deacetylase.
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Affiliation(s)
- Aileen S W Li
- Developmental and Reproductive Biology Graduate Program, Institute for Biogenesis Research, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii, USA
| | - Yusuke Marikawa
- Developmental and Reproductive Biology Graduate Program, Institute for Biogenesis Research, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii, USA
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Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism. Ther Drug Monit 2020; 41:503-508. [PMID: 31259880 DOI: 10.1097/ftd.0000000000000619] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. METHODS A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. RESULTS The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). CONCLUSIONS The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.
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La Merrill MA, Vandenberg LN, Smith MT, Goodson W, Browne P, Patisaul HB, Guyton KZ, Kortenkamp A, Cogliano VJ, Woodruff TJ, Rieswijk L, Sone H, Korach KS, Gore AC, Zeise L, Zoeller RT. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol 2020; 16:45-57. [PMID: 31719706 PMCID: PMC6902641 DOI: 10.1038/s41574-019-0273-8] [Citation(s) in RCA: 476] [Impact Index Per Article: 95.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2019] [Indexed: 12/11/2022]
Abstract
Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.
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Affiliation(s)
- Michele A La Merrill
- Department of Environmental Toxicology, University of California, Davis, CA, USA.
| | - Laura N Vandenberg
- Department of Environmental Health Science, School of Public Health and Health Sciences, University of Masschusetts, Amherst, MA, USA
| | - Martyn T Smith
- School of Public Health, University of California, Berkeley, CA, USA
| | - William Goodson
- California Pacific Medical Center Research Institute, Sutter Hospital, San Francisco, CA, USA
| | - Patience Browne
- Environmental Directorate, Organisation for Economic Co-operation and Development, Paris, France
| | - Heather B Patisaul
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Kathryn Z Guyton
- International Agency for Research on Cancer, World Health Organization, Lyon, France
| | | | - Vincent J Cogliano
- Office of the Science Advisor, United States Environmental Protection Agency, Washington, DC, USA
| | - Tracey J Woodruff
- Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Linda Rieswijk
- School of Public Health, University of California, Berkeley, CA, USA
- Institute of Data Science, Maastricht University, Maastricht, Netherlands
| | - Hideko Sone
- Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Ibaraki, Japan
| | - Kenneth S Korach
- Receptor Biology, Section Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Science, Durham, NC, USA
| | - Andrea C Gore
- Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USA
| | - Lauren Zeise
- Office of the Director, Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency, Sacramento, CA, USA
| | - R Thomas Zoeller
- Biology Department, University of Masschusetts, Amherst, MA, USA
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12
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Jones L, Kumar J, Mistry A, Sankar Chittoor Mana T, Perry G, Reddy VP, Obrenovich M. The Transformative Possibilities of the Microbiota and Mycobiota for Health, Disease, Aging, and Technological Innovation. Biomedicines 2019; 7:E24. [PMID: 30925795 PMCID: PMC6631383 DOI: 10.3390/biomedicines7020024] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 03/13/2019] [Accepted: 03/19/2019] [Indexed: 12/20/2022] Open
Abstract
The gut microbiota is extremely important for the health of the host across its lifespan.Recent studies have elucidated connections between the gut microbiota and neurological diseaseand disorders such as depression, anxiety, Alzheimer's disease (AD), autism, and a host of otherbrain illnesses. Dysbiosis of the normal gut flora can have negative consequences for humans,especially throughout key periods during our lifespan as the gut microbes change with age in bothphenotype and number of bacterial species. Neurologic diseases, mental disorders, and euthymicstates are influenced by alterations in the metabolites produced by gut microbial milieu. Weintroduce a new concept, namely, the mycobiota and microbiota-gut-brain neuroendocrine axis anddiscuss co-metabolism with emphasis on means to influence or correct disruptions to normal gutflora throughout the lifespan from early development to old age. These changes involveinflammation and involve the permeability of barriers, such as the intestine blood barrier, the blood⁻brain barrier, and others. The mycobiota and microbiota⁻gut⁻brain axis offer new research horizonsand represents a great potential target for new therapeutics, including approaches based aroundinflammatory disruptive process, genetically engineered drug delivery systems, diseased cellculling "kill switches", phage-like therapies, medicinal chemistry, or microbial parabiosis to namea few.
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Affiliation(s)
- Lucas Jones
- Geriatric Research, Education, and Clinical Center, Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA.
- Department of Molecular and Microbiology, Case Western Reserve University School of Medicine, Cleveland OH 44106, USA.
| | - Jessica Kumar
- Geriatric Research, Education, and Clinical Center, Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA.
| | - Adil Mistry
- Departments of Engineering and Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
| | | | - George Perry
- Distinguished University Chair in Neurobiology, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
| | - V Prakash Reddy
- Missouri University of Science and Technology, Rolla, MI, 65409, USA.
| | - Mark Obrenovich
- Geriatric Research, Education, and Clinical Center, Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA.
- Departments of Engineering and Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
- Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
- MD and CSO, the Gilgamesh Foundation.org, Cleveland, OH 44106, USA.
- Department of Physics, University of Toledo, Toledo, OH 43606, USA.
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13
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Lathe R, Houston DR. Fatty-acylation target sequence in the ligand-binding domain of vertebrate steroid receptors demarcates evolution from estrogen-related receptors. J Steroid Biochem Mol Biol 2018; 184:20-28. [PMID: 30026064 DOI: 10.1016/j.jsbmb.2018.07.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 07/02/2018] [Accepted: 07/10/2018] [Indexed: 12/15/2022]
Abstract
Present-day nuclear receptors (NRs) responding to adrenal and sex steroids are key regulators of reproduction and growth in mammals, and are thought to have evolved from an ancestral NR most closely related to extant estrogen-related receptors (ERRs). The molecular events (and ligands) that distinguish steroid-activated NRs (SRs) from their inferred ancestor, that gave rise to both the ERRs and SRs, remain unknown. We report that target sequences for fatty-acylation (palmitoylation) at a key cysteine residue (corresponding to Cys447 in human estrogen receptor ERα) in helix 8 of the ligand-binding domain accurately demarcate SRs from ERRs. Docking studies are consistent with the hypothesis that palmitate embeds into a key groove in the receptor surface. The implications of lipidation, and of potential alternative ligands for the key cysteine residue, for receptor function and the evolution of SRs are discussed.
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Affiliation(s)
- Richard Lathe
- Division of Infection and Pathway Medicine, University of Edinburgh, Little France, Edinburgh EH16 4SB, UK.
| | - Douglas R Houston
- School of Biological Sciences, University of Edinburgh, King's Buildings, Edinburgh EH9 3BF, UK.
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14
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Folkerts J, Stadhouders R, Redegeld FA, Tam SY, Hendriks RW, Galli SJ, Maurer M. Effect of Dietary Fiber and Metabolites on Mast Cell Activation and Mast Cell-Associated Diseases. Front Immunol 2018; 9:1067. [PMID: 29910798 PMCID: PMC5992428 DOI: 10.3389/fimmu.2018.01067] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 04/30/2018] [Indexed: 12/14/2022] Open
Abstract
Many mast cell-associated diseases, including allergies and asthma, have seen a strong increase in prevalence during the past decades, especially in Western(ized) countries. It has been suggested that a Western diet may contribute to the prevalence and manifestation of allergies and asthma through reduced intake of dietary fiber and the subsequent production of their metabolites. Indeed, dietary fiber and its metabolites have been shown to positively influence the development of immune disorders via changes in microbiota composition and the regulation of B- and T-cell activation. However, the effects of these dietary components on the activation of mast cells, key effector cells of the inflammatory response in allergies and asthma, remain poorly characterized. Due to their location in the gut and vascularized tissues, mast cells are exposed to high concentrations of dietary fiber and/or its metabolites. Here, we provide a focused overview of current findings regarding the direct effects of dietary fiber and its various metabolites on the regulation of mast cell activity and the pathophysiology of mast cell-associated diseases.
