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Mechanisms of Toxicity of Dioxins and Related Compounds

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (15 April 2014) | Viewed by 122373

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Special Issue Editor

Prof. Raimo Pohjanvirta

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Department of Food Hygiene and Environmental Health, University of Helsinki, Mustialankatu 1, FI-00790 Helsinki, Finland
Interests: dioxins; AH receptor; estrogenic and genotoxic chemicals in foodstuffs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dioxins have been subject to extensive research activity for the past half a century. It has become clear that these compounds are ubiquitous and persistent environmental contaminants, and that the group encompasses congeners with exceptionally high toxic potency, as exemplified by the model compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

The elucidation of the canonical AH receptor (AHR) signaling in the 1970s and 80s was a major breakthrough in our understanding of dioxin toxicity mechanisms. The present view is that an inappropriately intense and/or protracted activation of this signal transduction system constitutes the basis of most, if not all, major toxicities elicited by dioxins. However, the pathogenetic processes following AHR activation that eventually culminate in the well-described manifestations of dioxin exposure in laboratory animals have largely remained elusive – even to the extent that the critical target tissue for the acute toxicity of TCDD has yet to be established.

On the other hand, progress has been made in some subfields. In the last decade, the increasing interest of the scientific community in AHR’s physiological functions has simultaneously helped advance the elucidation of dioxin action mechanisms. This is because TCDD has been one of the most common AHR activators employed. TCDD has also been exploited as a potent pharmacological tool in studies aimed at shedding light on insufficiently understood physiological or pathological phenomena. Consequently, novel information has been gained on the interference of dioxins with the immune system (e.g., autoimmune reactions), reproductive organs, and liver functions (steatohepatitis).

A Special Issue devoted to dioxin toxicity mechanisms in the International Journal of Molecular Sciences is thus timely and well-grounded. All manuscripts furthering our current understanding on how dioxins impart their adverse health effects are welcome, be they based on in vivo or in vitro experiments. Of particular interest would be studies on impacts mediated by alternative, non-canonical signaling pathways, or by epigenetic mechanisms. As mentioned above, there is still a notable data gap of biochemical steps between AHR-mediated gene regulation and toxic signs. At the cellular or tissue level, some intriguing topics would be the effects of dioxins on stem cells and on the central nervous system. Mechanistic explanations for the wide differences in sensitivities to dioxin toxicity, both among and within species, are further called for. More information is also needed on the mechanisms of dioxin carcinogenicity.

Dr. Raimo Pohjanvirta
Guest Editor

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Keywords

dioxins
TCDD
2,3,7,8-Tetrachlorodibenzo-p-dioxin
aryl hydrocarbon receptor
AH receptor
persistent organic pollutants
toxicity mechanisms
transcription factors
bHLH/PAS proteins

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Novel Aspects of Toxicity Mechanisms of Dioxins and Related Compounds in International Journal of Molecular Sciences (13 articles)

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34 pages, 11229 KiB

Open AccessReview

Intersection of AHR and Wnt Signaling in Development, Health, and Disease

by Andrew J. Schneider, Amanda M. Branam and Richard E. Peterson^*

School of Pharmacy and Molecular and Environmental Toxicology Center University of Wisconsin, Madison, WI 53705, USA

Int. J. Mol. Sci. 2014, 15(10), 17852-17885; https://doi.org/10.3390/ijms151017852 - 3 Oct 2014

Cited by 90 | Viewed by 10967

Abstract

The AHR (aryl hydrocarbon receptor) and Wnt (wingless-related MMTV integration site) signaling pathways have been conserved throughout evolution. Appropriately regulated signaling through each pathway is necessary for normal development and health, while dysregulation can lead to developmental defects and disease. Though both pathways have been vigorously studied, there is relatively little research exploring the possibility of crosstalk between these pathways. In this review, we provide a brief background on (1) the roles of both AHR and Wnt signaling in development and disease, and (2) the molecular mechanisms that characterize activation of each pathway. We also discuss the need for careful and complete experimental evaluation of each pathway and describe existing research that explores the intersection of AHR and Wnt signaling. Lastly, to illustrate in detail the intersection of AHR and Wnt signaling, we summarize our recent findings which show that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced disruption of Wnt signaling impairs fetal prostate development. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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18 pages, 2435 KiB

