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Stephens VR, Horner KB, Avila WM, Spicer SK, Chinni R, Bernabe EB, Hinton AO, Damo SM, Eastman AJ, McCallister MM, Osteen KG, Gaddy JA. The impact of persistent organic pollutants on fertility: exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive tract immune responses. Front Immunol 2024; 15:1497405. [PMID: 39720712 PMCID: PMC11666484 DOI: 10.3389/fimmu.2024.1497405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/18/2024] [Indexed: 12/26/2024] Open
Abstract
Exposure to environmental contaminants can result in profound effects on the host immune system. One class of environmental toxicants, known as dioxins, are persistent environmental contaminants termed "forever chemicals". The archetype toxicant from this group of chemicals is 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), an immunotoxicant that activates the aryl-hydrocarbon receptor pathway leading to a variety of changes in immune cell responses. Immune cell functions are crucial to the development and maintenance of healthy reproduction. Immune cells facilitate tolerance between at the maternal-fetal interface between the parent and the semi-allogenic fetus and help defend the gravid reproductive tract from infectious assault. Epidemiological studies reveal that exposure to environmental contaminants (such as TCDD) are linked to adverse reproductive health outcomes including endometriosis, placental inflammation, and preterm birth. However, little is known about the molecular mechanisms that underpin how environmental toxicant exposures impact immune functions at the maternal-fetal interface or within the reproductive tract in general. This review presents the most recent published work that studies interactions between dioxin or TCDD exposure, the host immune system, and reproduction.
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Affiliation(s)
- Victoria R. Stephens
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Kensley B. Horner
- Department of Life and Physical Sciences, Fisk University, Nashville, TN, United States
| | - Walter M. Avila
- Department of Life and Physical Sciences, Fisk University, Nashville, TN, United States
| | - Sabrina K. Spicer
- Department of Chemistry, Vanderbilt University, Nashville, TN, United States
| | - Riya Chinni
- Department of Medicine, Health, and Society, Vanderbilt University, Nashville, TN, United States
| | - Emily B. Bernabe
- Tennessee Valley Health Systems, Department of Veterans Affairs, Nashville, TN, United States
| | - Antentor O. Hinton
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
| | - Steven M. Damo
- Department of Life and Physical Sciences, Fisk University, Nashville, TN, United States
- Department of Biochemistry, Vanderbilt University, Nashville, TN, United States
- Center for Structural Biology, Vanderbilt University, Nashville, TN, United States
| | - Alison J. Eastman
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Monique M. McCallister
- Department of Biological Sciences, Tennessee State University, Nashville, TN, United States
| | - Kevin G. Osteen
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
- Tennessee Valley Health Systems, Department of Veterans Affairs, Nashville, TN, United States
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, TN, United States
| | - Jennifer A. Gaddy
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Medicine, Health, and Society, Vanderbilt University, Nashville, TN, United States
- Tennessee Valley Health Systems, Department of Veterans Affairs, Nashville, TN, United States
- Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, United States
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Zyoud SH. Global dioxin research trends and focal points: A century-long visual and bibliometric analysis (1923-2022). Toxicol Ind Health 2024; 40:504-518. [PMID: 38838663 DOI: 10.1177/07482337241257276] [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] [Indexed: 06/07/2024]
Abstract
Dioxin-like compounds, recognized by the World Health Organization (WHO) as among the most enduring toxic chemical substances in the environment, are linked to various occupational activities and industrial accidents worldwide. The aim of this study was to examine and present research publications on dioxins, pinpoint current research trends, identify research gaps, and highlight potential avenues for future exploration in the field. The study period for relevant research articles ranged from 1923 to December 31, 2022, and these articles were sourced from the Scopus database. The analysis involved the identification of key contributors to the field and the visualization of topics, themes, and international collaboration. VOSviewer software (version 1.6.20) was used for visualization analysis. A total of 11,620 publications on dioxins were documented in the Scopus database. The predominant category of these documents comprised 9780 original articles, which represents 84.17% of the total publications. The United States lead in the number of publications, with 3992 (34.35%), followed by Japan, with 1429 (12.3%), China, with 1005 (8.65%), and Germany, with 974 (8.38%). Before 2002, scholarly attention in this field focused primarily on the health effects, environmental fate, and mechanism of toxicity of tetrachlorodibenzo-p-dioxin (TCDD). However, a noticeable change in research focus has been observed since 2002, highlighting the emergence of a topic related to the health effects and environmental fate of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PFDFs). This study is the first to conduct a comprehensive quantitative bibliometric analysis of dioxins over time. These findings indicate a significant increase in the overall growth of the dioxin literature over the past 30 years. These findings may prove crucial in guiding and organizing subsequent investigations related to dioxins.
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Affiliation(s)
- Sa'ed H Zyoud
- Poison Control and Drug Information Center (PCDIC), An-Najah National University, Nablus, Palestine
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
- Clinical Research Centre, An-Najah National University Hospital, Nablus, Palestine
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Anitha M, Kumar SM, Koo I, Perdew GH, Srinivasan S, Patterson AD. Modulation of Ceramide-Induced Apoptosis in Enteric Neurons by Aryl Hydrocarbon Receptor Signaling: Unveiling a New Pathway beyond ER Stress. Int J Mol Sci 2024; 25:8581. [PMID: 39201268 PMCID: PMC11354200 DOI: 10.3390/ijms25168581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/26/2024] [Accepted: 08/01/2024] [Indexed: 09/02/2024] Open
Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant and a potent aryl hydrocarbon receptor (AHR) ligand, causes delayed intestinal motility and affects the survival of enteric neurons. In this study, we investigated the specific signaling pathways and molecular targets involved in TCDD-induced enteric neurotoxicity. Immortalized fetal enteric neuronal (IM-FEN) cells treated with 10 nM TCDD exhibited cytotoxicity and caspase 3/7 activation, indicating apoptosis. Increased cleaved caspase-3 expression with TCDD treatment, as assessed by immunostaining in enteric neuronal cells isolated from WT mice but not in neural crest cell-specific Ahr deletion mutant mice (Wnt1Cre+/-/Ahrb(fl/fl)), emphasized the pivotal role of AHR in this process. Importantly, the apoptosis in IM-FEN cells treated with TCDD was mediated through a ceramide-dependent pathway, independent of endoplasmic reticulum stress, as evidenced by increased ceramide synthesis and the reversal of cytotoxic effects with myriocin, a potent inhibitor of ceramide biosynthesis. We identified Sptlc2 and Smpd2 as potential gene targets of AHR in ceramide regulation by a chromatin immunoprecipitation (ChIP) assay in IM-FEN cells. Additionally, TCDD downregulated phosphorylated Akt and phosphorylated Ser9-GSK-3β levels, implicating the PI3 kinase/AKT pathway in TCDD-induced neurotoxicity. Overall, this study provides important insights into the mechanisms underlying TCDD-induced enteric neurotoxicity and identifies potential targets for the development of therapeutic interventions.
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Affiliation(s)
- Mallappa Anitha
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (M.A.); (I.K.); (G.H.P.)
| | - Supriya M. Kumar
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (M.A.); (I.K.); (G.H.P.)
| | - Imhoi Koo
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (M.A.); (I.K.); (G.H.P.)
| | - Gary H. Perdew
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (M.A.); (I.K.); (G.H.P.)
| | - Shanthi Srinivasan
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA;
- Atlanta VA Medical Center, Decatur, GA 30033, USA
| | - Andrew D. Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (M.A.); (I.K.); (G.H.P.)
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Daood NJ, Russo DP, Chung E, Qin X, Zhu H. Predicting Chemical Immunotoxicity through Data-Driven QSAR Modeling of Aryl Hydrocarbon Receptor Agonism and Related Toxicity Mechanisms. ENVIRONMENT & HEALTH (WASHINGTON, D.C.) 2024; 2:474-485. [PMID: 39049897 PMCID: PMC11264268 DOI: 10.1021/envhealth.4c00026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 07/27/2024]
Abstract
Computational modeling has emerged as a time-saving and cost-effective alternative to traditional animal testing for assessing chemicals for their potential hazards. However, few computational modeling studies for immunotoxicity were reported, with few models available for predicting toxicants due to the lack of training data and the complex mechanisms of immunotoxicity. In this study, we employed a data-driven quantitative structure-activity relationship (QSAR) modeling workflow to extensively enlarge the limited training data by revealing multiple targets involved in immunotoxicity. To this end, a probe data set of 6,341 chemicals was obtained from a high-throughput screening (HTS) assay testing for the activation of the aryl hydrocarbon receptor (AhR) signaling pathway, a key event leading to immunotoxicity. Searching this probe data set against PubChem yielded 3,183 assays with testing results for varying proportions of these 6,341 compounds. 100 assays were selected to develop QSAR models based on their correlations to AhR agonism. Twelve individual QSAR models were built for each assay using combinations of four machine-learning algorithms and three molecular fingerprints. 5-fold cross-validation of the resulting models showed good predictivity (average CCR = 0.73). A total of 20 assays were further selected based on QSAR model performance, and their resulting QSAR models showed good predictivity of potential immunotoxicants from external chemicals. This study provides a computational modeling strategy that can utilize large public toxicity data sets for modeling immunotoxicity and other toxicity endpoints, which have limited training data and complicated toxicity mechanisms.
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Affiliation(s)
- Nada J. Daood
- Department
of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
| | - Daniel P. Russo
- Department
of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
| | - Elena Chung
- Department
of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
- Center
for Biomedical Informatics and Genomics, Tulane University School of Medicine, New Orleans, Louisiana 70112, United States
| | - Xuebin Qin
- Tulane
National Primate Research Center, Tulane
University School of Medicine, Covington, Louisiana 70433, United States
| | - Hao Zhu
- Department
of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
- Center
for Biomedical Informatics and Genomics, Tulane University School of Medicine, New Orleans, Louisiana 70112, United States
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5
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Drago G, Aloi N, Ruggieri S, Longo A, Contrino ML, Contarino FM, Cibella F, Colombo P, Longo V. Guardians under Siege: Exploring Pollution's Effects on Human Immunity. Int J Mol Sci 2024; 25:7788. [PMID: 39063030 PMCID: PMC11277414 DOI: 10.3390/ijms25147788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Chemical pollution poses a significant threat to human health, with detrimental effects on various physiological systems, including the respiratory, cardiovascular, mental, and perinatal domains. While the impact of pollution on these systems has been extensively studied, the intricate relationship between chemical pollution and immunity remains a critical area of investigation. The focus of this study is to elucidate the relationship between chemical pollution and human immunity. To accomplish this task, this study presents a comprehensive review that encompasses in vitro, ex vivo, and in vivo studies, shedding light on the ways in which chemical pollution can modulate human immunity. Our aim is to unveil the complex mechanisms by which environmental contaminants compromise the delicate balance of the body's defense systems going beyond the well-established associations with defense systems and delving into the less-explored link between chemical exposure and various immune disorders, adding urgency to our understanding of the underlying mechanisms and their implications for public health.
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Affiliation(s)
- Gaspare Drago
- Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; (G.D.); (N.A.); (S.R.); (A.L.); (F.C.); (V.L.)
| | - Noemi Aloi
- Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; (G.D.); (N.A.); (S.R.); (A.L.); (F.C.); (V.L.)
| | - Silvia Ruggieri
- Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; (G.D.); (N.A.); (S.R.); (A.L.); (F.C.); (V.L.)
| | - Alessandra Longo
- Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; (G.D.); (N.A.); (S.R.); (A.L.); (F.C.); (V.L.)
| | - Maria Lia Contrino
- Azienda Sanitaria Provinciale di Siracusa, Corso Gelone 17, 96100 Siracusa, Italy; (M.L.C.); (F.M.C.)
| | - Fabio Massimo Contarino
- Azienda Sanitaria Provinciale di Siracusa, Corso Gelone 17, 96100 Siracusa, Italy; (M.L.C.); (F.M.C.)
| | - Fabio Cibella
- Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; (G.D.); (N.A.); (S.R.); (A.L.); (F.C.); (V.L.)
| | - Paolo Colombo
- Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; (G.D.); (N.A.); (S.R.); (A.L.); (F.C.); (V.L.)
| | - Valeria Longo
- Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; (G.D.); (N.A.); (S.R.); (A.L.); (F.C.); (V.L.)