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Affiliation(s)
- Jelle Folkerts
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.,Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States.,Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ralph Stadhouders
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.,Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands
| | - Frank A Redegeld
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - See-Ying Tam
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
| | - Stephen J Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
| | - Marcus Maurer
- Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
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15
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Warembourg C, Binter AC, Giton F, Fiet J, Labat L, Monfort C, Chevrier C, Multigner L, Cordier S, Garlantézec R. Prenatal exposure to glycol ethers and sex steroid hormones at birth. ENVIRONMENT INTERNATIONAL 2018; 113:66-73. [PMID: 29421409 DOI: 10.1016/j.envint.2018.01.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 01/15/2018] [Accepted: 01/15/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Glycol ethers (GEs) are oxygenated solvents widely found in occupational and consumer water-based products. Some of them are well-known reproductive and developmental toxicants. OBJECTIVES To study the variations in circulating sex steroid hormones, measured in cord blood, according to biomarkers of prenatal GE exposure. METHODS The study population comes from the PELAGIE mother-child cohort, which enrolled pregnant women from Brittany (France, 2002-2006). Maternal urine samples were collected from a random subcohort (n = 338) before 19 weeks' gestation, from which we measured 8 alkoxycarboxylic metabolites of GEs. We subsequently measured 13 sex steroid hormones and sex hormone-binding globulin (SHBG) in cord blood samples. Linear regressions adjusted for potential confounders were used, and nonlinear dose-response associations were investigated. RESULTS The detection rates of GE metabolites ranged from 4% to 98%; only the 5 most detected (>20%) metabolites were investigated further. Phenoxyacetic acid (detection rate > 95%) was associated with lower levels of SHBG and various steroids (17-alpha-hydroxy-Pregnenolone, delta-5-androstenediol, and dehydroepiandrosterone) among boys and higher SHBG and 16-alpha-hydroxy-dehydroepiandrosterone levels among girls. The two other highly detected metabolites, methoxyetoxyacetic acid and butoxyacetic acid, were associated with variations in estradiol. Butoxyacetic acid was associated with higher delta-5-androstenediol levels while detectable levels of methoxyacetic acid were associated with lower levels of this hormone. CONCLUSION Our study suggests that prenatal exposure to GE may affect endocrine response patterns, estimated by determining blood levels of sex steroid hormones in newborns. These results raise questions about the potential role of these changes in the pathways between prenatal GE exposure and previously reported adverse developmental outcomes, including impaired neurocognitive performance.
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Affiliation(s)
- Charline Warembourg
- Inserm UMR 1085 Irset, Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, F-35000 Rennes, France; Université de Rennes I, F-35043 Rennes, France..
| | - Anne-Claire Binter
- Inserm UMR 1085 Irset, Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, F-35000 Rennes, France; Université de Rennes I, F-35043 Rennes, France
| | - Frank Giton
- AP-HP, Pôle biologie-Pathologie Henri Mondor, Créteil 94000, France.; INSERM U955 eq07, Recherche Translationnelle en oncogenèse génitale, Créteil 94000, France
| | - Jean Fiet
- INSERM U955 eq07, Recherche Translationnelle en oncogenèse génitale, Créteil 94000, France
| | - Laurence Labat
- Assistance publique-hopitaux de Paris, Groupe Cochin, Laboratoire Pharmacologie Toxicologie, F-75004 Paris, France
| | - Christine Monfort
- Inserm UMR 1085 Irset, Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, F-35000 Rennes, France; Université de Rennes I, F-35043 Rennes, France
| | - Cécile Chevrier
- Inserm UMR 1085 Irset, Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, F-35000 Rennes, France; Université de Rennes I, F-35043 Rennes, France
| | - Luc Multigner
- Inserm UMR 1085 Irset, Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, F-35000 Rennes, France; Université de Rennes I, F-35043 Rennes, France
| | - Sylvaine Cordier
- Inserm UMR 1085 Irset, Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, F-35000 Rennes, France
| | - Ronan Garlantézec
- Inserm UMR 1085 Irset, Exposure Assessment and Epidemiological Research on Environment, Reproduction and Development, F-35000 Rennes, France; Université de Rennes I, F-35043 Rennes, France.; Centre Hospitalo-Universitaire de Rennes, Service de Santé Publique et d'Epidémiologie, F-35033 Rennes, France
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16
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Pham TX, Bae M, Lee Y, Park YK, Lee JY. Transcriptional and posttranscriptional repression of histone deacetylases by docosahexaenoic acid in macrophages. J Nutr Biochem 2018; 57:162-169. [PMID: 29734115 DOI: 10.1016/j.jnutbio.2018.03.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 01/13/2018] [Accepted: 03/01/2018] [Indexed: 01/12/2023]
Abstract
Histone deacetylation is one of the posttranslational modifications of histones by which eukaryotic cells alter gene transcription. Although fatty acids are the best known macronutrients that modulate gene expression in inflammatory pathways, it is unclear whether common fatty acids in diets can regulate the expression of histone deacetylases (HDACs) in macrophages. We determined the effects of fatty acids, including palmitic acid (PA), oleic acid (OA), linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the expression of HDAC isoforms in RAW 264.7 macrophages, mouse bone marrow-derived macrophages (BMDM) and human THP-1 cells. In RAW 264.7 macrophages, OA significantly increased mRNA levels of Hdac1, 2 and 3, and EPA induced Hdac2 expression compared with control. Marked repression of Hdac9 mRNA levels by EPA and DHA, with DHA being more potent, was observed in RAW 264.7 macrophages and BMDM. DHA also decreased HDAC3, 4 and 9 protein levels. EPA and DHA facilitated the proteasomal degradation of HDAC3 and 4 protein, while the transcriptional repression of HDAC9 by DHA may be mediated by the repression of myocyte enhancer factor 2 or by the activation of retinoid X receptor. Functionally, inhibition of HDAC activity or knockdown of Hdac9 in macrophages reduced lipopolysaccharide-induced inflammatory gene expression. Our results demonstrate that DHA represses the expression of HDAC3, 4 and 9 at the transcriptional or posttranscriptional levels in murine macrophages. This suggests that the anti-inflammatory effect of DHA may be mediated by the reduction of HDACs.
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Affiliation(s)
- Tho X Pham
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Yoojin Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
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17
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Park SS, Yang G, Kim E. Lactobacillus acidophilus NS1 Reduces Phosphoenolpyruvate Carboxylase Expression by Regulating HNF4α Transcriptional Activity. Korean J Food Sci Anim Resour 2017; 37:529-534. [PMID: 28943765 PMCID: PMC5599573 DOI: 10.5851/kosfa.2017.37.4.529] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/12/2017] [Accepted: 07/12/2017] [Indexed: 12/19/2022] Open
Abstract
Probiotics have been known to reduce high-fat diet (HFD)-induced metabolic diseases, such as obesity, insulin resistance, and type 2 diabetes. We recently observed that Lactobacillus acidophilus NS1 (LNS1), distinctly suppresses increase of blood glucose levels and insulin resistance in HFD-fed mice. In the present study, we demonstrated that oral administration of LNS1 with HFD feeding to mice significantly reduces hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme in gluconeogenesis which is highly increased by HFD feeding. This suppressive effect of LNS1 on hepatic expression of PEPCK was further confirmed in HepG2 cells by treatment of LNS1 conditioned media (LNS1-CM). LNS1-CM strongly and specifically inhibited HNF4α-induced PEPCK promoter activity in HepG2 cells without change of HNF4α mRNA levels. Together, these data demonstrate that LNS1 suppresses PEPCK expression in the liver by regulating HNF4α transcriptional activity, implicating its role as a preventive or therapeutic approach for metabolic diseases.