Open AccessArticle

TCDD Induces the Hypoxia-Inducible Factor (HIF)-1α Regulatory Pathway in Human Trophoblastic JAR Cells

by Tien-Ling Liao^1,2,†, Su-Chee Chen^3,†, Chii-Reuy Tzeng^4,5 and Shu-Huei Kao^2,4,*

¹ Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

² School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan

³ Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 110, Taiwan

⁴ Center for Reproductive Medicine & Sciences Taipei Medical University Hospital, Taipei 110, Taiwan

⁵ Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei 110, Taiwan

^† These authors contributed equally to this study.

Int. J. Mol. Sci. 2014, 15(10), 17733-17750; https://doi.org/10.3390/ijms151017733 - 30 Sep 2014

Cited by 20 | Viewed by 10607

Abstract

The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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14 pages, 1146 KiB

Open AccessReview

Defining Molecular Sensors to Assess Long-Term Effects of Pesticides on Carcinogenesis

by Fanny L'Héritier^†, Maud Marques^†, Myriam Fauteux and Luc Gaudreau^*

¹ Département de Biologie, Université de Sherbrooke, 2500 boul. de l'Université, Sherbrooke, QC J1K 2R1, Canada

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(9), 17148-17161; https://doi.org/10.3390/ijms150917148 - 25 Sep 2014

Cited by 14 | Viewed by 7723

Abstract

The abundance of dioxins and dioxin-like pollutants has massively increased in the environment due to human activity. These chemicals are particularly persistent and accumulate in the food chain, which raises major concerns regarding long-term exposure to human health. Most dioxin-like pollutants activate the aryl hydrocarbon receptor (AhR) transcription factor, which regulates xenobiotic metabolism enzymes that belong to the cytochrome P450 1A family (that includes CYP1A1 and CYP1B1). Importantly, a crosstalk exists between estrogen receptor α (ERα) and AhR. More specifically, ERα represses the expression of the CYP1A1 gene, which encodes an enzyme that converts 17β-estradiol into 2-hydroxyestradiol. However, (ERα) does not repress the CYP1B1 gene, which encodes an enzyme that converts 17β-estradiol into 4-hydroxyestradiol, one of the most genotoxic estrogen metabolites. In this review, we discuss how chronic exposure to xenobiotic chemicals, such as pesticides, might affect the expression of genes regulated by the AhR–ERα crosstalk. Here, we focus on recent advances in the understanding of molecular mechanisms that mediate this crosstalk repression, and particularly on how ERα represses the AhR target gene CYP1A1, and could subsequently promote breast cancer. Finally, we propose that genes implicated in this crosstalk could constitute important biomarkers to assess long-term effects of pesticides on human health. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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14 pages, 1429 KiB

Open AccessReview

Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls

by Hideyuki Inui^1,*, Toshimasa Itoh², Keiko Yamamoto², Shin-Ichi Ikushiro³

and Toshiyuki Sakaki³

¹ Research Center for Environmental Genomics, Kobe University, 1-1 Rokkodaicho, Nada-ku, Kobe, Hyogo 657-8501, Japan

² Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan

³ Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan

Int. J. Mol. Sci. 2014, 15(8), 14044-14057; https://doi.org/10.3390/ijms150814044 - 13 Aug 2014