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6
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Liang M, Gao Y, Shen Y, Zhang X, Gu J, Ji G. Serum metabolism distribution in individuals exposed to dioxins: A case study of residents near the municipal solid waste incinerators in China. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 947:174431. [PMID: 38960151 DOI: 10.1016/j.scitotenv.2024.174431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/27/2024] [Accepted: 06/30/2024] [Indexed: 07/05/2024]
Abstract
Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) have attracted considerable attention owing to their environmental persistence, bioaccumulation, and high toxicity. This study aimed to investigate changes in serum metabolites following exposure to PCDD/Fs and to reveal a novel pathogenesis of PCDD/Fs. Serum samples were collected from 75 residents living near a municipal solid waste incinerator in China to analyse the relationship between PCDD/Fs and serum metabolic components. The serum level in the low-exposure group [19.07 (13.44-23.89) pg-TEQ/L] was significantly lower than that in the high-exposure group [115.60 (52.28-592.65) pg-TEQ/L]. Non-targeted metabolomic studies based on liquid chromatography-high resolution mass spectrometry have been applied to the metabolomic analysis of serum. Thirty-seven metabolites with significant differences among the different groups were identified as biomarkers. Pathway analysis revealed that high dioxin exposure perturbed various biological processes, including glycerol phospholipid metabolism and the interconversion of pentose and glucuronate. The results of a population health survey showed that the serum dioxin concentration in patients with diabetes was significantly higher than that in the control population. These findings suggest that dioxin exposure is associated with several potential adverse health risks, including inflammation, diabetes, and cardiovascular disease, through metabolic changes.
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Affiliation(s)
- Mengyuan Liang
- Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China
| | - Yuanyun Gao
- Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China
| | - Yuehong Shen
- Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China
| | - Xinyu Zhang
- School of Environmental Science and Engineering, Changzhou University, Changzhou 213164, China
| | - Jie Gu
- Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China
| | - Guixiang Ji
- Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China.
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7
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Jonić N, Koprivica I, Chatzigiannis CM, Tsiailanis AD, Kyrkou SG, Tzakos EP, Pavić A, Dimitrijević M, Jovanović A, Jovanović MB, Marinho S, Castro-Almeida I, Otašević V, Moura-Alves P, Tzakos AG, Stojanović I. Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells. Molecules 2024; 29:2988. [PMID: 38998940 PMCID: PMC11243367 DOI: 10.3390/molecules29132988] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/05/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects. In this study, we designed, synthesized and evaluated three indole-containing potential AHR ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5 actively induced Treg differentiation from naïve CD4+ cells, and promoted Treg proliferation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish embryos and was therefore considered safe for animal studies. Following oral administration to C57BL/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1 cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the small intestine). These findings make AGT-5 a promising candidate for further exploration in the treatment of inflammatory and autoimmune diseases.
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Affiliation(s)
- Natalija Jonić
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (N.J.); (I.K.); (M.D.)
| | - Ivan Koprivica
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (N.J.); (I.K.); (M.D.)
| | - Christos M. Chatzigiannis
- Section of Organic Chemistry & Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece; (C.M.C.); (A.D.T.); (S.G.K.)
| | - Antonis D. Tsiailanis
- Section of Organic Chemistry & Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece; (C.M.C.); (A.D.T.); (S.G.K.)
| | - Stavroula G. Kyrkou
- Section of Organic Chemistry & Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece; (C.M.C.); (A.D.T.); (S.G.K.)
| | | | - Aleksandar Pavić
- Laboratory for Microbial Molecular Genetics and Ecology, Institute for Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia;
| | - Mirjana Dimitrijević
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (N.J.); (I.K.); (M.D.)
| | - Andjelina Jovanović
- Department of Otorhinolaryngology with Maxillofacial Surgery, Clinical Hospital Center “Zemun”, 11080 Belgrade, Serbia; (A.J.); (M.B.J.)
| | - Milan B. Jovanović
- Department of Otorhinolaryngology with Maxillofacial Surgery, Clinical Hospital Center “Zemun”, 11080 Belgrade, Serbia; (A.J.); (M.B.J.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Sérgio Marinho
- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135 Porto, Portugal; (S.M.); (I.C.-A.)
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal
| | - Inês Castro-Almeida
- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135 Porto, Portugal; (S.M.); (I.C.-A.)
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal
| | - Vesna Otašević
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia;
| | - Pedro Moura-Alves
- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-135 Porto, Portugal; (S.M.); (I.C.-A.)
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal
| | - Andreas G. Tzakos
- Section of Organic Chemistry & Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece; (C.M.C.); (A.D.T.); (S.G.K.)
- Institute of Materials Science and Computing, University Research Center of Ioannina (URCI), 45110 Ioannina, Greece
| | - Ivana Stojanović
- Department of Immunology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (N.J.); (I.K.); (M.D.)
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8
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Aldeli N, Murphy D, Hanano A. Impact of dioxins on reproductive health in female mammals. FRONTIERS IN TOXICOLOGY 2024; 6:1392257. [PMID: 38774538 PMCID: PMC11106427 DOI: 10.3389/ftox.2024.1392257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 04/22/2024] [Indexed: 05/24/2024] Open
Abstract
Extensive research has been conducted to investigate the toxicological impact of dioxins on mammals, revealing profound effects on the female reproductive system in both humans and animals. Dioxin exposure significantly disrupts the intricate functions of the ovary, a pivotal organ responsible for reproductive and endocrine processes. This disruption manifests as infertility, premature ovarian failure, and disturbances in sex steroid hormone levels. Comprehensive studies, encompassing accidental human exposure and experimental animal data, have raised a wealth of information with consistent yet varied conclusion influenced by experimental factors. This review begins by providing an overarching background on the ovary, emphasizing its fundamental role in reproductive health, particularly in ovarian steroidogenesis and hormone receptor regulation. Subsequently, a detailed examination of the Aryl hydrocarbon Receptor (AhR) and its role in governing ovarian function is presented. The review then outlines the sources and toxicity of dioxins, with a specific focus on AhR involvement in mediating reproductive toxicity in mammals. Within this context, the impact of dioxins, notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on Folliculogenesis and Preimplantation embryos is discussed. Furthermore, the review delves into the disruptions of the female hormonal system caused by TCDD and their ramifications in endometriosis. Notably, variations in the effects of TCDD on the female reproductive and hormonal system are highlighted in relation to TCDD dose, animal species, and age. As a forward-looking perspective, questions arise regarding the potential involvement of molecular mechanisms beyond AhR in mediating the female reproductive toxicity of dioxins.
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Affiliation(s)
- Nour Aldeli
- Department of Animal Biology, Faculty of Science, Al Furat University, Deir-ez-Zor, Syria
| | - Denis Murphy
- School of Applied Sciences, University of South Wales, Cardiff, Wales, United Kingdom
| | - Abdulsamie Hanano
- Department of Molecular Biology and Biotechnology, Atomic Energy Commission of Syria (AECS), Damascus, Syria
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9
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Lin X, Meng X, Lin J. The Role of Aryl Hydrocarbon Receptor in the Pathogenesis and Treatment of Psoriasis. J Cutan Med Surg 2024; 28:276-286. [PMID: 38497283 DOI: 10.1177/12034754241239050] [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] [Indexed: 03/19/2024]
Abstract
The pathogenesis of psoriasis is complex. Aryl hydrocarbon receptor (AhR) is a transcription factor that can be bound and activated by structurally diverse ligands and plays an important role in a range of biological processes and in the pathogenesis of different diseases. Recently, the role of AhR in psoriasis has attracted attention. AhR has toxicological functions and physiological functions. The overexpression and activation of AhR induced by the environmental pollutant and exogenous AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can drive the development of psoriasis. This TCDD-mediated toxicological response disrupts the physiological functions of AhR resulting in skin barrier disorders and the release of inflammatory cytokines, 2 of the pivotal factors of psoriasis. In addition, highly upregulated kynureninase in psoriasis decreases endogenous AhR agonists, thereby weakening the physiological functions of AhR. Activating AhR physiological signalling should be useful in the treatment of psoriasis. Studies have demonstrated that physiological activation of AhR can dampen the severity of psoriasis. The oldest and effective treatment for psoriasis coal tar works by activating AhR, and both new anti-psoriasis drugs tapinarof and benvitimod are formulations of AhR agonist, supporting that activation of AhR can be used as a new strategy for the treatment of psoriasis. Preclinical and preliminary clinical studies have revealed the anti-psoriasis effects of a number of AhR agonists, providing potential candidates for the development of new drugs for the treatment of psoriasis.
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Affiliation(s)
- Xiran Lin
- Department of Dermatology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xianmin Meng
- Department of Pathology and Laboratory Medicine, Axia Women's Health, Oaks, PA, USA
| | - Jingrong Lin
- Department of Dermatology, First Affiliated Hospital of Dalian Medical University, Dalian, China
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10
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Liu J, Zhang B, Zhang G, Shang D. Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point? Front Immunol 2024; 15:1345838. [PMID: 38449875 PMCID: PMC10915070 DOI: 10.3389/fimmu.2024.1345838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 01/29/2024] [Indexed: 03/08/2024] Open
Abstract
Overcoming the immunosuppressive tumor microenvironment and identifying widely used immunosuppressants with minimal side effects are two major challenges currently hampering cancer immunotherapy. Regulatory T cells (Tregs) are present in almost all cancer tissues and play an important role in preserving autoimmune tolerance and tissue homeostasis. The tumor inflammatory microenvironment causes the reprogramming of Tregs, resulting in the conversion of Tregs to immunosuppressive phenotypes. This process ultimately facilitates tumor immune escape or tumor progression. However, current systemic Treg depletion therapies may lead to severe autoimmune toxicity. Therefore, it is crucial to understand the mechanism of Treg reprogramming and develop immunotherapies that selectively target Tregs within tumors. This article provides a comprehensive review of the potential mechanisms involved in Treg cell reprogramming and explores the application of Treg cell immunotherapy. The interference with reprogramming pathways has shown promise in reducing the number of tumor-associated Tregs or impairing their function during immunotherapy, thereby improving anti-tumor immune responses. Furthermore, a deeper understanding of the mechanisms that drive Treg cell reprogramming could reveal new molecular targets for future treatments.
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Affiliation(s)
- Jinming Liu
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Biao Zhang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guolin Zhang
- Department of Cardiology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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11
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Zhao Y, Meijer J, Walker DI, Kim J, Portengen L, Jones DP, Saberi Hosnijeh F, Vlaanderen J, Vermeulen R. Dioxin(-like)-Related Biological Effects through Integrated Chemical-wide and Metabolome-wide Analyses. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:258-268. [PMID: 38149779 PMCID: PMC10785760 DOI: 10.1021/acs.est.3c07588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 12/28/2023]
Abstract
Dioxin(-like) exposures are linked to adverse health effects, including cancer. However, metabolic alterations induced by these chemicals remain largely unknown. Beyond known dioxin(-like) compounds, we leveraged a chemical-wide approach to assess chlorinated co-exposures and parent compound products [termed dioxin(-like)-related compounds] among 137 occupational workers. Endogenous metabolites were profiled by untargeted metabolomics, namely, reversed-phase chromatography with negative electrospray ionization (C18-negative) and hydrophilic interaction liquid chromatography with positive electrospray ionization (HILIC-positive). We performed a metabolome-wide association study to select dioxin(-like) associated metabolic features using a 20% false discovery rate threshold. Metabolic features were then characterized by pathway enrichment analyses. There are no significant features associated with polychlorinated dibenzo-p-dioxins (PCDDs), a subgroup of known dioxin(-like) compounds. However, 3,110 C18-negative and 2,894 HILIC-positive features were associated with at least one of the PCDD-related compounds. Abundant metabolic changes were also observed for polychlorinated dibenzofuran-related and polychlorinated biphenyl-related compounds. These metabolic features were primarily enriched in pathways of amino acids, lipid and fatty acids, carbohydrates, cofactors, and nucleotides. Our study highlights the potential of chemical-wide analysis for comprehensive exposure assessment beyond targeted chemicals. Coupled with advanced endogenous metabolomics, this approach allows for an in-depth exploration of metabolic alterations induced by environmental chemicals.