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Affiliation(s)
- Sung-Soo Park
- Department of Biological Sciences, College of Science, Chonnam National University, Gwangju 61186, Korea
| | - Garam Yang
- Department of Biological Sciences, College of Science, Chonnam National University, Gwangju 61186, Korea
| | - Eungseok Kim
- Department of Biological Sciences, College of Science, Chonnam National University, Gwangju 61186, Korea
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18
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Matsuyama T, Yabe K, Kuwata C, Ito K, Ando Y, Iida H, Mori K. Transcriptional profile of ethylene glycol monomethyl ether-induced testicular toxicity in rats. Drug Chem Toxicol 2017; 41:105-112. [DOI: 10.1080/01480545.2017.1320406] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Takuya Matsuyama
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Koichi Yabe
- Daiichi Sankyo India Pharma Pvt. Ltd, Gurgaon, Haryana, India
| | - Chiharu Kuwata
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Kazumi Ito
- Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Yosuke Ando
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
| | - Hiroshi Iida
- Laboratory of Zoology, Graduate School of Agriculture, Kyushu University, Fukuoka, Japan
| | - Kazuhiko Mori
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
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19
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Geer LA, Pycke BFG, Waxenbaum J, Sherer DM, Abulafia O, Halden RU. Association of birth outcomes with fetal exposure to parabens, triclosan and triclocarban in an immigrant population in Brooklyn, New York. JOURNAL OF HAZARDOUS MATERIALS 2017; 323:177-183. [PMID: 27156397 PMCID: PMC5018415 DOI: 10.1016/j.jhazmat.2016.03.028] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 03/07/2016] [Accepted: 03/10/2016] [Indexed: 05/21/2023]
Abstract
BACKGROUND Prior studies suggest associations between fetal exposure to antimicrobial and paraben compounds with adverse reproductive outcomes, mainly in animal models. We have previously reported elevated levels of these compounds for a cohort of mothers and neonates. OBJECTIVE We examined the relationship between human exposure to parabens and antimicrobial compounds and birth outcomes including birth weight, body length and head size, and gestational age at birth. METHODS Maternal third trimester urinary and umbilical cord blood plasma concentrations of methylparaben (MePB), ethylparaben (EtPB), propylparaben (PrPB), butylparaben (BuPB), benzylparaben (BePB), triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether or TCS) and triclocarban (1-(4-chlorophenyl)-3-(3,4-dichlorophenyl) urea or TCC), were measured in 185 mothers and 34 paired singleton neonates in New York, 2007-2009. RESULTS In regression models adjusting for confounders, adverse exposure-outcome associations observed included increased odds of PTB (BuPB), decreased gestational age at birth (BuPB and TCC) and birth weight (BuPB), decreased body length (PrPB) and protective effects on PTB (BePB) and LBW (3'-Cl-TCC) (p<0.05). No associations were observed for MePB, EtPB, or TCS. CONCLUSIONS This study provides the first evidence of associations between antimicrobials and potential adverse birth outcomes in neonates. Findings are consistent with animal data suggesting endocrine-disrupting potential resulting in developmental and reproductive toxicity.
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Affiliation(s)
- Laura A Geer
- Department of Environmental and Occupational Health Sciences, State University of New York, Downstate School of Public Health, BOX 43, 450 Clarkson Ave., Brooklyn, NY, USA.
| | - Benny F G Pycke
- Center for Environmental Security, The Biodesign Institute, Global Security Initiative, and School of Sustainable Engineering and the Built Environment, Arizona State University, 781 East Terrace Mall, Tempe, AZ 85287, USA
| | - Joshua Waxenbaum
- Department of Environmental and Occupational Health Sciences, State University of New York, Downstate School of Public Health, BOX 43, 450 Clarkson Ave., Brooklyn, NY, USA
| | - David M Sherer
- Department of Obstetrics and Gynecology, State University of New York Downstate Medical Center, 445 Lenox Road, Brooklyn, NY, USA
| | - Ovadia Abulafia
- Department of Obstetrics and Gynecology, State University of New York Downstate Medical Center, 445 Lenox Road, Brooklyn, NY, USA
| | - Rolf U Halden
- Center for Environmental Security, The Biodesign Institute, Global Security Initiative, and School of Sustainable Engineering and the Built Environment, Arizona State University, 781 East Terrace Mall, Tempe, AZ 85287, USA; Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA
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20
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Endocrine Disruption and In Vitro Ecotoxicology: Recent Advances and Approaches. IN VITRO ENVIRONMENTAL TOXICOLOGY - CONCEPTS, APPLICATION AND ASSESSMENT 2017; 157:1-58. [DOI: 10.1007/10_2016_2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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21
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Higashimura Y, Naito Y, Takagi T, Uchiyama K, Mizushima K, Yoshikawa T. Propionate Promotes Fatty Acid Oxidation through the Up-Regulation of Peroxisome Proliferator-Activated Receptor α in Intestinal Epithelial Cells. J Nutr Sci Vitaminol (Tokyo) 2016; 61:511-5. [PMID: 26875495 DOI: 10.3177/jnsv.61.511] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Short chain fatty acids (SCFAs) are produced in the colonic lumen mainly by bacterial fermentation of dietary fiber. Emerging evidence shows that SCFA has important physiological and pathophysiological effects on colonic and systemic events. Recently, propionate, known as a kind of SCFA, has been shown to lower fatty acid contents in plasma and reduce food intake. However, the detailed mechanism underlying the propionate-mediated lipid metabolism action remains poorly understood. The intestinal lipid metabolism process is critical for systemic energy homeostasis. Therefore, we investigate here the effects of propionate on intestinal lipid metabolism. Results show that propionate induced peroxisome proliferator-activated receptor α (PPARα) expression time-dependently and concentration-dependently in YAMC (a mouse intestinal epithelial cell line) cells. The expression levels of PPARα-responsive genes such as carnitine palmitoyl transferase II (CPTII) and trifunctional protein α (TFPα) were up-regulated in the presence of propionate, thereby suppressing triglyceride (TG) accumulation. Furthermore, propionate-mediated PPARα induction required phosphorylation of extracellular signal-regulated kinase. Collectively, these data indicate that propionate regulates intestinal lipid metabolism through the induction of PPARα expression. Results suggest that the inhibitory effect of propionate on TG accumulation partly contributes to the propionate-mediated fatty acid-lowering effect.
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Affiliation(s)
- Yasuki Higashimura
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
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22
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Valproate inhibits MAP kinase signalling and cell cycle progression in S. cerevisiae. Sci Rep 2016; 6:36013. [PMID: 27782169 PMCID: PMC5080547 DOI: 10.1038/srep36013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 10/10/2016] [Indexed: 01/27/2023] Open
Abstract
The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression. We further investigated the impact of VPA on selected processes and found that this drug: i) activates markers of the unfolded protein stress response such as Hac1 mRNA splicing; ii) modulates the cell wall integrity pathway by inhibiting the activation of the Slt2 MAP kinase, and synergizes with cell wall stressors such as micafungin and calcofluor white in preventing yeast growth; iii) prevents activation of the Kss1 and Fus3 MAP kinases of the mating pheromone pathway, which in turn abolishes cellular responses to alpha factor; and iv) blocks cell cycle progression and DNA replication. Overall, our data identify heretofore unknown biological responses to VPA in budding yeast, and highlight the broad spectrum of cellular pathways influenced by this chemical in eukaryotes.