Cited by 40 | Viewed by 12346

Abstract

Polychlorinated dibenzo-p-dioxins (PCDDs) and coplanar polychlorinated biphenyls (PCBs) contribute to dioxin toxicity in humans and wildlife after bioaccumulation through the food chain from the environment. The authors examined human and rat cytochrome P450 (CYP)-dependent metabolism of PCDDs and PCBs. A number of human CYP isoforms belonging to the CYP1 and CYP2 families showed remarkable activities toward low-chlorinated PCDDs. In particular, human CYP1A1, CYP1A2, and CYP1B1 showed high activities toward monoCDDs, diCDDs, and triCDDs but no detectable activity toward 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-tetraCDD). Large amino acids located at putative substrate-recognition sites and the F-G loop in rat CYP1A1 contributed to the successful metabolism of 2,3,7,8-tetraCDD. Rat, but not human, CYP1A1 metabolized 3,3',4,4',5-pentachlorobiphenyl (CB126) to two hydroxylated metabolites. These metabolites are probably less toxic than is CB126, due to their higher solubility. Homology models of human and rat CYP1A1s and CB126 docking studies indicated that two amino acid differences in the CB126-binding cavity were important for CB126 metabolism. In this review, the importance of CYPs in the metabolism of dioxins and PCBs in mammals and the species-based differences between humans and rats are described. In addition, the authors reveal the molecular mechanism behind the binding modes of dioxins and PCBs in the heme pocket of CYPs. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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29 pages, 3273 KiB

Open AccessArticle

Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain

by Jere Lindén^1,*,†, Sanna Lensu^2,3,† and Raimo Pohjanvirta⁴

¹ Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, FI-00014 Helsinki, Finland

² Department of Biology of Physical Activity, Faculty of Sport and Health Sciences, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland

³ Department of Environmental Health, National Institute for Health and Welfare (THL), P.O. Box 95, FI-70701 Kuopio, Finland

⁴ Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, FI-00014 Helsinki, Finland

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(8), 13938-13966; https://doi.org/10.3390/ijms150813938 - 12 Aug 2014

Cited by 21 | Viewed by 7624

Abstract

One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD on the serum levels of several energy balance-influencing hormones, clinical chemistry variables, and hepatic aryl hydrocarbon receptor (AHR) expression in two rat strains that differ widely in their TCDD sensitivities, for up to 10 days. TCDD affected most of the analytes in sensitive Long-Evans rats, while there were few alterations in the resistant Han/Wistar strain. However, analyses of feed-restricted unexposed Long-Evans rats indicated several of the perturbations to be secondary to energy deficiency. Notable increases in ghrelin and glucagon occurred in TCDD-treated Long-Evans rats alone, which links these hormones to the wasting syndrome. The newly found energy balance regulators, insulin-like growth factor 1 and fibroblast growth factor 21 (FGF-21), appeared to function in concert in body weight loss-induced metabolic state, and FGF-21 was putatively linked to increased lipolysis induced by TCDD. Finally, we demonstrate a reverse set of changes in the AHR protein and mRNA response to TCDD and feed restriction, suggesting that AHR might function also as a physiological regulator, possibly involved in the maintenance of energy balance. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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16 pages, 1069 KiB

Open AccessArticle

Epigenetic Determinants of CYP1A1 Induction by the Aryl Hydrocarbon Receptor Agonist 3,3',4,4',5-Pentachlorobiphenyl (PCB 126)

by Sabine U. Vorrink^1,2, Danielle R. Hudachek^2,3 and Frederick E. Domann^1,2,*

¹ Interdisciplinary Graduate Program in Human Toxicology, the University of Iowa, Iowa City, IA 52242, USA

² Department of Radiation Oncology, the University of Iowa, Iowa City, IA 52242, USA

³ Summer Undergraduate Research Program, Interdisciplinary Graduate Program in Molecular and Cellular Biology, the University of Iowa, Iowa City, IA 52242, USA

Int. J. Mol. Sci. 2014, 15(8), 13916-13931; https://doi.org/10.3390/ijms150813916 - 11 Aug 2014