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Affiliation(s)
- Yujia Zhao
- Institute
for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, The Netherlands
| | - Jeroen Meijer
- Institute
for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, The Netherlands
- Department
Environment & Health, Vrije Universiteit, Amsterdam 1081 HV, The Netherlands
| | - Douglas I. Walker
- Gangarosa
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, United States
| | - Juni Kim
- Gangarosa
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, United States
| | - Lützen Portengen
- Institute
for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, The Netherlands
| | - Dean P. Jones
- Division
of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of
Medicine, Emory University, Atlanta, Georgia 30322, United States
| | - Fatemeh Saberi Hosnijeh
- Institute
for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, The Netherlands
| | - Jelle Vlaanderen
- Institute
for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, The Netherlands
| | - Roel Vermeulen
- Institute
for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, The Netherlands
- Julius
Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht 3584 CX, The Netherlands
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12
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Sandoval S, Malany K, Thongphanh K, Martinez CA, Goodson ML, Souza FDC, Lin LW, Sweeney N, Pennington J, Lein PJ, Kerkvliet NI, Ehrlich AK. Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2-responding CD4 + T cells. Front Immunol 2023; 14:1193535. [PMID: 38035105 PMCID: PMC10682649 DOI: 10.3389/fimmu.2023.1193535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 10/24/2023] [Indexed: 12/02/2023] Open
Abstract
Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4+ T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4+ T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4+ T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4+ T cells, Nrp1 expression was assessed in vivo and in vitro following AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4+ T cells increases over the course of activation and proliferation in vivo. The actively dividing Nrp1+Foxp3- cells express the classic effector phenotype of CD44hiCD45RBlo, and the increase in Nrp1+Foxp3- cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4+ T cells. The downregulation of Nrp1 on CD4+ T cells was recapitulated in vitro in cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4+Foxp3- cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression both in vitro and in vivo. Collectively, the data demonstrate that Nrp1 is a CD4+ T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4+ T cell responses.
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Affiliation(s)
- Simone Sandoval
- Department of Environmental Toxicology, College of Agriculture and Environmental Science, University of California, Davis, Davis, CA, United States
| | - Keegan Malany
- Department of Environmental Toxicology, College of Agriculture and Environmental Science, University of California, Davis, Davis, CA, United States
| | - Krista Thongphanh
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Clarisa A. Martinez
- Department of Environmental Toxicology, College of Agriculture and Environmental Science, University of California, Davis, Davis, CA, United States
| | - Michael L. Goodson
- Department of Environmental Toxicology, College of Agriculture and Environmental Science, University of California, Davis, Davis, CA, United States
| | - Felipe Da Costa Souza
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Lo-Wei Lin
- Department of Environmental Toxicology, College of Agriculture and Environmental Science, University of California, Davis, Davis, CA, United States
| | - Nicolle Sweeney
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California, Davis, Davis, CA, United States
| | - Jamie Pennington
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
| | - Pamela J. Lein
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Nancy I. Kerkvliet
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
| | - Allison K. Ehrlich
- Department of Environmental Toxicology, College of Agriculture and Environmental Science, University of California, Davis, Davis, CA, United States
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13
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Sandoval S, Malany K, Thongphanh K, Martinez CA, Goodson ML, Souza FDC, Lin LW, Pennington J, Lein PJ, Kerkvliet NI, Ehrlich AK. Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2 responding CD4 + T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.25.559429. [PMID: 37808764 PMCID: PMC10557576 DOI: 10.1101/2023.09.25.559429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4 + T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4 + T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4 + T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4 + T cells, Nrp1 expression was assessed in vivo and in vitro following AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4 + T cells increases over the course of activation and proliferation in vivo . The actively dividing Nrp1 + Foxp3 - cells express the classic effector phenotype of CD44 hi CD45RB lo , and the increase in Nrp1 + Foxp3 - cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4 + T cells. The downregulation of Nrp1 on CD4 + T cells was recapitulated in vitro in cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4 + Foxp3 - cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression both in vitro and in vivo . Collectively, the data demonstrate that Nrp1 is a CD4 + T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4 + T cell responses.
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14
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Chu H, Jo J, Son Y, Lee JY, Ahn YG. Developing an Improved Strategy for the Analysis of Polychlorinated Dibenzo-p-Dioxins/Furans and Dioxin-like Polychlorinated Biphenyls in Contaminated Soils Using a Combination of a One-Step Cleanup Method and Gas Chromatography with Triple Quadrupole Mass Spectrometry. TOXICS 2023; 11:738. [PMID: 37755748 PMCID: PMC10536111 DOI: 10.3390/toxics11090738] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/16/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023]
Abstract
Soils contaminated with polychlorodibenzo-p-dioxins (PCDDs), polychlorodibenzofurans (PCDFs), and dioxin-like (dl) polychlorinated biphenyls (PCBs), known as persistent organic pollutants (POPs), have garnered global attention because of their toxicity and persistence in the environment. The standard method for target analytes has been used; however, it is an obstacle in large-scale sample analysis due to the comprehensive sample preparation and high-cost instrumental analysis. Thus, analytical development of inexpensive methods with lower barriers to determine PCDDs/Fs and dl-PCBs in soil is needed. In this study, a one-step cleanup method was developed and validated by combining a multilayer silica gel column and Florisil micro-column followed by gas chromatography with triple quadrupole mass spectrometry (GC-QqQ-MS/MS). To optimize the separation and quantification of 17 PCDDs/Fs and 12 dl-PCBs in soils, the sample cleanup and instrumental conditions were investigated. For quantification method validation, spiking experiments were conducted to determine the linearity of the calibration, recovery, and method detection limit of PCDDs/Fs and dl-PCBs using isotopic dilution GC-QqQ-MS/MS. The applicability of the simultaneous determination of PCDDs/Fs and dl-PCBs was confirmed by the recovery of native target congeners and labeled surrogate congeners spiked into the quality-control and actual soil samples. The results were in good agreement with the requirements imposed by standard methods. The findings in this work demonstrated the high accessibility of the sample cleanup and analysis methods for the efficient determination of PCDDs/Fs and dl-PCBs in contaminated soils.
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Affiliation(s)
- Haena Chu
- Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea;
| | - Jungmin Jo
- Department of Environmental Science and Engineering, Ewha Womans University, Seoul 03760, Republic of Korea; (J.J.); (J.Y.L.)
| | - Younggyu Son
- Department of Environmental Engineering, Kumoh National Institute of Technology, Gumi 39177, Republic of Korea;
- Department of Energy Engineering Convergence, Kumoh National Institute of Technology, Gumi 39177, Republic of Korea
| | - Ji Yi Lee
- Department of Environmental Science and Engineering, Ewha Womans University, Seoul 03760, Republic of Korea; (J.J.); (J.Y.L.)
| | - Yun Gyong Ahn
- Western Seoul Center, Korea Basic Science Institute, Seoul 03759, Republic of Korea;
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15
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Vijay A, Boyle NR, Kumar SM, Perdew GH, Srinivasan S, Patterson AD. Aryl hydrocarbon receptor activation affects nitrergic neuronal survival and delays intestinal motility in mice. Toxicol Sci 2023; 192:117-128. [PMID: 36782369 PMCID: PMC10025877 DOI: 10.1093/toxsci/kfad014] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Despite progress describing the effects of persistent organic pollutants (POPs) on the central nervous system, the effect of POPs on enteric nervous system (ENS) function remains underexplored. We studied the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a POP, and a potent aryl hydrocarbon receptor (AHR) ligand, on the ENS and intestinal motility in mice. C57Bl/6J mice treated with TCDD (2.4 µg/kg body weight) for 8 weeks (once per week) exhibited significant delay in intestinal motility as shown by reduced stool frequency, prolonged intestinal transit time, and a persistence of dye in the jejunum compared to control mice with maximal dye retention in the ileum. TCDD significantly increased Cyp1a1 expression, an AHR target gene, and reduced the total number of neurons and affected nitrergic neurons in cells isolated from WT mice, but not Ahr-/- mice. In immortalized fetal enteric neuronal cells, TCDD-induced nuclear translocation of AHR as well as increased Cyp1a1 expression. AHR activation did not affect neuronal proliferation. However, AHR activation resulted in enteric neuronal toxicity, specifically, nitrergic neurons. Our results demonstrate that TCDD adversely affects nitrergic neurons and thereby contributes to delayed intestinal motility. These findings suggest that AHR signaling in the ENS may play a role in modulating TCDD-induced gastrointestinal pathophysiology.
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Affiliation(s)
- Anitha Vijay
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
| | - Nina R Boyle
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
| | - Supriya M Kumar
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
| | - Gary H Perdew
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
| | - Shanthi Srinivasan
- Department of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia, USA
- Atlanta VA Medical Center, Decatur, Georgia, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
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16
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Sondermann NC, Faßbender S, Hartung F, Hätälä AM, Rolfes KM, Vogel CFA, Haarmann-Stemmann T. Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway. Biochem Pharmacol 2023; 208:115371. [PMID: 36528068 PMCID: PMC9884176 DOI: 10.1016/j.bcp.2022.115371] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022]
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor regulating adaptive and maladaptive responses toward exogenous and endogenous signals. Research from various biomedical disciplines has provided compelling evidence that the AHR is critically involved in the pathogenesis of a variety of diseases and disorders, including autoimmunity, inflammatory diseases, endocrine disruption, premature aging and cancer. Accordingly, AHR is considered an attractive target for the development of novel preventive and therapeutic measures. However, the ligand-based targeting of AHR is considerably complicated by the fact that the receptor does not always follow the beaten track, i.e. the canonical AHR/ARNT signaling pathway. Instead, AHR might team up with other transcription factors and signaling molecules to shape gene expression patterns and associated physiological or pathophysiological functions in a ligand-, cell- and micromilieu-dependent manner. Herein, we provide an overview about some of the most important non-canonical functions of AHR, including crosstalk with major signaling pathways involved in controlling cell fate and function, immune responses, adaptation to low oxygen levels and oxidative stress, ubiquitination and proteasomal degradation. Further research on these diverse and exciting yet often ambivalent facets of AHR biology is urgently needed in order to exploit the full potential of AHR modulation for disease prevention and treatment.
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Affiliation(s)
- Natalie C Sondermann
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Sonja Faßbender
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Frederick Hartung
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Anna M Hätälä
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Katharina M Rolfes
- IUF - Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
| | - Christoph F A Vogel
- Department of Environmental Toxicology and Center for Health and the Environment, University of California, Davis, CA 95616, USA
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17
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Pelaez MA, Torti MF, Alvarez De Lauro AE, Marquez AB, Giovannoni F, Damonte EB, García CC. Modulation of the Aryl Hydrocarbon Receptor Signaling Pathway Impacts on Junín Virus Replication. Viruses 2023; 15:v15020369. [PMID: 36851583 PMCID: PMC9967227 DOI: 10.3390/v15020369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/31/2023] Open
Abstract
Junín virus (JUNV), a member of the family Arenaviridae, is the etiological agent of the Argentine hemorrhagic fever, an endemic disease in the rural region of Argentina lacking a specific chemotherapy. Aryl hydrocarbon receptor (AHR) is expressed in several mammalian tissues and has been indicated as a sensor of ligands from variable sources and a modulator of the cell immune response. Interestingly, recent studies have suggested that the activation or depression of the AHR signaling pathway may play a role in the outcome of diverse human viral infections. In the present report, the effect of the pharmacological modulation of AHR on JUNV in vitro infection was analyzed. An initial microarray screening showed that the AHR pathway was overexpressed in JUNV-infected hepatic cells. Concomitantly, the infection of Vero and Huh-7 cells with the JUNV strains IV4454 and Candid#1 was significantly inhibited in a dose-dependent manner by treatment with CH223191, a specific AHR antagonist, as detected by infectivity assays, real-time RT-PCR and immunofluorescence detection of viral proteins. Furthermore, the pro-viral role of AHR in JUNV infection appears to be independent of the IFN-I pathway. Our findings support the promising perspectives of the pharmacological modulation of AHR as a potential target for the control of AHF.