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23
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Kassotis CD, Bromfield JJ, Klemp KC, Meng CX, Wolfe A, Zoeller RT, Balise VD, Isiguzo CJ, Tillitt DE, Nagel SC. Adverse Reproductive and Developmental Health Outcomes Following Prenatal Exposure to a Hydraulic Fracturing Chemical Mixture in Female C57Bl/6 Mice. Endocrinology 2016; 157:3469-81. [PMID: 27560547 PMCID: PMC5393361 DOI: 10.1210/en.2016-1242] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 07/19/2016] [Indexed: 11/19/2022]
Abstract
Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 μg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies.
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Affiliation(s)
- Christopher D Kassotis
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - John J Bromfield
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Kara C Klemp
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Chun-Xia Meng
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Andrew Wolfe
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - R Thomas Zoeller
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Victoria D Balise
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Chiamaka J Isiguzo
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Donald E Tillitt
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Susan C Nagel
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Animal Sciences (J.J.B.) and D. H. Barron Reproductive and Perinatal Biology Research Program (J.J.B.), University of Florida, Gainesville, Florida 32611; Department of Obstetrics, Gynecology and Women's Health (K.C.K., C.-X.M.,V.D.B., C.J.I., S.C.N.) and Division of Biological Sciences (V.D.B., S.C.N.), University of Missouri, Columbia, Missouri 65211; Department of Pediatrics (A.W.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Biology (RTZ), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and United States Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
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Kassotis CD, Iwanowicz LR, Akob DM, Cozzarelli IM, Mumford AC, Orem WH, Nagel SC. Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal site. THE SCIENCE OF THE TOTAL ENVIRONMENT 2016; 557-558:901-10. [PMID: 27073166 DOI: 10.1016/j.scitotenv.2016.03.113] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/15/2016] [Accepted: 03/16/2016] [Indexed: 05/23/2023]
Abstract
Currently, >95% of end disposal of hydraulic fracturing wastewater from unconventional oil and gas operations in the US occurs via injection wells. Key data gaps exist in understanding the potential impact of underground injection on surface water quality and environmental health. The goal of this study was to assess endocrine disrupting activity in surface water at a West Virginia injection well disposal site. Water samples were collected from a background site in the area and upstream, on, and downstream of the disposal facility. Samples were solid-phase extracted, and extracts assessed for agonist and antagonist hormonal activities for five hormone receptors in mammalian and yeast reporter gene assays. Compared to reference water extracts upstream and distal to the disposal well, samples collected adjacent and downstream exhibited considerably higher antagonist activity for the estrogen, androgen, progesterone, glucocorticoid and thyroid hormone receptors. In contrast, low levels of agonist activity were measured in upstream/distal sites, and were inhibited or absent at downstream sites with significant antagonism. Concurrent analyses by partner laboratories (published separately) describe the analytical and geochemical profiling of the water; elevated conductivity as well as high sodium, chloride, strontium, and barium concentrations indicate impacts due to handling of unconventional oil and gas wastewater. Notably, antagonist activities in downstream samples were at equivalent authentic standard concentrations known to disrupt reproduction and/or development in aquatic animals. Given the widespread use of injection wells for end-disposal of hydraulic fracturing wastewater, these data raise concerns for human and animal health nearby.
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Affiliation(s)
| | - Luke R Iwanowicz
- U.S. Geological Survey, Leetown Science Center, Fish Health Branch, 11649 Leetown Road, Kearneysville, WV 25430, USA
| | - Denise M Akob
- U.S. Geological Survey, National Research Program, 12201 Sunrise Valley Drive, MS 430, Reston, VA 20192, USA
| | - Isabelle M Cozzarelli
- U.S. Geological Survey, National Research Program, 12201 Sunrise Valley Drive, MS 430, Reston, VA 20192, USA
| | - Adam C Mumford
- U.S. Geological Survey, National Research Program, 12201 Sunrise Valley Drive, MS 430, Reston, VA 20192, USA
| | - William H Orem
- U.S. Geological Survey, Eastern Energy Resources Science Center, 12201 Sunrise Valley Drive, MS 956, Reston, VA 20192, USA
| | - Susan C Nagel
- Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO 65211, USA.
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25
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Kassotis CD, Klemp KC, Vu DC, Lin CH, Meng CX, Besch-Williford CL, Pinatti L, Zoeller RT, Drobnis EZ, Balise VD, Isiguzo CJ, Williams MA, Tillitt DE, Nagel SC. Endocrine-Disrupting Activity of Hydraulic Fracturing Chemicals and Adverse Health Outcomes After Prenatal Exposure in Male Mice. Endocrinology 2015; 156:4458-73. [PMID: 26465197 DOI: 10.1210/en.2015-1375] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Oil and natural gas operations have been shown to contaminate surface and ground water with endocrine-disrupting chemicals. In the current study, we fill several gaps in our understanding of the potential environmental impacts related to this process. We measured the endocrine-disrupting activities of 24 chemicals used and/or produced by oil and gas operations for five nuclear receptors using a reporter gene assay in human endometrial cancer cells. We also quantified the concentration of 16 of these chemicals in oil and gas wastewater samples. Finally, we assessed reproductive and developmental outcomes in male C57BL/6J mice after the prenatal exposure to a mixture of these chemicals. We found that 23 commonly used oil and natural gas operation chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors, and mixtures of these chemicals can behave synergistically, additively, or antagonistically in vitro. Prenatal exposure to a mixture of 23 oil and gas operation chemicals at 3, 30, and 300 μg/kg · d caused decreased sperm counts and increased testes, body, heart, and thymus weights and increased serum testosterone in male mice, suggesting multiple organ system impacts. Our results suggest possible adverse developmental and reproductive health outcomes in humans and animals exposed to potential environmentally relevant levels of oil and gas operation chemicals.
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Affiliation(s)
- Christopher D Kassotis
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Kara C Klemp
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Danh C Vu
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Chung-Ho Lin
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Chun-Xia Meng
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Cynthia L Besch-Williford
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Lisa Pinatti
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - R Thomas Zoeller
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Erma Z Drobnis
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Victoria D Balise
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Chiamaka J Isiguzo
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Michelle A Williams
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Donald E Tillitt
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
| | - Susan C Nagel
- Nicholas School of the Environment (C.D.K.), Duke University, Durham, North Carolina 27708; Department of Obstetrics, Gynecology, and Women's Health (K.C.K., C.-X.M., E.Z.D., V.D.B., C.J.I., S.C.N.), Department of Forestry (D.C.V., C.-H.L.), Division of Biological Sciences (V.D.B., M.A.W., S.C.N.), University of Missouri, Columbia, Missouri 65211; IDEXX RADIL Pathology Services (C.L.B.-W.), Columbia, Missouri 65201; Department of Biology (L.P., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; and US Geological Survey (D.E.T.), Columbia Environmental Research Center, Columbia, Missouri 65201
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Maqbool F, Mostafalou S, Bahadar H, Abdollahi M. Review of endocrine disorders associated with environmental toxicants and possible involved mechanisms. Life Sci 2015; 145:265-73. [PMID: 26497928 DOI: 10.1016/j.lfs.2015.10.022] [Citation(s) in RCA: 210] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 10/16/2015] [Accepted: 10/20/2015] [Indexed: 12/21/2022]
Abstract
Endocrine disrupting chemicals (EDC) are released into environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDC have major risks for human by targeting different organs and systems in the body. Multiple mechanisms are involved in targeting the normal system, through estrogen receptors, nuclear receptors and steroidal receptors activation. In this review, different methods by which xenobiotics stimulate signaling pathways and genetic mutation or DNA methylation have been discussed. These methods help to understand the results of xenobiotic action on the endocrine system. Endocrine disturbances in the human body result in breast cancer, ovarian problems, thyroid eruptions, testicular carcinoma, Alzheimer disease, schizophrenia, nerve damage and obesity. EDC characterize a wide class of compounds such as organochlorinated pesticides, industrial wastes, plastics and plasticizers, fuels and numerous other elements that exist in the environment or are in high use during daily life. The interactions and mechanism of toxicity in relation to human general health problems, especially endocrine disturbances with particular reference to reproductive problems, diabetes, and breast, testicular and ovarian cancers should be deeply investigated. There should also be a focus on public awareness of these EDC risks and their use in routine life. Therefore, the aim of this review is to summarize all evidence regarding different physiological disruptions in the body and possible involved mechanisms, to prove the association between endocrine disruptions and human diseases.