Cited by 24 | Viewed by 7183

Abstract

Many enzymes involved in xenobiotic metabolism, including cytochrome P450 (CYP) 1A1, are regulated by the aryl hydrocarbon receptor (AhR). 3,3',4,4',5-Penta chlorobiphenyl (PCB 126) is a potent ligand for AhR and can thus induce the expression of CYP1A1. Interestingly, we observed that human carcinoma cell lines derived from different types of epithelial cells displayed divergent degrees of CYP1A1 induction after exposure to PCB 126. Since epigenetic mechanisms are known to be involved in cell type-specific gene expression, we sought to assess the epigenetic determinants of CYP1A1 induction in these carcinoma cell lines. In contrast to HepG2 hepatocarcinoma cells, HeLa cervical carcinoma cells showed significantly lower levels of CYP1A1 mRNA expression following PCB 126 exposure. Our results show that the two cell lines maintained differences in the chromatin architecture along the CYP1A1 promoter region. Furthermore, treatment with the epigenetic modifiers, trichostatin A (TSA) and 5-aza-2'-deoxycytidine (5-Aza-dC), significantly increased the expression of CYP1A1 after PCB 126 treatment in HeLa cells. However, we did not observe apparent differences in methylation levels or specific location of CpG DNA methylation between the two cell lines in the analyzed CYP1A1 promoter region. Taken together, our findings suggest that the differences in CYP1A1 expression between HepG2 and HeLa cells are due to differences in the chromatin architecture of the CYP1A1 promoter and thus establish a role of epigenetic regulation in cell-specific CYP1A1 expression. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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13 pages, 970 KiB

Open AccessReview

Interplay between Dioxin-Mediated Signaling and Circadian Clock: A Possible Determinant in Metabolic Homeostasis

by Chun Wang¹, Zhi-Ming Zhang², Can-Xin Xu¹ and Shelley A. Tischkau^1,*

¹ Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA

² Department of Anesthesiology, Institute of Translation Medicine, the First People's Hospital of Chenzhou, Chenzhou 423000, China

Int. J. Mol. Sci. 2014, 15(7), 11700-11712; https://doi.org/10.3390/ijms150711700 - 1 Jul 2014

Cited by 23 | Viewed by 9430

Abstract

The rotation of the earth on its axis creates the environment of a 24 h solar day, which organisms on earth have used to their evolutionary advantage by integrating this timing information into their genetic make-up in the form of a circadian clock. This intrinsic molecular clock is pivotal for maintenance of synchronized homeostasis between the individual organism and the external environment to allow coordinated rhythmic physiological and behavioral function. Aryl hydrocarbon receptor (AhR) is a master regulator of dioxin-mediated toxic effects, and is, therefore, critical in maintaining adaptive responses through regulating the expression of phase I/II drug metabolism enzymes. AhR expression is robustly rhythmic, and physiological cross-talk between AhR signaling and circadian rhythms has been established. Increasing evidence raises a compelling argument that disruption of endogenous circadian rhythms contributes to the development of disease, including sleep disorders, metabolic disorders and cancers. Similarly, exposure to environmental pollutants through air, water and food, is increasingly cited as contributory to these same problems. Thus, a better understanding of interactions between AhR signaling and the circadian clock regulatory network can provide critical new insights into environmentally regulated disease processes. This review highlights recent advances in the understanding of the reciprocal interactions between dioxin-mediated AhR signaling and the circadian clock including how these pathways relate to health and disease, with emphasis on the control of metabolic function. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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11 pages, 1081 KiB

Open AccessReview

Coactivator Recruitment of AhR/ARNT1

by Alexander Endler^*, Li Chen and Futoshi Shibasaki^*

Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan

Int. J. Mol. Sci. 2014, 15(6), 11100-11110; https://doi.org/10.3390/ijms150611100 - 19 Jun 2014