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Affiliation(s)
- Miguel Angel Pelaez
- Laboratory of Antiviral Strategies, Biochemistry Department, School of Sciences, University of Buenos Aires, IQUIBICEN, University of Buenos Aires/Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina
| | - María Florencia Torti
- Laboratory of Antiviral Strategies, Biochemistry Department, School of Sciences, University of Buenos Aires, IQUIBICEN, University of Buenos Aires/Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina
| | - Aaron Ezequiel Alvarez De Lauro
- Laboratory of Antiviral Strategies, Biochemistry Department, School of Sciences, University of Buenos Aires, IQUIBICEN, University of Buenos Aires/Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina
| | - Agostina Belén Marquez
- Laboratory of Antiviral Strategies, Biochemistry Department, School of Sciences, University of Buenos Aires, IQUIBICEN, University of Buenos Aires/Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina
| | - Federico Giovannoni
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Elsa Beatriz Damonte
- Laboratory of Antiviral Strategies, Biochemistry Department, School of Sciences, University of Buenos Aires, IQUIBICEN, University of Buenos Aires/Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina
- Correspondence: (E.B.D.); (C.C.G.)
| | - Cybele Carina García
- Laboratory of Antiviral Strategies, Biochemistry Department, School of Sciences, University of Buenos Aires, IQUIBICEN, University of Buenos Aires/Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires 1428, Argentina
- Correspondence: (E.B.D.); (C.C.G.)
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18
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Safe S, Zhang L. The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer. Cancers (Basel) 2022; 14:5574. [PMID: 36428667 PMCID: PMC9688153 DOI: 10.3390/cancers14225574] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/27/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Breast cancer is a complex disease which is defined by numerous cellular and molecular markers that can be used to develop more targeted and successful therapies. The aryl hydrocarbon receptor (AhR) is overexpressed in many breast tumor sub-types, including estrogen receptor -positive (ER+) tumors; however, the prognostic value of the AhR for breast cancer patient survival is not consistent between studies. Moreover, the functional role of the AhR in various breast cancer cell lines is also variable and exhibits both tumor promoter- and tumor suppressor- like activity and the AhR is expressed in both ER-positive and ER-negative cells/tumors. There is strong evidence demonstrating inhibitory AhR-Rα crosstalk where various AhR ligands induce ER degradation. It has also been reported that different structural classes of AhR ligands, including halogenated aromatics, polynuclear aromatics, synthetic drugs and other pharmaceuticals, health promoting phytochemical-derived natural products and endogenous AhR-active compounds inhibit one or more of breast cancer cell proliferation, survival, migration/invasion, and metastasis. AhR-dependent mechanisms for the inhibition of breast cancer by AhR agonists are variable and include the downregulation of multiple genes/gene products such as CXCR4, MMPs, CXCL12, SOX4 and the modulation of microRNA levels. Some AhR ligands, such as aminoflavone, have been investigated in clinical trials for their anticancer activity against breast cancer. In contrast, several publications have reported that AhR agonists and antagonists enhance and inhibit mammary carcinogenesis, respectively, and differences between the anticancer activities of AhR agonists in breast cancer may be due in part to cell context and ligand structure. However, there are reports showing that the same AhR ligand in the same breast cancer cell line gives opposite results. These differences need to be resolved in order to further develop and take advantage of promising agents that inhibit mammary carcinogenesis by targeting the AhR.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
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19
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Bulka CM, Enggasser AE, Fry RC. Epigenetics at the Intersection of COVID-19 Risk and Environmental Chemical Exposures. Curr Environ Health Rep 2022; 9:477-489. [PMID: 35648356 PMCID: PMC9157479 DOI: 10.1007/s40572-022-00353-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW Several environmental contaminants have been implicated as contributors to COVID-19 susceptibility and severity. Immunomodulation and epigenetic regulation have been hypothesized as mediators of this relationship, but the precise underlying molecular mechanisms are not well-characterized. This review examines the evidence for epigenetic modification at the intersection of COVID-19 and environmental chemical exposures. RECENT FINDINGS Numerous environmental contaminants including air pollutants, toxic metal(loid)s, per- and polyfluorinated substances, and endocrine disrupting chemicals are hypothesized to increase susceptibility to the SARS-CoV-2 virus and the risk of severe COVID-19, but few studies currently exist. Drawing on evidence that many environmental chemicals alter the epigenetic regulation of key immunity genes and pathways, we discuss how exposures likely perturb host antiviral responses. Specific mechanisms vary by contaminant but include general immunomodulation as well as regulation of viral entry and recognition, inflammation, and immunologic memory pathways, among others. Associations between environmental contaminants and COVID-19 are likely mediated, in part, by epigenetic regulation of key immune pathways involved in the host response to SARS-CoV-2.
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Affiliation(s)
- Catherine M Bulka
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Adam E Enggasser
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rebecca C Fry
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, 166A Rosenau Hall, CB #7431, Chapel Hill, NC, 27599, USA.
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20
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Abstract
ComptoxAI is a new data infrastructure for computational and artificial intelligence research in predictive toxicology. Here, we describe and showcase ComptoxAI's graph-structured knowledge base in the context of three real-world use-cases, demonstrating that it can rapidly answer complex questions about toxicology that are infeasible using previous technologies and data resources. These use-cases each demonstrate a tool for information retrieval from the knowledge base being used to solve a specific task: The "shortest path" module is used to identify mechanistic links between perfluorooctanoic acid (PFOA) exposure and nonalcoholic fatty liver disease; the "expand network" module identifies communities that are linked to dioxin toxicity; and the quantitative structure-activity relationship (QSAR) dataset generator predicts pregnane X receptor agonism in a set of 4,021 pesticide ingredients. The contents of ComptoxAI's source data are rigorously aggregated from a diverse array of public third-party databases, and ComptoxAI is designed as a free, public, and open-source toolkit to enable diverse classes of users including biomedical researchers, public health and regulatory officials, and the general public to predict toxicology of unknowns and modes of action.
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Affiliation(s)
- Joseph D Romano
- Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Yun Hao
- Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Jason H Moore
- Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, California 90069, United States
| | - Trevor M Penning
- Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
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21
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Grishanova AY, Perepechaeva ML. Aryl Hydrocarbon Receptor in Oxidative Stress as a Double Agent and Its Biological and Therapeutic Significance. Int J Mol Sci 2022; 23:6719. [PMID: 35743162 PMCID: PMC9224361 DOI: 10.3390/ijms23126719] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/14/2022] [Accepted: 06/14/2022] [Indexed: 12/02/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR) has long been implicated in the induction of a battery of genes involved in the metabolism of xenobiotics and endogenous compounds. AhR is a ligand-activated transcription factor necessary for the launch of transcriptional responses important in health and disease. In past decades, evidence has accumulated that AhR is associated with the cellular response to oxidative stress, and this property of AhR must be taken into account during investigations into a mechanism of action of xenobiotics that is able to activate AhR or that is susceptible to metabolic activation by enzymes encoded by the genes that are under the control of AhR. In this review, we examine various mechanisms by which AhR takes part in the oxidative-stress response, including antioxidant and prooxidant enzymes and cytochrome P450. We also show that AhR, as a participant in the redox balance and as a modulator of redox signals, is being increasingly studied as a target for a new class of therapeutic compounds and as an explanation for the pathogenesis of some disorders.
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Affiliation(s)
| | - Maria L. Perepechaeva
- Federal Research Center of Fundamental and Translational Medicine, Institute of Molecular Biology and Biophysics, Timakova Str. 2, 630117 Novosibirsk, Russia;
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22
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Holme JA, Valen H, Brinchmann BC, Vist GE, Grimsrud TK, Becher R, Holme AM, Øvrevik J, Alexander J. Polycyclic aromatic hydrocarbons (PAHs) may explain the paradoxical effects of cigarette use on preeclampsia (PE). Toxicology 2022; 473:153206. [PMID: 35550401 DOI: 10.1016/j.tox.2022.153206] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 11/21/2022]
Abstract
Tobacco smoking and use of snus (smokeless tobacco) are associated with adverse effects on pregnancy and neonatal outcomes. Nicotine is considered a key toxicant involved in effects caused by both smoking and snus, while pyrolysis products including polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke represents the constituents most unequally divided between these two groups of tobacco products. The aim of this review was: i) to compare the impact, in terms of relative effect estimates, of cigarette smoking and use of Swedish snus on pregnancy outcomes using similar non-tobacco user controls, and ii) to examine whether exposure to PAHs from smoking could explain possible differences in impact on pregnancy outcomes. We systematically searched MEDLINE, Embase, PsycInfo, Web of Science and the Cochrane Database of Systematic Reviews up to October 2021 and identified studies reporting risks for adverse pregnancy and neonatal outcomes associated with snus use and with smoking relative to pregnant women with no use of tobacco. Both snus use and smoking were associated with increased risk of stillbirth, preterm birth, and oral cleft malformation, with comparable point estimates. These effects were likely due to comparable nicotine exposure. We also found striking differences. While both smoking and snus increased the risk of having small for gestational age (SGA) infants, risk from maternal smoking was markedly higher as was the reduction in birthweight. In contrast, the risk of preeclampsia (PE) was markedly lower in smokers than in controls, while snus use was associated with a slightly increased risk. We suggest that PAHs acting via AhR may explain the stronger effects of tobacco smoking on SGA and also to the apparent protective effect of cigarette smoking on PE. Possible mechanisms involved include: i) disrupted endocrine control of fetal development as well as placental development and function, and ii) stress adaption and immune suppression in placenta and mother.
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Affiliation(s)
- Jørn A Holme
- Division of Climate and Health, Norwegian Institute of Public Health, Oslo, Norway.
| | - Håkon Valen
- Division of Climate and Health, Norwegian Institute of Public Health, Oslo, Norway.
| | - Bendik C Brinchmann
- Division of Climate and Health, Norwegian Institute of Public Health, Oslo, Norway; Department of Occupational Medicine and Epidemiology, National Institute of Occupational Health, Oslo, Norway.
| | - Gunn E Vist
- Division for Health Services, Norwegian Institute of Public Health, Oslo, Norway.
| | - Tom K Grimsrud
- Department of Research, Cancer Registry of Norway, Oslo, Norway.
| | - Rune Becher
- Division of Climate and Health, Norwegian Institute of Public Health, Oslo, Norway.
| | - Ane M Holme
- Department of Obstetrics and Gynecology, Oslo University Hospital, Oslo, Norway.
| | - Johan Øvrevik
- Division of Climate and Health, Norwegian Institute of Public Health, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway.
| | - Jan Alexander
- Division of Climate and Health, Norwegian Institute of Public Health, Oslo, Norway.
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23
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Haimbaugh A, Meyer D, Akemann C, Gurdziel K, Baker TR. Comparative Toxicotranscriptomics of Single Cell RNA-Seq and Conventional RNA-Seq in TCDD-Exposed Testicular Tissue. FRONTIERS IN TOXICOLOGY 2022; 4:821116. [PMID: 35615540 PMCID: PMC9126299 DOI: 10.3389/ftox.2022.821116] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 03/03/2022] [Indexed: 12/18/2022] Open
Abstract
In this report, we compare the outcomes and limitations of two methods of transcriptomic inquiry on adult zebrafish testes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during sexual differentiation: conventional or bulk RNA-seq (bulk-seq) and single cell RNA sequencing (scRNA-seq) data. scRNA-seq has emerged as a valuable tool for uncovering cell type-specific transcriptome dynamics which exist in heterogeneous tissue. Our lab previously showed the toxicological value of the scRNA-seq pipeline to characterize the sequelae of TCDD exposure in testes, demonstrating that loss of spermatids and spermatozoa, but not other cell types, contributed to the pathology of infertility in adult male zebrafish exposed during sexual differentiation. To investigate the potential for technical artifacts in scRNA-seq such as cell dissociation effects and reduced transcriptome coverage, we compared bulk-sequenced and scRNA-seq-paired samples from control and TCDD-exposed samples to understand what is gained and lost in scRNA-seq vs bulk-seq, both transcriptomically and toxicologically. We hypothesized that the testes may be sensitive to tissue disruption as they contain multiple cell types under constant division and/or maturation, and that TCDD exposure may mediate the extent of sensitivity. Thus, we sought to understand the extent to which this dissociation impacts the toxicological value of data returned from scRNA-seq. We confirm that the required dissociation of individual cells from intact tissue has a significant impact on gene expression, affecting gene pathways with the potential to confound toxicogenomics studies on exposures if findings are not well-controlled and well-situated in context. Additionally, a common scRNA-seq method using cDNA amplified from the 3' end of mRNA under-detects low-expressing transcripts including transcription factors. We confirm this, and show TCDD-related genes may be overlooked by scRNA-seq, however, this under-detection effect is not mediated by TCDD exposure. Even so, scRNA-seq generally extracted toxicologically relevant information better than the bulk-seq method in the present study. This report aims to inform future experimental design for transcriptomic investigation in the growing field of toxicogenomics by demonstrating the differential information extracted from sequencing cells-despite being from the same tissue and exposure scheme-is influenced by the specific protocol used, with implications for the interpretation of exposure-induced risk.