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Affiliation(s)
- Faheem Maqbool
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, International Campus (TUMS-IC), Tehran 1417614411, Iran; Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Sara Mostafalou
- School of Pharmacy, Ardebil University of Medical Sciences, Ardebil, Iran
| | - Haji Bahadar
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, International Campus (TUMS-IC), Tehran 1417614411, Iran
| | - Mohammad Abdollahi
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, International Campus (TUMS-IC), Tehran 1417614411, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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27
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Aminomethylphosphonic acid and methoxyacetic acid induce apoptosis in prostate cancer cells. Int J Mol Sci 2015; 16:11750-65. [PMID: 26006246 PMCID: PMC4463728 DOI: 10.3390/ijms160511750] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 05/15/2015] [Indexed: 01/06/2023] Open
Abstract
Aminomethylphosphonic acid (AMPA) and its parent compound herbicide glyphosate are analogs to glycine, which have been reported to inhibit proliferation and promote apoptosis of cancer cells, but not normal cells. Methoxyacetic acid (MAA) is the active metabolite of ester phthalates widely used in industry as gelling, viscosity and stabilizer; its exposure is associated with developmental and reproductive toxicities in both rodents and humans. MAA has been reported to suppress prostate cancer cell growth by inducing growth arrest and apoptosis. However, it is unknown whether AMPA and MAA can inhibit cancer cell growth. In this study, we found that AMPA and MAA inhibited cell growth in prostate cancer cell lines (LNCaP, C4-2B, PC-3 and DU-145) through induction of apoptosis and cell cycle arrest at the G1 phase. Importantly, the AMPA-induced apoptosis was potentiated with the addition of MAA, which was due to downregulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2), leading to activation of caspases 7 and 3. These results demonstrate that the combination of AMPA and MAA can promote the apoptosis of prostate cancer cells, suggesting that they can be used as potential therapeutic drugs in the treatment of prostate cancer.
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Chen RY, Fan YM, Zhang Q, Liu S, Li Q, Ke GL, Li C, You Z. Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT promoter. THE JOURNAL OF IMMUNOLOGY 2015; 194:4019-28. [PMID: 25769926 DOI: 10.4049/jimmunol.1400806] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 02/09/2015] [Indexed: 12/24/2022]
Abstract
The symptoms of vaginal candidiasis exacerbate in the second half of the menstrual cycle in premenopausal women when the serum estradiol level is elevated. Estradiol has been shown to inhibit Th17 differentiation and production of antifungal IL-17 cytokines. However, little is known about the mechanisms. In the present study, we used mouse splenocytes and found that estradiol inhibited Th17 differentiation through downregulation of Rorγt mRNA and protein expression. Estradiol activated estrogen receptor (ER)α to recruit repressor of estrogen receptor activity (REA) and form the ERα/REA complex. This complex bound to three estrogen response element (ERE) half-sites on the Rorγt promoter region to suppress Rorγt expression. Estradiol induced Rea mRNA and protein expression in mouse splenocytes. Using Rea small interfering RNA to knock down Rea expression enhanced Rorγt expression and Th17 differentiation. Alternatively, histone deacetylase 1 and 2 bound to the three ERE half-sites, independent of estradiol. Histone deacetylase inhibitor MS-275 dose- and time-dependently increased Rorγt expression and subsequently enhanced Th17 differentiation. In 15 healthy premenopausal women, high serum estradiol levels are correlated with low RORγT mRNA levels and high REA mRNA levels in the vaginal lavage. These results demonstrate that estradiol upregulates REA expression and recruits REA via ERα to the EREs on the RORγT promoter region, thus inhibiting RORγT expression and Th17 differentiation. This study suggests that the estradiol/ERα/REA axis may be a feasible target in the management of recurrent vaginal candidiasis.
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Affiliation(s)
- Rong-Yi Chen
- Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China; Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and
| | - Yi-Ming Fan
- Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China;
| | - Qiuyang Zhang
- Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and
| | - Sen Liu
- Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and
| | - Qingli Li
- Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Guo-Lin Ke
- Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China
| | - Chen Li
- Department of Dermatology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China
| | - Zongbing You
- Department of Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA 70112; and Department of Orthopaedic Surgery, Tulane University Health Sciences Center, New Orleans, LA 70112; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center, New Orleans, LA 70112; Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA 70112; and Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112
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Prakash C, Zuniga B, Song CS, Jiang S, Cropper J, Park S, Chatterjee B. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions. NUCLEAR RECEPTOR RESEARCH 2015; 2:101178. [PMID: 27478824 PMCID: PMC4963026 DOI: 10.11131/2015/101178] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and microfluidic organs-on-chips, which mimic the physiology of a multicellular environment, will likely replace the current cell-based workflow.
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Affiliation(s)
- Chandra Prakash
- Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245
- William Carey University College of Osteopathic Medicine, 498 Tucsan Ave, Hattiesburg, Mississipi 39401
| | - Baltazar Zuniga
- Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245
- University of Texas at Austin, 2100 Comal Street, Austin, Texas 78712
| | - Chung Seog Song
- Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245
| | - Shoulei Jiang
- Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245
| | - Jodie Cropper
- Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245
| | - Sulgi Park
- Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245
| | - Bandana Chatterjee
- Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245
- South Texas Veterans Health Care System, Audie L Murphy VA Hospital, 7400 Merton Minter Boulevard, San Antonio, Texas 78229
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Parajuli KR, Zhang Q, Liu S, Patel NK, Lu H, Zeng SX, Wang G, Zhang C, You Z. Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY 2014; 2:300-312. [PMID: 25606576 PMCID: PMC4297326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/09/2014] [Indexed: 06/04/2023]
Abstract
Methoxyacetic acid (MAA) is a primary metabolite of ester phthalates that are used in production of consumer products and pharmaceutical products. MAA causes embryo malformation and spermatocyte death through inhibition of histone deacetylases (HDACs). Little is known about MAA's effects on cancer cells. In this study, two immortalized human normal prostatic epithelial cell lines (RWPE-1 and pRNS-1-1) and four human prostate cancer cell lines (LNCaP, C4-2B, PC-3, and DU-145) were treated with MAA at different doses and for different time periods. Cell viability, apoptosis, and cell cycle analysis were performed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR, Western blot, and chromatin immunoprecipitation analyses. We found that MAA dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. MAA-induced apoptosis was due to down-regulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, also named cIAP1), leading to activation of caspases 7 and 3 and turning on the downstream apoptotic events. MAA-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and CDK2 expression at the late time. MAA up-regulated p21 expression through inhibition of HDAC activities, independently of p53/p63/p73. These findings demonstrate that MAA suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which suggests that MAA could be used as a potential therapeutic drug for prostate cancer.