Cited by 18 | Viewed by 8174

Abstract

A common feature of nuclear receptors (NRs) is the transformation of external cell signals into specific transcriptions of the signal molecule. Signal molecules function as ligands for NRs and, after their uptake, activated NRs form homo- or heterodimers at promoter recognition sequences of the specific genes in the nucleus. Another common feature of NRs is their dependence on coactivators, which bridge the basic transcriptional machinery and other cofactors to the target genes, in order to initiate transcription and to unwind histone-bound DNA for exposing additional promoter recognition sites via their histone acetyltransferase (HAT) function. In this review, we focus on our recent findings related to the recruitment of steroid receptor coactivator 1 (SRC1/NCoA1) by the estrogen receptor-α (ERα) and by the arylhydrocarbon receptor/arylhydrocarbon receptor nuclear translocator 1 (AhR/ARNT1) complex. We also describe the extension of our previously published findings regarding the binding between ARNT1.1 exon16 and SRC1e exon 21, via in silico analyses of androgen receptor (AR) NH2-carboxyl-terminal interactions, the results of which were verified by in vitro experiments. Based on these data, we suggest a newly derived tentative binding site of nuclear coactivator 2/glucocorticoid receptor interacting protein-1/transcriptional intermediary factor 2 (NCOA-2/ GRIP-1/TIF-2) for ARNT1.1 exon 16. Furthermore, results obtained by immunoprecipitation have revealed a second leucine-rich binding site for hARNT1.1 exon 16 in SRC1e exon 21 (LSSTDLL). Finally, we discuss the role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an endocrine disruptor for estrogen related transcription. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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20 pages, 484 KiB

Open AccessReview

The Role of AhR in Autoimmune Regulation and Its Potential as a Therapeutic Target against CD4 T Cell Mediated Inflammatory Disorder

by Conghui Zhu, Qunhui Xie and Bin Zhao^*

State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China

Int. J. Mol. Sci. 2014, 15(6), 10116-10135; https://doi.org/10.3390/ijms150610116 - 5 Jun 2014

Cited by 29 | Viewed by 9640

Abstract

AhR has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems. Since the AhR signaling pathway represents an important link between environmental stimulators and immune-mediated inflammatory disorder, it has become the object of great interest among researchers recently. The current review discusses new insights into the mechanisms of action of a select group of inflammatory autoimmune diseases and the ligand-activated AhR signaling pathway. Representative ligands of AhR, both exogenous and endogenous, are also reviewed relative to their potential use as tools for understanding the role of AhR and as potential therapeutics for the treatment of various inflammatory autoimmune diseases, with a focus on CD4 helper T cells, which play important roles both in self-immune tolerance and in inflammatory autoimmune diseases. Evidence indicating the potential use of these ligands in regulating inflammation in various diseases is highlighted, and potential mechanisms of action causing immune system effects mediated by AhR signaling are also discussed. The current review will contribute to a better understanding of the role of AhR and its signaling pathway in CD4 helper T cell mediated inflammatory disorder. Considering the established importance of AhR in immune regulation and its potential as a therapeutic target, we also think that both further investigation into the molecular mechanisms of immune regulation that are mediated by the ligand-specific AhR signaling pathway, and integrated research and development of new therapeutic drug candidates targeting the AhR signaling pathway should be pursued urgently. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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19 pages, 1011 KiB

Open AccessArticle

Aryl Hydrocarbon Receptor Repressor and TiPARP (ARTD14) Use Similar, but also Distinct Mechanisms to Repress Aryl Hydrocarbon Receptor Signaling

by Laura MacPherson¹, Shaimaa Ahmed¹, Laura Tamblyn¹, Jean Krutmann², Irmgard Förster³, Heike Weighardt^2,3 and Jason Matthews^1,*

¹ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada

² IUF-Leibniz Research Institute for Environmental Medicine gGmbH, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany

³ Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Straβe 31, 53115 Bonn, Germany

Int. J. Mol. Sci. 2014, 15(5), 7939-7957; https://doi.org/10.3390/ijms15057939 - 6 May 2014