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Affiliation(s)
- Alex Haimbaugh
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, United States
| | - Danielle Meyer
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, United States
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, United States
- Department of Environmental and Global Health, University of Florida, Gainesville, FL, United States
| | - Camille Akemann
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, United States
| | - Katherine Gurdziel
- Genome Sciences Core, Office of the Vice President for Research, Wayne State University, Detroit, MI, United States
| | - Tracie R. Baker
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, United States
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, United States
- Department of Environmental and Global Health, University of Florida, Gainesville, FL, United States
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24
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Lowery R, Latchney S, Peer R, Lamantia C, Lordy K, Opanashuk L, McCall M, Majewska A. Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin primes cortical microglia to tissue injury. Brain Behav Immun 2022; 101:288-303. [PMID: 35065196 PMCID: PMC9007156 DOI: 10.1016/j.bbi.2022.01.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 12/22/2021] [Accepted: 01/16/2022] [Indexed: 11/16/2022] Open
Abstract
Recent studies have shown that the aryl hydrocarbon receptor (AhR) is expressed in the brain's native immune cells, known as microglia. However, while the impact of exposure to AhR ligands is well studied in the peripheral immune system, the impact of such exposure on immune function in the brain is less well defined. Microglia serve dual roles in providing synaptic and immunological support for neighboring neurons and in mediating responses to environmental stimuli, including exposure to environmental chemicals. Because of their dual roles in regulating physiological and pathological processes, cortical microglia are well positioned to translate toxic stimuli into defects in cortical function via aberrant synaptic and immunological functioning, mediated either through direct microglial AhR activation or in response to AhR activation in neighboring cells. Here, we use gene expression studies, histology, and two-photon in vivo imaging to investigate how developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high-affinity and persistent AhR agonist, modulates microglial characteristics and function in the intact brain. Whole cortical RT-qPCR analysis and RNA-sequencing of isolated microglia revealed that gestational and lactational TCDD exposure produced subtle, but durable, changes in microglia transcripts. Histological examination and two-photon in vivo imaging revealed that while microglia density, distribution, morphology, and motility were unaffected by TCDD exposure, exposure resulted in microglia that responded more robustly to focal tissue injury. However, this effect was rectified with depletion and repopulation of microglia. These results suggest that gestational and lactational exposure to AhR ligands can result in long-term priming of microglia to produce heightened responses towards tissue injury which can be restored to normal function through microglial repopulation.
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Affiliation(s)
- R.L. Lowery
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY 14642
| | - S.E. Latchney
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY 14642
| | - R.P. Peer
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY 14642
| | - C.E. Lamantia
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY 14642
| | - K.A. Lordy
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY 14642
| | | | - M. McCall
- Department of Biostatistics and Computational Biology, University of Rochester, NY 14642,Department of Biomedical Genetics, University of Rochester, NY 14642
| | - A.K Majewska
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY 14642,Corresponding Author: Ania K. Majewska, University of Rochester, School of Medicine and Dentistry, Department of Neuroscience, Center for Visual Science, 601 Elmwood Avenue, Box 603, Rochester, New York 14642, , Phone: (585) 276-2254
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25
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Ishihara Y, Kado SY, Bein KJ, He Y, Pouraryan AA, Urban A, Haarmann-Stemmann T, Sweeney C, Vogel CFA. Aryl Hydrocarbon Receptor Signaling Synergizes with TLR/NF-κB-Signaling for Induction of IL-22 Through Canonical and Non-Canonical AhR Pathways. FRONTIERS IN TOXICOLOGY 2022; 3:787360. [PMID: 35295139 PMCID: PMC8915841 DOI: 10.3389/ftox.2021.787360] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/30/2021] [Indexed: 12/24/2022] Open
Abstract
Interleukin 22 (IL-22) is critically involved in gut immunity and host defense and primarily produced by activated T cells. In different circumstances IL-22 may contribute to pathological conditions or act as a cancer promoting cytokine secreted by infiltrating immune cells. Here we show that bone marrow-derived macrophages (BMM) express and produce IL-22 after activation of the aryl hydrocarbon receptor (AhR) when cells are activated through the Toll-like receptor (TLR) family. The additional activation of AhR triggered a significant induction of IL-22 in TLR-activated BMM. Deletion and mutation constructs of the IL-22 promoter revealed that a consensus DRE and RelBAhRE binding element are necessary to mediate the synergistic effects of AhR and TLR ligands. Inhibitor studies and analysis of BMM derived from knockout mice confirmed that the synergistic induction of IL-22 by AhR and TLR ligands depend on the expression of AhR and Nuclear Factor-kappa B (NF-κB) member RelB. The exposure to particulate matter (PM) collected from traffic related air pollution (TRAP) and wildfires activated AhR as well as NF-κB signaling and significantly induced the expression of IL-22. In summary this study shows that simultaneous activation of the AhR and NF-κB signaling pathways leads to synergistic and prolonged induction of IL-22 by integrating signals of the canonical and non-canonical AhR pathway.
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Affiliation(s)
- Yasuhiro Ishihara
- Center for Health and the Environment, University of California, Davis, Davis, CA, United States,Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima, Japan
| | - Sarah Y. Kado
- Center for Health and the Environment, University of California, Davis, Davis, CA, United States
| | - Keith J. Bein
- Center for Health and the Environment, University of California, Davis, Davis, CA, United States
| | - Yi He
- Center for Health and the Environment, University of California, Davis, Davis, CA, United States
| | - Arshia A. Pouraryan
- Center for Health and the Environment, University of California, Davis, Davis, CA, United States
| | - Angelika Urban
- Center for Health and the Environment, University of California, Davis, Davis, CA, United States
| | | | - Colleen Sweeney
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Christoph F. A. Vogel
- Center for Health and the Environment, University of California, Davis, Davis, CA, United States,Department of Environmental Toxicology, University of California, Davis, Davis, CA, United States,*Correspondence: Christoph F. A. Vogel,
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26
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Kakutani H, Yuzuriha T, Nakao T, Ohta S. Long-term orally exposure of dioxins affects antigen-specific antibody production in mice. Toxicol Rep 2022; 9:53-57. [PMID: 35004181 PMCID: PMC8717457 DOI: 10.1016/j.toxrep.2021.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 12/15/2021] [Accepted: 12/18/2021] [Indexed: 11/24/2022] Open
Abstract
Antigen-specific (OVA) antibody production in the serum increased dose-dependently by TCDD concentrations below 500 ng/kg after long-term (10 weeks) exposure. Similar increases were seen in fecal and vaginal samples but were not significant. Th1 and Th2 lymphocyte responses, as determined by antibody and cytokine production, also significantly increased dose-dependently up to 500 ng/kg TCDD, and the Th1/Th2 balance was shifted toward Th1. Dioxins are persistent environmental toxins that are still present in the food supply despite strong efforts to minimize exposure. Dioxins ingested by humans accumulate in fat and are excreted very slowly, so their long-term effects at low concentrations are a matter of concern. It is necessary to consider long-term, low-dose continuous administration under conditions that are as close as possible to a person's diet. In this study, we orally administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most common dioxin, at low doses in mice and observed the immunological effects. We found that antigen-specific (OVA) antibody production in the serum increased dose-dependently by TCDD concentrations below 500 ng/kg after long-term (10 weeks) exposure. Similar increases were seen in fecal and vaginal samples but were not significant. Th1 and Th2 lymphocyte responses, as determined by antibody and cytokine production, also significantly increased dose-dependently up to 500 ng/kg TCDD, and the Th1/Th2 balance was shifted toward Th1. These results indicate that low-dose, long-term TCDD exposure results in immunological abnormalities, perhaps by increasing antigen permeability. Different doses of dioxins may have opposing effects, being immunostimulatory at low doses (100 ng/kg/day) and immunosuppressive at high doses (500 ng/kg/day).
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Key Words
- 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
- AhR, aryl hydrocarbon receptor
- EROD, ethoxyresorufin O-deethylase
- IFN-γ, interferon-gamma
- IL-10, interleukin-10
- IL-13, interleukin-13
- IL-17, interleukin-17
- IL-2, interleukin-2
- IL-4, interleukin-4
- Ig, immunoglobulin
- OVA, ovalbumin
- OVA-specific antibody titer
- Subclinical oral exposure of TCDD
- TCDD, 2,3,7,8-tetrachlorobibenzo-p-dioxin
- TDI, tolerable daily intake
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Affiliation(s)
- Hideki Kakutani
- Laboratory of Disease Prevention, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Tomohiro Yuzuriha
- Laboratory of Disease Prevention, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Teruyuki Nakao
- Laboratory of Disease Prevention, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Souichi Ohta
- Laboratory of Disease Prevention, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
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27
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Williams MR, Stedtfeld RD, Stedtfeld TM, Crawford RB, Kuwahara T, Kaminski NE, Tiedje JM, Hashsham SA. MicroRNA-based host response to toxicant exposure is influenced by the presence of gut microbial populations. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 797:149130. [PMID: 34311349 PMCID: PMC8464502 DOI: 10.1016/j.scitotenv.2021.149130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/27/2021] [Accepted: 07/14/2021] [Indexed: 06/13/2023]
Abstract
Segmented filamentous bacteria (SFB) and Bacteroides fragilis are known to interact with the host immune response through the aryl hydrocarbon receptor (Ahr). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental toxicant and a high-affinity Ahr ligand has the potential to modify the effect of SFB and B. fragilis. MicroRNAs (miRNA) with their role in regulating gene expression post-transcriptionally, may potentially be used to observe such interactions between SFB, B. fragilis, and TCDD. However, little is known regarding the impact of gut microbial members on miRNA expression or its modulation in the presence of an environmental toxicant. This information is important in understanding toxicant-mediated dysbiosis in gut microbiome and the resulting human health impacts. In this study, C57BL/6 germ-free (GF) mice were colonized with SFB and B. fragilis and administered 30 μg/kg TCDD every 4 d for 28 d and miRNA were measured. Compared to GF mice, colonization with SFB resulted in an increase in up- and down-regulated Ileal miRNAs. TCDD treatment of this group decreased the number of upregulated miRNA and increased the number of down-regulated miRNAs. Association with SFB and B. fragilis together had a similar but less pronounced effect in response to TCDD treatment. TCDD treatment of GF mice had no miRNA expression response. Immune and inflammatory responses and T-cell differentiation were the key functions impacted by these miRNAs. Overall, these results reveal that the host response to toxicants may also depend on the presence of specific gut microbial populations.
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Affiliation(s)
- Maggie R Williams
- School of Engineering & Technology, Institute for Great Lakes Research, Central Michigan University, Mt Pleasant, MI, USA
| | | | | | - Robert B Crawford
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Tomomi Kuwahara
- Department of Microbiology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Norbert E Kaminski
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA; Center for Research on Ingredient Safety, Michigan State University, East Lansing, MI 48824, USA
| | - James M Tiedje
- Center for Microbial Ecology, Michigan State University, East Lansing, MI 48824, USA; Department of Plant, Soil, and Microbial Sciences, Michigan State University, East Lansing, MI 48824, USA
| | - Syed A Hashsham
- Center for Microbial Ecology, Michigan State University, East Lansing, MI 48824, USA; Department of Plant, Soil, and Microbial Sciences, Michigan State University, East Lansing, MI 48824, USA; Department of Civil and Environmental Engineering, East Lansing, MI 48824, USA.