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Affiliation(s)
- Keshab R Parajuli
- Department of Structural & Cellular Biology, Tulane UniversityNew Orleans, LA, USA
| | - Qiuyang Zhang
- Department of Structural & Cellular Biology, Tulane UniversityNew Orleans, LA, USA
| | - Sen Liu
- Department of Structural & Cellular Biology, Tulane UniversityNew Orleans, LA, USA
| | - Neil K Patel
- Department of Structural & Cellular Biology, Tulane UniversityNew Orleans, LA, USA
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane UniversityNew Orleans, LA, USA
- Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane UniversityNew Orleans, LA, USA
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane UniversityNew Orleans, LA, USA
- Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane UniversityNew Orleans, LA, USA
| | - Guangdi Wang
- Department of Chemistry and RCMI Cancer Research Center, Xavier University of LouisianaNew Orleans, LA, USA
| | - Changde Zhang
- Department of Chemistry and RCMI Cancer Research Center, Xavier University of LouisianaNew Orleans, LA, USA
| | - Zongbing You
- Department of Structural & Cellular Biology, Tulane UniversityNew Orleans, LA, USA
- Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane UniversityNew Orleans, LA, USA
- Department of Orthopaedic Surgery, Tulane UniversityNew Orleans, LA, USA
- Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane UniversityNew Orleans, LA, USA
- Tulane Center for Aging, Tulane UniversityNew Orleans, LA, USA
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Yamada T, Tanaka Y, Hasegawa R, Sakuratani Y, Yamazoe Y, Ono A, Hirose A, Hayashi M. Development of a category approach to predict the testicular toxicity of chemical substances structurally related to ethylene glycol methyl ether. Regul Toxicol Pharmacol 2014; 70:711-9. [DOI: 10.1016/j.yrtph.2014.10.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 10/20/2014] [Accepted: 10/21/2014] [Indexed: 11/26/2022]
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Pogrmic-Majkic K, Samardzija D, Fa S, Hrubik J, Glisic B, Kaisarevic S, Andric N. Atrazine Enhances Progesterone Production Through Activation of Multiple Signaling Pathways in FSH-Stimulated Rat Granulosa Cells: Evidence for Premature Luteinization1. Biol Reprod 2014; 91:124. [DOI: 10.1095/biolreprod.114.122606] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Russo F, Linsalata M, Orlando A. Probiotics against neoplastic transformation of gastric mucosa: Effects on cell proliferation and polyamine metabolism. World J Gastroenterol 2014; 20:13258-13272. [PMID: 25309063 PMCID: PMC4188884 DOI: 10.3748/wjg.v20.i37.13258] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 04/02/2014] [Accepted: 06/05/2014] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is still the second leading cause of cancer death worldwide, accounting for about 10% of newly diagnosed neoplasms. In the last decades, an emerging role has been attributed to the relations between the intestinal microbiota and the onset of both gastrointestinal and non-gastrointestinal neoplasms. Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. The internationally accepted definition of probiotics is live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The possible effects on the gastrointestinal tract following probiotic administration have been investigated in vitro and in animal models, as well as in healthy volunteers and in patients suffering from different human gastrointestinal diseases. Although several evidences are available on the use of probiotics against the carcinogen Helicobacter pylori, little is still known about the potential cross-interactions among probiotics, the composition and quality of intestinal flora and the neoplastic transformation of gastric mucosa. In this connection, a significant role in cell proliferation is played by polyamines (putrescine, spermidine, and spermine). These small amines are required in both pre-neoplastic and neoplastic tissue to sustain the cell growth and the evidences here provided suggest that probiotics may act as antineoplastic agents in the stomach by affecting also the polyamine content and functions. This review will summarize data on the most widely recognized effects of probiotics against neoplastic transformation of gastric mucosa and in particular on their ability in modulating cell proliferation, paying attention to the polyamine metabolism.
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34
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Hsu P, Nanan R. Foetal immune programming: hormones, cytokines, microbes and regulatory T cells. J Reprod Immunol 2014; 104-105:2-7. [DOI: 10.1016/j.jri.2014.02.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 02/05/2014] [Accepted: 02/10/2014] [Indexed: 01/19/2023]
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Dayan C, Hales BF. Effects of ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro. ACTA ACUST UNITED AC 2014; 101:254-61. [PMID: 24798094 PMCID: PMC4227605 DOI: 10.1002/bdrb.21108] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/11/2014] [Accepted: 03/12/2014] [Indexed: 02/05/2023]
Abstract
Exposure to ethylene glycol monomethyl ether (EGME), a glycol ether compound found in numerous industrial products, or to its active metabolite, 2-methoxyacetic acid (2-MAA), increases the incidence of developmental defects. Using an in vitro limb bud culture system, we tested the hypothesis that the effects of EGME on limb development are mediated by 2-MAA-induced alterations in acetylation programming. Murine gestation day 12 embryonic forelimbs were exposed to 3, 10, or 30 mM EGME or 2-MAA in culture for 6 days to examine effects on limb morphology; limbs were cultured for 1 to 24 hr to monitor effects on the acetylation of histones (H3K9 and H4K12), a nonhistone protein, p53 (p53K379), and markers for cell cycle arrest (p21) and apoptosis (cleaved caspase-3). EGME had little effect on limb morphology and no significant effects on the acetylation of histones or p53 or on biomarkers for cell cycle arrest or apoptosis. In contrast, 2-MAA exposure resulted in a significant concentration-dependent increase in limb abnormalities. 2-MAA induced the hyperacetylation of histones H3K9Ac and H4K12Ac at all concentrations tested (3, 10, and 30 mM). Exposure to 10 or 30 mM 2-MAA significantly increased acetylation of p53 at K379, p21 expression, and caspase-3 cleavage. Thus, 2-MAA, the proximate metabolite of EGME, disrupts limb development in vitro, modifies acetylation programming, and induces biomarkers of cell cycle arrest and apoptosis
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Affiliation(s)
- Caroline Dayan
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
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36
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Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014; 20:159-66. [PMID: 24390308 DOI: 10.1038/nm.3444] [Citation(s) in RCA: 2010] [Impact Index Per Article: 182.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 12/06/2013] [Indexed: 02/06/2023]
Abstract
Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.
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Yoon K, Kwack SJ, Kim HS, Lee BM. Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2014; 17:127-174. [PMID: 24749480 DOI: 10.1080/10937404.2014.882194] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Endocrine-disrupting chemicals (EDC), including phthalates, bisphenol A (BPA), phytoestrogens such as genistein and daidzein, dichlorodiphenyltrichloroethane (DDT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are associated with a variety of adverse health effects in organisms or progeny by altering the endocrine system. Environmental estrogens, including BPA, phthalates, and phytoestrogens, are the most extensively studied and are considered to mimic the actions of endogenous estrogen, 17β-estradiol (E2). Diverse modes of action of estrogen and estrogen receptors (ERα and ERβ) have been described, but the mode of action of estrogenic EDC is postulated to be more complex and needs to be more clearly elucidated. This review examines the adverse effects of estrogenic EDC on male or female reproductive systems and molecular mechanisms underlying EDC effects that modulate ER-mediated signaling. Mechanisms of action for estrogenic EDC may involve both ER-dependent and ER-independent pathways. Recent findings from systems toxicology of examining estrogenic EDC are also discussed.