Cited by 55 | Viewed by 8572

Abstract

The aryl hydrocarbon receptor (AHR) regulates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The AHR repressor (AHRR) is an AHR target gene and functions as a ligand-induced repressor of AHR; however, its mechanism of inhibition is controversial. Recently, we reported that TCDD-inducible poly (ADP-ribose) polymerase (TiPARP; ARTD14) also acts as a repressor of AHR, representing a new player in the mechanism of AHR action. Here we compared the ability of AHRR- and TiPARP-mediated inhibition of AHR activity. TCDD increased AHRR mRNA levels and recruitment of AHRR to cytochrome P450 1A1 (CYP1A1) in MCF7 cells. Knockdown of TiPARP, but not AHRR, increased TCDD-induced CYP1A1 mRNA and AHR protein levels. Similarly, immortalized TiPARP^−/− mouse embryonic fibroblasts (MEFs) and AHRR^−/− MEFs exhibited enhanced AHR transactivation. However, unlike TiPARP^−/− MEFs, AHRR^−/− MEFs did not exhibit increased AHR protein levels. Overexpression of TiPARP in AHRR^−/− MEFs or AHRRΔ8, the active isoform of AHRR, in TiPARP^−/− MEFs reduced TCDD-induced CYP1A1 mRNA levels, suggesting that they independently repress AHR. GFP-AHRRΔ8 and GFP-TiPARP expressed as small diffuse nuclear foci in MCF7 and HuH7 cells. GFP-AHRRΔ8_Δ1-49, which lacks its putative nuclear localization signal, localized to both the nucleus and the cytoplasm, while the GFP-AHRRΔ8_Δ1-100 mutant localized predominantly in large cytoplasmic foci. Neither GFP-AHRRΔ8_Δ1-49 nor GFP-AHRRΔ8_Δ1-100 repressed AHR. Taken together, AHRR and TiPARP repress AHR transactivation by similar, but also different mechanisms. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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25 pages, 374 KiB

Open AccessReview

Association of Dioxin and Other Persistent Organic Pollutants (POPs) with Diabetes: Epidemiological Evidence and New Mechanisms of Beta Cell Dysfunction

by Vincenzo De Tata

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma, 55, Scuola Medica, 56126 Pisa, Italy

Int. J. Mol. Sci. 2014, 15(5), 7787-7811; https://doi.org/10.3390/ijms15057787 - 5 May 2014

Cited by 31 | Viewed by 11285

Abstract

The worldwide explosion of the rates of diabetes and other metabolic diseases in the last few decades cannot be fully explained only by changes in the prevalence of classical lifestyle-related risk factors, such as physical inactivity and poor diet. For this reason, it has been recently proposed that other “nontraditional” risk factors could contribute to the diabetes epidemics. In particular, an increasing number of reports indicate that chronic exposure to and accumulation of a low concentration of environmental pollutants (especially the so-called persistent organic pollutants (POPs)) within the body might be associated with diabetogenesis. In this review, the epidemiological evidence suggesting a relationship between dioxin and other POPs exposure and diabetes incidence will be summarized, and some recent developments on the possible underlying mechanisms, with particular reference to dioxin, will be presented and discussed. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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15 pages, 243 KiB

Open AccessArticle

The Relationship between Dioxin Congeners in the Breast Milk of Vietnamese Women and Sister Chromatid Exchange

by Hiroyuki Suzuki^1,2,†, Teruhiko Kido^2,*, Rie Okamoto^2,†, Dang Duc Nhu³, Muneko Nishijo⁴, Hideaki Nakagawa⁴, Kenji Tawara⁵, Hiroaki Horikawa⁶, Yuko Sato⁶, Phung Tri Dung⁷, Le Hong Thom⁸ and Nguyen Ngoc Hung^8,†

¹ Department of Nursing, Toyota West Hospital, 100 Yokoyama, Homi-cho, Toyota, Aichi 470-0344, Japan