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28
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Williams MM, Hafeez SA, Christenson JL, O’Neill KI, Hammond NG, Richer JK. Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways. Pharmaceuticals (Basel) 2021; 14:ph14111122. [PMID: 34832904 PMCID: PMC8622696 DOI: 10.3390/ph14111122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/16/2022] Open
Abstract
Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors.
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29
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Dopkins N, Neameh WH, Hall A, Lai Y, Rutkovsky A, Gandy AO, Lu K, Nagarkatti PS, Nagarkatti M. Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile. Int J Mol Sci 2021; 22:11801. [PMID: 34769237 PMCID: PMC8583798 DOI: 10.3390/ijms222111801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 10/28/2021] [Accepted: 10/28/2021] [Indexed: 02/06/2023] Open
Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a polyhalogenated planar hydrocarbon belonging to a group of highly toxic and persistent environmental contaminants known as "dioxins". TCDD is an animal teratogen and carcinogen that is well characterized for causing immunosuppression through activation of aryl hydrocarbon receptor (AHR). In this study, we investigated the effect of exposure of mice to an acute dose of TCDD on the metabolic profile within the serum and cecal contents to better define the effects of TCDD on host physiology. Our findings demonstrated that within the circulating metabolome following acute TCDD exposure, there was significant dysregulation in the metabolism of bioactive lipids, amino acids, and carbohydrates when compared with the vehicle (VEH)-treated mice. These widespread changes in metabolite abundance were identified to regulate host immunity via modulating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated protein kinase (ERK1/2) activity and work as biomarkers for a variety of organ injuries and dysfunctions that follow TCDD exposure. Within the cecal content of mice exposed to TCDD, we were able to detect changes in inflammatory markers that regulate NF-κB, markers of injury-related inflammation, and changes in lysine degradation, nicotinamide metabolism, and butanoate metabolism, which collectively suggested an immediate suppression of broad-scale metabolic processes in the gastrointestinal tract. Collectively, these results demonstrate that acute TCDD exposure results in immediate irregularities in the circulating and intestinal metabolome, which likely contribute to TCDD toxicity and can be used as biomarkers for the early detection of individual exposure.
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Affiliation(s)
- Nicholas Dopkins
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Wurood Hantoosh Neameh
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Alina Hall
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Yunjia Lai
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Alex Rutkovsky
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Alexa Orr Gandy
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Kun Lu
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Prakash S Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
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30
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Nomura T, Kabashima K. Advances in Atopic Dermatitis in 2019-2020: Endotypes from skin barrier, ethnicity, properties of antigen, cytokine profiles, microbiome, and engagement of immune cells. J Allergy Clin Immunol 2021; 148:1451-1462. [PMID: 34756922 DOI: 10.1016/j.jaci.2021.10.022] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 11/16/2022]
Abstract
Key research advances in atopic dermatitis (AD) suggest the complexity of its endotypes. A comprehensive serum biomarker panel revealed at least four types of AD. Some represent classic TH2-dominant AD with filaggrin mutations commonly reported in Europeans, a simultaneously activated multipolar axes of cytokines often reported in Asians, and an intrinsic type characterized by TH2-inferiority. Innate lymphoid cells, including NK cells, NKT cells, and fibroblasts, play a role in AD development and heterogeneity. Here, we discuss the endotypes of AD from the perspective of antigen types (hapten vs. protein antigens), barrier function, and a novel set of immune cells. Endotypic stratification of AD may lead to the development of customized therapeutic strategies in the future.
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Affiliation(s)
- Takashi Nomura
- Department of Dermatology, Faculty of Medicine, Kyoto University 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kenji Kabashima
- Department of Dermatology, Faculty of Medicine, Kyoto University 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
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31
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Islam MB, Chowdhury UN, Nain Z, Uddin S, Ahmed MB, Moni MA. Identifying molecular insight of synergistic complexities for SARS-CoV-2 infection with pre-existing type 2 diabetes. Comput Biol Med 2021; 136:104668. [PMID: 34340124 PMCID: PMC8299293 DOI: 10.1016/j.compbiomed.2021.104668] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/30/2021] [Accepted: 07/17/2021] [Indexed: 01/07/2023]
Abstract
The ongoing COVID-19 outbreak, caused by SARS-CoV-2, has posed a massive threat to global public health, especially to people with underlying health conditions. Type 2 diabetes (T2D) is lethal comorbidity of COVID-19. However, its pathogenetic link remains unclear. This research aims to determine the genetic factors and processes contributing to the synergistic severity of SARS-CoV-2 infection among T2D patients through bioinformatics approaches. We analyzed two sets of transcriptomic data of SARS-CoV-2 infection obtained from lung epithelium cells and PBMCs, and two sets of T2D data from pancreatic islet cells and PBMCs to identify the associated differentially expressed genes (DEGs) followed by their functional enrichment analyses in terms of protein-protein interaction (PPI) to detect hub-proteins and associated comorbidities, transcription factors (TFs), microRNAs (miRNAs) as well as the potential drug candidates. In PPI analysis, four potential hub-proteins (i.e., BIRC3, C3, MME, and IL1B) were identified among 25 DEGs shared between the disease pair. Enrichment analyses using the mutually overlapped DEGs revealed the most prevalent GO and cell signalling pathways, including TNF signalling, cytokine-cytokine receptor interaction, and IL-17 signalling, which are related to cytokine activities. Furthermore, as significant TFs, we identified IRF1, KLF11, FOSL1, and CREB3L1 while miRNAs including miR-1-3p, 34a-5p, 16–5p, 155–5p, 20a-5p, and let-7b-5p were found to be noteworthy. The findings illustrated the significant association between COVID-19 and T2D at the molecular level. These genetic determinants can further be explored for their specific roles in disease progression and therapeutic intervention, while significant pathways can also be studied as molecular checkpoints. Finally, the identified drug candidates may be evaluated for their potency to minimize the severity of COVID-19 patients with pre-existing T2D.
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Affiliation(s)
- M Babul Islam
- Department of Electrical and Electronic Engineering, University of Rajshahi, Rajshahi, Bangladesh
| | - Utpala Nanda Chowdhury
- Department of Computer Science and Engineering, University of Rajshahi, Rajshahi, Bangladesh
| | - Zulkar Nain
- Department of Biotechnology and Genetic Engineering, Islamic University, Kushtia, Bangladesh
| | - Shahadat Uddin
- Complex Systems Research Group & Project Management Program, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia
| | - Mohammad Boshir Ahmed
- School of Material Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Mohammad Ali Moni
- Healthy Ageing Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; WHO Collaborating Centre on eHealth, UNSW Digital Health, School of Public Health and Community Medicine, Faculty of Medicine, UNSW Sydney, NSW, 2052, Australia.
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Bungsu I, Kifli N, Ahmad SR, Ghani H, Cunningham AC. Herbal Plants: The Role of AhR in Mediating Immunomodulation. Front Immunol 2021; 12:697663. [PMID: 34249001 PMCID: PMC8264659 DOI: 10.3389/fimmu.2021.697663] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/08/2021] [Indexed: 12/25/2022] Open
Abstract
The prevalence of chronic inflammatory diseases including inflammatory bowel disease (IBD), autoimmunity and cancer have increased in recent years. Herbal-based compounds such as flavonoids have been demonstrated to contribute to the modulation of these diseases although understanding their mechanism of action remains limited. Flavonoids are able to interact with cellular immune components in a distinct way and influence immune responses at a molecular level. In this mini review, we highlight recent progress in our understanding of the modulation of immune responses by the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor whose activity can be regulated by diverse molecules including flavonoids. We focus on the role of AhR in integrating signals from flavonoids to modulate inflammatory responses using in vitro and experimental animal models. We also summarize the limitations of these studies. Medicinal herbs have been widely used to treat inflammatory disorders and may offer a valuable therapeutic strategy to treat aberrant inflammatory responses by modulation of the AhR pathway.
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Affiliation(s)
- Izzah Bungsu
- Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah (PAPRSB), Institute of Health Sciences, Universiti Brunei Darussalam, Bandar Seri Begawan, Brunei
| | - Nurolaini Kifli
- Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah (PAPRSB), Institute of Health Sciences, Universiti Brunei Darussalam, Bandar Seri Begawan, Brunei
| | - Siti Rohaiza Ahmad
- Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah (PAPRSB), Institute of Health Sciences, Universiti Brunei Darussalam, Bandar Seri Begawan, Brunei
| | - Hazim Ghani
- Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah (PAPRSB), Institute of Health Sciences, Universiti Brunei Darussalam, Bandar Seri Begawan, Brunei
| | - Anne Catherine Cunningham
- Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah (PAPRSB), Institute of Health Sciences, Universiti Brunei Darussalam, Bandar Seri Begawan, Brunei
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33
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E-waste management: A review of recycling process, environmental and occupational health hazards, and potential solutions. ACTA ACUST UNITED AC 2021. [DOI: 10.1016/j.enmm.2020.100409] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Sun L. Recent advances in the development of AHR antagonists in immuno-oncology. RSC Med Chem 2021; 12:902-914. [PMID: 34223158 DOI: 10.1039/d1md00015b] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/15/2021] [Indexed: 12/26/2022] Open
Abstract
The arylhydrocarbon receptor (AHR) is a ligand activated transcription factor that controls the expression of a number of immunosuppressive signaling molecules, including the immune checkpoint proteins PD-1/L1 and cytokine IL-10. AHR activation also stimulates the formation and recruitment of tolerogenic dendritic cells, tumor associated macrophages, and regulatory T cells in the tumor microenvironment, which restrains antitumoral immune response. Overexpression of AHR has been observed in a number of different types of cancer and suggested to contribute to immune dysfunction and cancer progression. One prominent endogenous ligand of AHR is the oncometabolite kynurenine, a product of tryptophan metabolism catalyzed by the dioxygenases IDO1 and TDO that are often aberrantly activated in cancer. AHR has gained significant interest as a drug target for the development of novel small molecule cancer immunotherapies, as evidenced by the advancement of two clinical candidates into phase 1 clinical trials in patients with advanced cancer. Discussed in this Review is a brief background of AHR in immuno-oncology and the recent progress in the discovery and development of AHR antagonists.
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Affiliation(s)
- Lijun Sun
- Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA 02215 USA
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Abdulla OA, Neamah W, Sultan M, Chatterjee S, Singh N, Nagarkatti M, Nagarkatti P. AhR Ligands Differentially Regulate miRNA-132 Which Targets HMGB1 and to Control the Differentiation of Tregs and Th-17 Cells During Delayed-Type Hypersensitivity Response. Front Immunol 2021; 12:635903. [PMID: 33679792 PMCID: PMC7933657 DOI: 10.3389/fimmu.2021.635903] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/28/2021] [Indexed: 12/20/2022] Open
Abstract
Aryl hydrocarbon receptor (AhR), is a transcription factor and an environmental sensor that has been shown to regulate T cell differentiation. Interestingly, AhR ligands exert varying effects from suppression to exacerbation of inflammation through induction of Tregs and Th-17 cells, respectively. In the current study, we investigated whether the differential effects of AhR ligands on T cell differentiation are mediated by miRNA during delayed-type hypersensitivity (DTH) reaction against methylated Bovine Serum Albumin (mBSA). Treatment of C57BL/6 mice with TCDD attenuated mBSA-mediated DTH response, induced Tregs, decreased Th-17 cells, and caused upregulation of miRNA-132. TCDD caused an increase in several Treg subsets including inducible peripheral, natural thymic, and Th3 cells. Also, TCDD increased TGF-β and Foxp3 expression. In contrast, treating mice with FICZ exacerbated the DTH response, induced inflammatory Th17 cells, induced IL-17, and RORγ. Analysis of miRNA profiles from draining lymph nodes showed that miR-132 was upregulated in the TCDD group and downregulated in the FICZ group. Transfection studies revealed that miRNA-132 targeted High Mobility Group Box 1 (HMGB1). Downregulation of HMGB1 caused an increase in FoxP3+ Treg differentiation and suppression of Th-17 cells while upregulation of HMGB1 caused opposite effects. Moreover, TCDD was less effective in suppressing DTH response and induction of Tregs in mice that were deficient in miR-132. In summary, this study demonstrates that TCDD and FICZ have divergent effects on DTH response and T cell differentiation, which is mediated through, at least in part, regulation of miRNA-132 that targets HMGB1.