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Affiliation(s)
- Kyungsil Yoon
- a Lung Cancer Branch , Research Institute, National Cancer Center , Goyang , Gyeonggi-do , South Korea
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Maggi A, Villa A. In vivo dynamics of estrogen receptor activity: the ERE-Luc model. J Steroid Biochem Mol Biol 2014; 139:262-9. [PMID: 23262261 DOI: 10.1016/j.jsbmb.2012.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 11/23/2012] [Accepted: 12/10/2012] [Indexed: 01/24/2023]
Abstract
In recent years several studies demonstrated the presence of estrogen receptors in mammalian tissues and significantly improved our understanding of their ability to control biological processes in reproductive as well as non-reproductive organs. Considering the manifold mechanisms and organs that are involved in estrogen action and the implication of estrogens in human female physiology, innovative approaches are required to shed light on the widespread activities of estrogen receptors in woman physiology. This is particularly relevant for the definition of novel, more efficacious hormonal replacement therapies or for the evaluation of the risk associated with the exposure to endocrine disruptors. The introduction of genetic engineering and the development and application of in vivo imaging techniques offer new tools for pre-clinical studies. The generation of the ERE-Luc mouse, a reporter animal developed for in vivo studies of the estrogen receptor activity, allows assessing the activity state of the ER signaling pathway in all target tissues and organs at once, under physiological stimuli or as a result of a pharmacological treatment. This review summarizes the main steps in the generation and appraisal of the estrogen receptor reporter mouse ERE-Luc, designed for in vivo molecular imaging studies, and describes examples demonstrating the suitability of the ERE-Luc model for drug development and for the investigation of the effects of endogenous, environmental, and dietary estrogens in vivo. This article is part of a Special Issue entitled 'Phytoestrogens'.
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Affiliation(s)
- Adriana Maggi
- Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological and Biomolecular Sciences, University of Milan, via Balzaretti 9, 20133, Milan, Italy.
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Stempin S, Andres S, Bumke Scheer M, Rode A, Nau H, Seidel A, Lampen A. Valproic acid and its derivatives enhanced estrogenic activity but not androgenic activity in a structure dependent manner. Reprod Toxicol 2013; 42:49-57. [DOI: 10.1016/j.reprotox.2013.07.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 06/17/2013] [Accepted: 07/17/2013] [Indexed: 10/26/2022]
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Unsaturated fatty acids repress expression of ATP binding cassette transporter A1 and G1 in RAW 264.7 macrophages. J Nutr Biochem 2012; 23:1271-6. [DOI: 10.1016/j.jnutbio.2011.07.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2011] [Revised: 05/28/2011] [Accepted: 07/13/2011] [Indexed: 12/28/2022]
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Marx-Stoelting P, Pfeil R, Solecki R, Ulbrich B, Grote K, Ritz V, Banasiak U, Heinrich-Hirsch B, Moeller T, Chahoud I, Hirsch-Ernst K. Assessment strategies and decision criteria for pesticides with endocrine disrupting properties relevant to humans. Reprod Toxicol 2011; 31:574-84. [DOI: 10.1016/j.reprotox.2011.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 11/22/2010] [Accepted: 02/14/2011] [Indexed: 12/26/2022]
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42
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Lee CJJ, Gonçalves LL, Wells PG. Embryopathic effects of thalidomide and its hydrolysis products in rabbit embryo culture: evidence for a prostaglandin H synthase (PHS)-dependent, reactive oxygen species (ROS)-mediated mechanism. FASEB J 2011; 25:2468-83. [PMID: 21502285 DOI: 10.1096/fj.10-178814] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Thalidomide (TD) causes birth defects in humans and rabbits via several potential mechanisms, including bioactivation by embryonic prostaglandin H synthase (PHS) enzymes to a reactive intermediate that enhances reactive oxygen species (ROS) formation. We show herein that TD in rabbit embryo culture produces relevant embryopathies, including decreases in head/brain development by 28% and limb bud growth by 71% (P<0.05). Two TD hydrolysis products, 2-phthalimidoglutaramic acid (PGMA) and 2-phthalimidoglutaric acid (PGA), were similarly embryopathic, attenuating otic vesicle (ear) and limb bud formation by up to 36 and 77%, respectively (P<0.05). TD, PGMA, and PGA all increased embryonic DNA oxidation measured as 8-oxoguanine (8-oxoG) by up to 2-fold (P<0.05). Co- or pretreatment with the PHS inhibitors eicosatetraynoic acid (ETYA) or acetylsalicylic acid (ASA), or the free-radical spin trap phenylbutylnitrone (PBN), completely blocked embryonic 8-oxoG formation and/or embryopathies initiated by TD, PGMA, and PGA. This is the first demonstration of limb bud embryopathies initiated by TD, as well as its hydrolysis products, in a mammalian embryo culture model of a species susceptible to TD in vivo, indicating that all likely contribute to TD teratogenicity in vivo, in part through PHS-dependent, ROS-mediated mechanisms.
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Affiliation(s)
- Crystal J J Lee
- Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, ON, Canada
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Bagchi G, Zhang Y, Stanley KA, Waxman DJ. Complex modulation of androgen responsive gene expression by methoxyacetic acid. Reprod Biol Endocrinol 2011; 9:42. [PMID: 21453523 PMCID: PMC3083340 DOI: 10.1186/1477-7827-9-42] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Accepted: 03/31/2011] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Optimal androgen signaling is critical for testicular development and spermatogenesis. Methoxyacetic acid (MAA), the primary active metabolite of the industrial chemical ethylene glycol monomethyl ether, disrupts spermatogenesis and causes testicular atrophy. Transcriptional trans-activation studies have indicated that MAA can enhance androgen receptor activity, however, whether MAA actually impacts the expression of androgen-responsive genes in vivo, and which genes might be affected is not known. METHODS A mouse TM3 Leydig cell line that stably expresses androgen receptor (TM3-AR) was prepared and analyzed by transcriptional profiling to identify target gene interactions between MAA and testosterone on a global scale. RESULTS MAA is shown to have widespread effects on androgen-responsive genes, affecting processes ranging from apoptosis to ion transport, cell adhesion, phosphorylation and transcription, with MAA able to enhance, as well as antagonize, androgenic responses. Moreover, testosterone is shown to exert both positive and negative effects on MAA gene responses. Motif analysis indicated that binding sites for FOX, HOX, LEF/TCF, STAT5 and MEF2 family transcription factors are among the most highly enriched in genes regulated by testosterone and MAA. Notably, 65 FOXO targets were repressed by testosterone or showed repression enhanced by MAA with testosterone; these include 16 genes associated with developmental processes, six of which are Hox genes. CONCLUSIONS These findings highlight the complex interactions between testosterone and MAA, and provide insight into the effects of MAA exposure on androgen-dependent processes in a Leydig cell model.
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Affiliation(s)
- Gargi Bagchi
- Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
| | - Yijing Zhang
- Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
| | - Kerri A Stanley
- Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
| | - David J Waxman
- Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
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Moutsatsou P, Papoutsi Z, Kassi E, Heldring N, Zhao C, Tsiapara A, Melliou E, Chrousos GP, Chinou I, Karshikoff A, Nilsson L, Dahlman-Wright K. Fatty acids derived from royal jelly are modulators of estrogen receptor functions. PLoS One 2010; 5:e15594. [PMID: 21203528 PMCID: PMC3008742 DOI: 10.1371/journal.pone.0015594] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2010] [Accepted: 11/15/2010] [Indexed: 12/28/2022] Open
Abstract
Royal jelly (RJ) excreted by honeybees and used as a nutritional and medicinal agent has estrogen-like effects, yet the compounds mediating these effects remain unidentified. The possible effects of three RJ fatty acids (FAs) (10-hydroxy-2-decenoic-10H2DA, 3,10-dihydroxydecanoic-3,10DDA, sebacic acid-SA) on estrogen signaling was investigated in various cellular systems. In MCF-7 cells, FAs, in absence of estradiol (E2), modulated the estrogen receptor (ER) recruitment to the pS2 promoter and pS2 mRNA levels via only ERβ but not ERα, while in presence of E2 FAs modulated both ERβ and ERα. Moreover, in presence of FAs, the E2-induced recruitment of the EAB1 co-activator peptide to ERα is masked and the E2-induced estrogen response element (ERE)-mediated transactivation is inhibited. In HeLa cells, in absence of E2, FAs inhibited the ERE-mediated transactivation by ERβ but not ERα, while in presence of E2, FAs inhibited ERE-activity by both ERβ and ERα. Molecular modeling revealed favorable binding of FAs to ERα at the co-activator-binding site, while binding assays showed that FAs did not bind to the ligand-binding pocket of ERα or ERβ. In KS483 osteoblasts, FAs, like E2, induced mineralization via an ER-dependent way. Our data propose a possible molecular mechanism for the estrogenic activities of RJ's components which, although structurally entirely different from E2, mediate estrogen signaling, at least in part, by modulating the recruitment of ERα, ERβ and co-activators to target genes.