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MESH Headings
- Animals
- Basic Helix-Loop-Helix Transcription Factors/agonists
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Carbazoles/toxicity
- Cell Differentiation/drug effects
- Cells, Cultured
- Cytokines/genetics
- Cytokines/metabolism
- Disease Models, Animal
- Female
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- HMGB1 Protein/genetics
- HMGB1 Protein/metabolism
- Hypersensitivity, Delayed/genetics
- Hypersensitivity, Delayed/immunology
- Hypersensitivity, Delayed/metabolism
- Hypersensitivity, Delayed/prevention & control
- Ligands
- Mice, Inbred C57BL
- Mice, Knockout
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Phenotype
- Polychlorinated Dibenzodioxins/toxicity
- Receptors, Aryl Hydrocarbon/agonists
- Receptors, Aryl Hydrocarbon/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Mice
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Affiliation(s)
- Osama A. Abdulla
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Wurood Neamah
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Muthanna Sultan
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, United States
| | - Narendra Singh
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
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Lowery RL, Latchney SE, Peer RP, Lamantia CE, Opanashuk L, McCall M, Majewska AK. Acute 2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure in adult mice does not alter the morphology or inflammatory response of cortical microglia. Neurosci Lett 2020; 742:135516. [PMID: 33227371 DOI: 10.1016/j.neulet.2020.135516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 10/15/2020] [Accepted: 11/16/2020] [Indexed: 10/23/2022]
Abstract
Microglia, the immune cells of the brain, have a canonical role in regulating responses to neurological disease or injury, but have also recently been implicated as regulators of neurophysiological processes such as learning and memory. Given these dual immune and physiological roles, microglia are a likely mechanism by which external toxic stimuli are converted into deficits in neuronal circuitry and subsequently function. However, while it is well established that exposure to environmental toxicants negatively affects the peripheral immune system, it remains unknown whether and how such exposure causes neuroinflammation which, in turn, may negatively impact microglial functions in vivo. Here, we examined how acute 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in adulthood, which negatively impacts immune cells in the periphery, affects microglial characteristics in the cortex of the mouse. We found that microglia density, distribution, morphology, inflammatory signaling, and response to a secondary, pathological activation were unaffected by acute TCDD exposure. These results suggest that acute, peripheral TCDD exposure in adulthood is not sufficient to induce an overt inflammatory phenotype in cortical microglia.
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Affiliation(s)
- R L Lowery
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY, 14642, United States
| | - S E Latchney
- Biology Department, St. Mary's College of Maryland, St. Mary's City, MD, 20686, United States
| | - R P Peer
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY, 14642, United States
| | - C E Lamantia
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY, 14642, United States
| | - L Opanashuk
- National Institute on Aging, Bethesda, MD, 20892, United States
| | - M McCall
- Department of Biostatistics and Computational Biology, University of Rochester, NY, 14642, United States; Department of Biomedical Genetics, University of Rochester, NY, 14642, United States
| | - A K Majewska
- Department of Neuroscience, Center for Visual Science, University of Rochester, Rochester, NY, 14642, United States.
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37
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Prasad Singh N, Nagarkatti M, Nagarkatti P. From Suppressor T cells to Regulatory T cells: How the Journey That Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation. Int J Mol Sci 2020; 21:E7849. [PMID: 33105907 PMCID: PMC7660163 DOI: 10.3390/ijms21217849] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022] Open
Abstract
Aryl hydrocarbon receptor (AhR) was identified in the early 1970s as a receptor for the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), which is a member of halogenated aromatic hydrocarbons (HAHs). TCDD was found to be highly toxic to the immune system, causing thymic involution and suppression of a variety of T and B cell responses. The fact that environmental chemicals cause immunosuppression led to the emergence of a new field, immunotoxicology. While studies carried out in early 1980s demonstrated that TCDD induces suppressor T cells that attenuate the immune response to antigens, further studies on these cells were abandoned due to a lack of specific markers to identify such cells. Thus, it was not until 2001 when FoxP3 was identified as a master regulator of Regulatory T cells (Tregs) that the effect of AhR activation on immunoregulation was rekindled. The more recent research on AhR has led to the emergence of AhR as not only an environmental sensor but also as a key regulator of immune response, especially the differentiation of Tregs vs. Th17 cells, by a variety of endogenous, microbial, dietary, and environmental ligands. This review not only discusses how the role of AhR emerged from it being an environmental sensor to become a key immunoregulator, but also confers the identification of new AhR ligands, which are providing novel insights into the mechanisms of Treg vs. Th17 differentiation. Lastly, we discuss how AhR ligands can trigger epigenetic pathways, which may provide new opportunities to regulate inflammation and treat autoimmune diseases.
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Affiliation(s)
| | | | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA; (N.P.S.); (M.N.)
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Liang Y, Tang Z, Jiang Y, Ai C, Peng J, Liu Y, Chen J, Zhang J, Cai Z. Serum metabolic changes associated with dioxin exposure in a Chinese male cohort. ENVIRONMENT INTERNATIONAL 2020; 143:105984. [PMID: 32712422 DOI: 10.1016/j.envint.2020.105984] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/03/2020] [Accepted: 07/13/2020] [Indexed: 06/11/2023]
Abstract
Dioxins, a group of persistent organic pollutants, have been proved to correlate with ranges of diseases by activating the aryl hydrocarbon receptor (AhR). However, previous dioxin toxicity studies primarily focused on the activation of AhR with signaling pathways at gene and protein levels. The investigation of underlying mechanisms at the metabolic level is still necessary. In this study, serum samples of 48 and 47 healthy participants with the highest and lowest dioxin levels based on quartile distribution of the serum dioxin concentrations of 215 male adults were selected for metabolomics analysis by using liquid chromatography coupled with orbitrap high-resolution mass spectrometry to investigate dioxin-related metabolic responses. The identified potential biomarkers included acylcarnitines, fatty acids and derivatives, glycerophospholipids, etc. suggested that metabolic pathways such as fatty acid β-oxidation, essential fatty acid metabolism, arachidonic acid metabolism, glycerophospholipid and sphingolipid metabolism and purine metabolism were disturbed by dioxin exposure. The results indicated that people with high dioxin exposure levels were at the potential health risks of inflammation, liver and cardiovascular diseases. The metabolic findings may help understand the link between dioxin exposure and the diseases.
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Affiliation(s)
- Yanshan Liang
- Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China; State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong Special Administrative Region; Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Zhi Tang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China; Department of Environmental and Occupational Health, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Yousheng Jiang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Chunyan Ai
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Jinling Peng
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Yuan Liu
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Jinru Chen
- Songgang Preventive Health Center of Baoan District, Shenzhen, China
| | - Jianqing Zhang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
| | - Zongwei Cai
- Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, China; State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong Special Administrative Region.
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Choudhary M, Malek G. The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases. Int J Mol Sci 2020; 21:ijms21186777. [PMID: 32947781 PMCID: PMC7555571 DOI: 10.3390/ijms21186777] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 02/06/2023] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which senses environmental, dietary or metabolic signals to mount a transcriptional response, vital in health and disease. As environmental stimuli and metabolic products have been shown to impact the central nervous system (CNS), a burgeoning area of research has been on the role of the AHR in ocular and non-ocular neurodegenerative diseases. Herein, we summarize our current knowledge, of AHR-controlled cellular processes and their impact on regulating pathobiology of select ocular and neurodegenerative diseases. We catalogue animal models generated to study the role of the AHR in tissue homeostasis and disease pathogenesis. Finally, we discuss the potential of targeting the AHR pathway as a therapeutic strategy, in the context of the maladies of the eye and brain.
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Affiliation(s)
- Mayur Choudhary
- Department of Ophthalmology, Duke University School of Medicine, 2351 Erwin Road, P.O. Box 3802, Durham, NC 27705, USA
- Correspondence: (M.C.); (G.M.)
| | - Goldis Malek
- Department of Ophthalmology, Duke University School of Medicine, 2351 Erwin Road, P.O. Box 3802, Durham, NC 27705, USA
- Department of Pathology, Duke University School of Medicine, Durham, NC 27705, USA
- Correspondence: (M.C.); (G.M.)
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40
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Safe S, Jin UH, Park H, Chapkin RS, Jayaraman A. Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs). Int J Mol Sci 2020; 21:6654. [PMID: 32932962 PMCID: PMC7555580 DOI: 10.3390/ijms21186654] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/01/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (U.-h.J.); (H.P.)
| | - Un-ho Jin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (U.-h.J.); (H.P.)
| | - Hyejin Park
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA; (U.-h.J.); (H.P.)
| | - Robert S. Chapkin
- Departments of Nutrition and Food Science and Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA;
| | - Arul Jayaraman
- Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA;
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IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell 2020; 182:1252-1270.e34. [PMID: 32818467 DOI: 10.1016/j.cell.2020.07.038] [Citation(s) in RCA: 331] [Impact Index Per Article: 66.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/25/2020] [Accepted: 07/28/2020] [Indexed: 01/01/2023]
Abstract
Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.
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Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, Sosman JA, Zhang B, Wu JD, Miller SD, Meeks JJ, Lukas RV, Wyatt E, Doglio L, Schiltz GE, McCusker RH, Wainwright DA. Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. Front Immunol 2020; 11:1185. [PMID: 32612606 PMCID: PMC7308527 DOI: 10.3389/fimmu.2020.01185] [Citation(s) in RCA: 149] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 05/13/2020] [Indexed: 12/24/2022] Open
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO; IDO1; INDO) is a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan, into downstream kynurenines. Canonically, the metabolic depletion of tryptophan and/or the accumulation of kynurenine is the mechanism that defines how immunosuppressive IDO inhibits immune cell effector functions and/or facilitates T cell death. Non-canonically, IDO also suppresses immunity through non-enzymic effects. Since IDO targeting compounds predominantly aim to inhibit metabolic activity as evidenced across the numerous clinical trials currently evaluating safety/efficacy in patients with cancer, in addition to the recent disappointment of IDO enzyme inhibitor therapy during the phase III ECHO-301 trial, the issue of IDO non-enzyme effects have come to the forefront of mechanistic and therapeutic consideration(s). Here, we review enzyme-dependent and -independent IDO-mediated immunosuppression as it primarily relates to glioblastoma (GBM); the most common and aggressive primary brain tumor in adults. Our group's recent discovery that IDO levels increase in the brain parenchyma during advanced age and regardless of whether GBM is present, highlights an immunosuppressive synergy between aging-increased IDO activity in cells of the central nervous system that reside outside of the brain tumor but collaborate with GBM cell IDO activity inside of the tumor. Because of their potential value for the in vivo study of IDO, we also review current transgenic animal modeling systems while highlighting three new constructs recently created by our group. This work converges on the central premise that maximal immunotherapeutic efficacy in subjects with advanced cancer requires both IDO enzyme- and non-enzyme-neutralization, which is not adequately addressed by available IDO-targeting pharmacologic approaches at this time.