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Affiliation(s)
- Paraskevi Moutsatsou
- Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece.
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Cho KI, Yi H, Tserentsoodol N, Searle K, Ferreira PA. Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress. Dis Model Mech 2010; 3:595-604. [PMID: 20682751 DOI: 10.1242/dmm.004648] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Oxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.
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Affiliation(s)
- Kyoung-in Cho
- Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA
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Henley DV, Korach KS. Physiological effects and mechanisms of action of endocrine disrupting chemicals that alter estrogen signaling. Hormones (Athens) 2010; 9:191-205. [PMID: 20688617 PMCID: PMC4782146 DOI: 10.14310/horm.2002.1270] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Derek V Henley
- Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Bagchi G, Zhang Y, Waxman DJ. Impact of methoxyacetic acid on mouse Leydig cell gene expression. Reprod Biol Endocrinol 2010; 8:65. [PMID: 20565877 PMCID: PMC2909983 DOI: 10.1186/1477-7827-8-65] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2010] [Accepted: 06/18/2010] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Methoxyacetic acid (MAA) is the active metabolite of the widely used industrial chemical ethylene glycol monomethyl ether, which is associated with various developmental and reproductive toxicities, including neural toxicity, blood and immune disorders, limb degeneration and testicular toxicity. Testicular toxicity is caused by degeneration of germ cells in association with changes in gene expression in both germ cells and Sertoli cells of the testis. This study investigates the impact of MAA on gene expression in testicular Leydig cells, which play a critical role in germ cell survival and male reproductive function. METHODS Cultured mouse TM3 Leydig cells were treated with MAA for 3, 8, and 24 h and changes in gene expression were monitored by genome-wide transcriptional profiling. RESULTS A total of 3,912 MAA-responsive genes were identified. Ingenuity Pathway analysis identified reproductive system disease, inflammatory disease and connective tissue disorder as the top biological functions affected by MAA. The MAA-responsive genes were classified into 1,366 early responders, 1,387 mid-responders, and 1,138 late responders, based on the time required for MAA to elicit a response. Analysis of enriched functional clusters for each subgroup identified 106 MAA early response genes involved in transcription regulation, including 32 genes associated with developmental processes. 60 DNA-binding proteins responded to MAA rapidly but transiently, and may contribute to the downstream effects of MAA seen for many mid and late response genes. Genes within the phosphatidylinositol/phospholipase C/calcium signaling pathway, whose activity is required for potentiation of nuclear receptor signaling by MAA, were also enriched in the set of early MAA response genes. In contrast, many of the genes responding to MAA at later time points encode membrane proteins that contribute to cell adhesion and membrane signaling. CONCLUSIONS These findings on the progressive changes in gene expression induced by MAA in a cultured Leydig cell model may help elucidate signaling pathways that lead to the testicular pathophysiological responses induced by MAA exposure and may identify useful biomarkers of MAA toxicity.
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Affiliation(s)
- Gargi Bagchi
- Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
| | - Yijing Zhang
- Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
| | - David J Waxman
- Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA
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Henley DV, Mueller S, Korach KS. The short-chain fatty acid methoxyacetic acid disrupts endogenous estrogen receptor-alpha-mediated signaling. ENVIRONMENTAL HEALTH PERSPECTIVES 2009; 117:1702-6. [PMID: 20049119 PMCID: PMC2801194 DOI: 10.1289/ehp.0900800] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Accepted: 06/16/2009] [Indexed: 05/05/2023]
Abstract
BACKGROUND Ethylene glycol monomethyl ether (EGME) exposure is associated with impaired reproductive function. The primary metabolite of EGME is methoxyacetic acid (MAA), a short-chain fatty acid that inhibits histone deacetylase activity and alters gene expression. OBJECTIVE Because estrogen signaling is necessary for normal reproductive function and modulates gene expression, the estrogen-signaling pathway is a likely target for MAA; however, little is known about the effects of MAA in this regard. METHODS We evaluated the mechanistic effects of MAA on estrogen receptor (ER) expression and estrogen signaling using in vitro and in vivo model systems. RESULTS MAA potentiates 17beta-estradiol (E(2)) stimulation of an estrogen-responsive reporter plasmid in HeLa cells transiently transfected with either a human ERalpha or ERbeta expression vector containing a cytomegalovirus (CMV) promoter. This result is attributed to increased exogenous ER expression due to MAA-mediated activation of the CMV promoter. In contrast to its effects on exogenous ER, MAA decreases endogenous ERalpha expression and attenuates E(2)-stimulated endogenous gene expression in both MCF-7 cells and the mouse uterus. CONCLUSIONS These results illustrate the importance of careful experimental design and analysis when assessing the potential endocrine-disrupting properties of a compound to ensure biological responses are in concordance with in vitro analyses. Given the established role of the ER in normal reproductive function, the effects of MAA on the endogenous ER reported here are consistent with the reproductive abnormalities observed after EGME exposure and suggest that these toxicities may be due, at least in part, to attenuation of endogenous ER-mediated signaling.
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Affiliation(s)
- Derek V. Henley
- Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA
| | - Stephanie Mueller
- German Cancer Research Center, Systems Biology of Signal Transduction, Heidelberg, Germany
| | - Kenneth S. Korach
- Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA
- Address correspondence to K.S. Korach, Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, MD B3-02, P.O. Box 12233, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-3512. Fax: (919) 541-0696. E-mail:
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Noh H, Oh EY, Seo JY, Yu MR, Kim YO, Ha H, Lee HB. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol 2009; 297:F729-39. [PMID: 19553350 DOI: 10.1152/ajprenal.00086.2009] [Citation(s) in RCA: 222] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-beta1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-beta1-treated normal rat kidney tubular epithelial cells (NRK52-E), we found that trichostatin A, a nonselective HDAC inhibitor, decreased mRNA and protein expressions of ECM components and prevented EMT. Valproic acid and class I-selective HDAC inhibitor SK-7041 also showed similar effects in NRK52-E cells. Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly increased in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-beta1-treated NRK52-E cells. Levels of mRNA expression of fibronectin and alpha-smooth muscle actin were decreased, whereas E-cadherin mRNA was increased when HDAC-2 was knocked down using RNA interference in NRK52-E cells. Interestingly, hydrogen peroxide increased HDAC-2 activity, and the treatment with an antioxidant, N-acetylcysteine, almost completely reduced TGF-beta1-induced activation of HDAC-2. These findings suggest that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-beta1-induced activation of HDAC-2.
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Affiliation(s)
- Hyunjin Noh
- Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea
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Rando G, Ramachandran B, Rebecchi M, Ciana P, Maggi A. Differential effect of pure isoflavones and soymilk on estrogen receptor activity in mice. Toxicol Appl Pharmacol 2009; 237:288-97. [DOI: 10.1016/j.taap.2009.03.022] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Revised: 03/17/2009] [Accepted: 03/26/2009] [Indexed: 01/06/2023]
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