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Affiliation(s)
- Lijie Zhai
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - April Bell
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Erik Ladomersky
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Kristen L. Lauing
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Lakshmi Bollu
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Jeffrey A. Sosman
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
| | - Bin Zhang
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Jennifer D. Wu
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Stephen D. Miller
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Joshua J. Meeks
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Rimas V. Lukas
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
- Division of Neuro-Oncology, Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Eugene Wyatt
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Transgenic and Targeted Mutagenesis Laboratory, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Lynn Doglio
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Transgenic and Targeted Mutagenesis Laboratory, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Gary E. Schiltz
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Center for Molecular Innovation and Drug Discovery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Robert H. McCusker
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Derek A. Wainwright
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review. Mediators Inflamm 2020; 2020:9706140. [PMID: 32617076 PMCID: PMC7306093 DOI: 10.1155/2020/9706140] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract resulting from the homeostasis imbalance of intestinal microenvironment, immune dysfunction, environmental and genetic factors, and so on. This disease is associated with multiple immune cells including regulatory T cells (Tregs). Tregs are a subset of T cells regulating the function of various immune cells to induce immune tolerance and maintain intestinal immune homeostasis. Tregs are correlated with the initiation and progression of IBD; therefore, strategies that affect the differentiation and function of Tregs may be promising for the prevention of IBD-associated pathology. It is worth noting that tryptophan (Trp) metabolism is effective in inducing the differentiation of Tregs through microbiota-mediated degradation and kynurenine pathway (KP), which is important for maintaining the function of Tregs. Interestingly, patients with IBD show Trp metabolism disorder in the pathological process, including changes in the concentrations of Trp and its metabolites and alteration in the activities of related catalytic enzymes. Thus, manipulation of Treg differentiation through Trp metabolism may provide a potential target for prevention of IBD. The purpose of this review is to highlight the relationship between Trp metabolism and Treg differentiation and the role of this interaction in the pathogenesis of IBD.
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Vogel CFA, Van Winkle LS, Esser C, Haarmann-Stemmann T. The aryl hydrocarbon receptor as a target of environmental stressors - Implications for pollution mediated stress and inflammatory responses. Redox Biol 2020; 34:101530. [PMID: 32354640 PMCID: PMC7327980 DOI: 10.1016/j.redox.2020.101530] [Citation(s) in RCA: 290] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/20/2020] [Accepted: 03/31/2020] [Indexed: 02/08/2023] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor regulating the expression of genes, for instance encoding the monooxygenases cytochrome P450 (CYP) 1A1 and CYP1A2, which are important enzymes in metabolism of xenobiotics. The AHR is activated upon binding of polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs), and related ubiquitous environmental chemicals, to mediate their biological and toxic effects. In addition, several endogenous and natural compounds can bind to AHR, thereby modulating a variety of physiological processes. In recent years, ambient particulate matter (PM) associated with traffic related air pollution (TRAP) has been found to contain significant amounts of PAHs. PM containing PAHs are of increasing concern as a class of agonists, which can activate the AHR. Several reports show that PM and AHR-mediated induction of CYP1A1 results in excessive generation of reactive oxygen species (ROS), causing oxidative stress. Furthermore, exposure to PM and PAHs induce inflammatory responses and may lead to chronic inflammatory diseases, including asthma, cardiovascular diseases, and increased cancer risk. In this review, we summarize findings showing the critical role that the AHR plays in mediating effects of environmental pollutants and stressors, which pose a risk of impacting the environment and human health.
PAHs present on ambient air pollution particles are ligands of the cellular AHR. AHR-dependent induction of CYP1, AKR, NOX and COX-2 genes can be a source of ROS generation. AHR signaling and NRF2 signaling interact to regulate the expression of antioxidant genes. Air pollution and ROS can affect inflammation, which is partially triggered by AHR and associated immune responses. Skin, lung, and the cardiovascular system are major target sites for air pollution-induced inflammation.
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Affiliation(s)
- Christoph F A Vogel
- Center for Health and the Environment, University of California, One Shields Avenue, Davis, CA, 95616, USA; Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Laura S Van Winkle
- Center for Health and the Environment, University of California, One Shields Avenue, Davis, CA, 95616, USA; School of Veterinary Medicine Department of Anatomy, University of California, One Shields Avenue, Davis, CA, 5616, USA
| | - Charlotte Esser
- IUF - Leibniz-Research Institute for Environmental Medicine, 40225, Düsseldorf, Germany
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Warner M, Rauch S, Ames J, Mocarelli P, Brambilla P, Signorini S, Eskenazi B. Prenatal dioxin exposure and thyroid hormone levels in the Seveso second generation study. ENVIRONMENTAL RESEARCH 2020; 183:109280. [PMID: 32311913 PMCID: PMC7176740 DOI: 10.1016/j.envres.2020.109280] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/14/2020] [Accepted: 02/19/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND In animal studies, perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters thyroid homoeostasis and thyroid hormone concentrations; epidemiologic evidence is limited. OBJECTIVES We aimed to determine the association of prenatal exposure to TCDD with thyroid hormone concentrations in the Seveso Second Generation Study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 chemical factory explosion in Seveso, Italy. METHODS We included 570 children (288 female, 282 male) with complete follow-up data, including a fasting blood draw. Serum levels of total and free thyroxine (T4), free triiodothyronine (T3), and thyroid stimulating hormone (TSH) were measured using immunoassays. We defined prenatal TCDD exposure as: 1) maternal initial TCDD concentration measured in serum collected soon after the explosion and 2) maternal TCDD estimated at pregnancy. RESULTS Compared to the lowest quartile (Q1), maternal initial serum TCDD was associated with lower free T3 (Q2: adj-β = -0.13, 95%CI -0.26, 0.00; Q3: adj-β = -0.22, 95%CI -0.35, -0.09; Q4: adj-β = -0.14, 95%CI -0.28, 0.00; p-trend = 0.02). In participants with high thyroid antibody status, inverse associations between maternal initial serum TCDD and free T3 were significantly stronger than in participants with normal antibody status (p-interaction = 0.02). We also observed a positive association between maternal initial serum TCDD and TSH concentrations in participants with high thyroid antibody status (Q2: adj-β = 11.4%, 95%CI -25.2, 66.1; Q3: adj-β = 49.0%, 95%CI 3.0, 115.5; Q4: adj-β = 105.5, 95%CI 36.6, 209.2; p-trend < 0.01) but not in those participants with normal antibody status (p-interaction < 0.01). Similar results were found for TCDD estimated at pregnancy. DISCUSSION Our results suggest prenatal exposure to TCDD, a potent endocrine-disrupting compound, may alter thyroid function later in life. Populations with additional thyroid stress may be particularly susceptible to in utero exposure of thyroid disrupting chemicals.
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Affiliation(s)
- Marcella Warner
- Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California at Berkeley, Berkeley, CA, USA.
| | - Stephen Rauch
- Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California at Berkeley, Berkeley, CA, USA
| | - Jennifer Ames
- Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California at Berkeley, Berkeley, CA, USA
| | - Paolo Mocarelli
- Department of Laboratory Medicine, University of Milano-Bicocca, School of Medicine, Hospital of Desio, Desio, Milano, Italy
| | - Paolo Brambilla
- Department of Laboratory Medicine, University of Milano-Bicocca, School of Medicine, Hospital of Desio, Desio, Milano, Italy
| | - Stefano Signorini
- Department of Laboratory Medicine, University of Milano-Bicocca, School of Medicine, Hospital of Desio, Desio, Milano, Italy
| | - Brenda Eskenazi
- Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California at Berkeley, Berkeley, CA, USA
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The imbalance of Treg/Th17 cells induced by perinatal bisphenol A exposure is associated with activation of the PI3K/Akt/mTOR signaling pathway in male offspring mice. Food Chem Toxicol 2020; 137:111177. [DOI: 10.1016/j.fct.2020.111177] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 01/20/2020] [Accepted: 01/29/2020] [Indexed: 01/02/2023]
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Schurman SH, O'Hanlon TP, McGrath JA, Gruzdev A, Bektas A, Xu H, Garantziotis S, Zeldin DC, Miller FW. Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene. J Autoimmun 2020; 107:102363. [PMID: 31759816 PMCID: PMC7237321 DOI: 10.1016/j.jaut.2019.102363] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity. OBJECTIVE To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes-aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) - and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR). METHODS Subjects (n = 3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (n = 1562), Caucasians (n = 1838), and Hispanics (n = 331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches. RESULTS ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval] = 1.29 [1.08-1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (OR = 1.25 [1.06-1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (OR = 1.99, [1.30-3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (OR = 1.39 [1.12-1.72] and 1.50 [1.12-2.02], respectively) and allergic disease (OR = 1.39 [1.12-1.71], and 1.62 [1.19-2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (OR = 1.31 [1.10-1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL OR = 1.50 [1.15-1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL OR = 1.58 [1.20-2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59). CONCLUSIONS Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders.
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Affiliation(s)
- Shepherd H Schurman
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Research Triangle Park, NC, USA.
| | - Terrance P O'Hanlon
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Bethesda, MD, USA.
| | | | - Artiom Gruzdev
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
| | - Arsun Bektas
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
| | - Hong Xu
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
| | - Stavros Garantziotis
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Research Triangle Park, NC, USA.
| | - Darryl C Zeldin
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
| | - Frederick W Miller
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Research Triangle Park, NC, USA; Bethesda, MD, USA.
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Lung Microbiome in Asthma: Current Perspectives. J Clin Med 2019; 8:jcm8111967. [PMID: 31739446 PMCID: PMC6912699 DOI: 10.3390/jcm8111967] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 11/12/2019] [Indexed: 12/20/2022] Open
Abstract
A growing body of evidence implicates the human microbiome as a potentially influential player actively engaged in shaping the pathogenetic processes underlying the endotypes and phenotypes of chronic respiratory diseases, particularly of the airways. In this article, we specifically review current evidence on the characteristics of lung microbiome, and specifically the bacteriome, the modes of interaction between lung microbiota and host immune system, the role of the “lung–gut axis”, and the functional effects thereof on asthma pathogenesis. We also attempt to explore the possibilities of therapeutic manipulation of the microbiome, aiming at the establishment of asthma prevention strategies and the optimization of asthma treatment.
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Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov 2019; 18:379-401. [PMID: 30760888 DOI: 10.1038/s41573-019-0016-5] [Citation(s) in RCA: 953] [Impact Index Per Article: 158.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.
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Cheng L, Li Z, Huang YZ, Zhang X, Dai XY, Shi L, Xi PW, Wei JF, Ding Q. TCDD-Inducible Poly-ADP-Ribose Polymerase (TIPARP), A Novel Therapeutic Target Of Breast Cancer. Cancer Manag Res 2019; 11:8991-9004. [PMID: 31695491 PMCID: PMC6805248 DOI: 10.2147/cmar.s219289] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 09/17/2019] [Indexed: 12/22/2022] Open
Abstract
Background TIPARP (TCDD-inducible poly-ADP-ribose polymerase), a mono-ADP-ribosyltransferase and a transcriptional repressor of aryl hydrocarbon receptor (AHR), was one of the potential therapeutic targets for human cancers identified by CRISPR–Cas9 screens recently. Studies about TIPARP on cancers are scarce till now, most of which just focus on expressions, while the functions have not been widely reported yet. Moreover, the TIPARP prognostic significance and therapeutic value of breast cancer is also uncertain. Methods The present study was performed to comprehensively analyze the expression pattern, prognostic effect, potential therapeutic function of TIPARP in breast cancer by pooling all currently available databases online including Oncomine, UALCAN, bc-GenExMiner, Kaplan–Meier Plotter, COSMIC, UCSC Xena, STRING, DAVID and Comparative Toxicogenomics Database. Further, we also performed several cell biology experiments including RT-qPCR, Western blot and CCK-8 in cellular and clinical sample levels to confirm the conclusions from bioinformatics analysis. Results TIPARP was expressed lower in tumor tissues comparing with normal tissues. Meanwhile, several clinical parameters of breast cancer patients were correlated with TIPARP expression. Further, higher TIPARP expression was related to preferable survival. Moreover, the mutations and DNA methylation of TIPARP might contribute to TIPARP dysregulation in breast cancer. Interactors with TIPARP were significantly enriched in telomere maintenance, telomere organization and mainly participated in pathways in cancer. Finally, several common drugs including metformin were observed to up-regulate the expression of TIPARP. Conclusion TIPARP might act as a preferable prognostic marker of breast cancer through multiple biological processes such as DNA methylation, mutation as well as pathway related to telomere and so on. TIPARP could be considered as a potential therapeutic target for breast cancer. However, large-scale and comprehensive research is needed to clarify our results.
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Affiliation(s)
- Lin Cheng
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China.,Department of Breast Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou 213003, People's Republic of China
| | - Zhi Li
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Yu-Zhou Huang
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Xu Zhang
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Xin-Yuan Dai
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Liang Shi
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Pei-Wen Xi
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Ji-Fu Wei
- Research Division of Clinical Pharmacology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Qiang Ding
- Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, People's Republic of China
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