² Faculty of Health Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942, Japan

³ School of Medicine and Pharmacy, Vietnam National University, 144 Xuan Thuy Str., Cau Giay Dist., Hanoi 100803, Vietnam

⁴ Department of Epidemiology and Public Health, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan

⁵ Department of Environment Technology and Measurement, Hyogo Environmental Advancement Association, 3-1-31 Yukihira-cho, Suma-ku, Kobe, Hyogo 654-0037, Japan

⁶ Division of Ultrafine Structure, Department of Pathology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan

⁷ Centre for Environment and Population Health, Griffith School of Environment, Griffith University, 170 Kessels Road, Nathan Campus, Brisbane, QLD 4111, Australia

⁸ Division for Mitigation of the Consequences of the Chemicals used during the War on Human Health (10-80 Division), Hanoi Medical University, 1 Ton That Tung Str., Dong Da Dist., Hanoi 100803, Vietnam

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(5), 7485-7499; https://doi.org/10.3390/ijms15057485 - 30 Apr 2014

Cited by 4 | Viewed by 7470

Abstract

The aim of this study was to clarify the relationship between dioxin concentrations in breast milk and the sister chromatid exchange (SCE) frequency in women from herbicide-sprayed and non sprayed areas. Blood samples were taken from 21 women with high TCDD (tetrachlorodibenzo-p-dioxin) levels from sprayed areas, 23 women with moderate TCDD levels from sprayed areas, and 19 women from non sprayed areas to determine their SCE frequency. The SCE frequencies for the high and moderate TCDD groups from the sprayed area and for the non sprayed area group were 2.40, 2.19, and 1.48 per cell, respectively. Multiple regression analysis showed that the standardized β values for 1,2,3,6,7,8-hexaCDD (β = 0.60), 1,2,3,4,6,7,8-heptaCDD (β = 0.64), and octaCDD (β = 0.65) were higher than those for TCDD (β = 0.34) and 1,2,3,7,8-pentaCDD (β = 0.42). The adjusted R² value for polyCDDs (R² = 0.38) was higher than that for polyCDD toxic equivalents (TEQ (toxic equivalents); R² = 0.23). This study therefore shows that levels of hexa-, hepta-, and octaCDD, which were previously regarded as being less toxic than TCDD, are closely related to SCE frequency and that the level of dioxin (pg/g lipid) is potentially more useful as an indicator than TEQ value for explaining SCE frequency. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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Open AccessArticle

Functional Analysis of the Dioxin Response Elements (DREs) of the Murine CYP1A1 Gene Promoter: Beyond the Core DRE Sequence

by Shuaizhang Li^1,†, Xinhui Pei^1,†, Wen Zhang², Heidi Qunhui Xie¹ and Bin Zhao^1,*

¹ Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China

² Foreign Economic Cooperation Office, Ministry of Environmental Protection, Beijing 100035, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2014, 15(4), 6475-6487; https://doi.org/10.3390/ijms15046475 - 16 Apr 2014

Cited by 32 | Viewed by 8153

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the biological and toxicological effects of halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). When activated by dioxin, the cytosolic AhR protein complex translocates into the nucleus and dimerizes with the ARNT (Ah receptor nuclear translocator) protein. The heteromeric ligand:AhR/Arnt complex then recognizes and binds to its specific DNA recognition site, the dioxin response element (DRE). DREs are located upstream of cytochrome P4501A1 (CYP1A1) and other AhR-responsive genes, and binding of the AhR complex stimulates their transcription. Although CYP1A1 expression has been used as the model system to define the biochemical and molecular mechanism of AhR action, there is still limited knowledge about the roles of each of the seven DREs located in the CYP1A1 promoter. These seven DREs are conserved in mouse, human and rat. Deletion analysis showed that a single DRE at -488 was enough to activate the transcription. Truncation analysis demonstrated that the DRE at site -981 has the highest transcriptional efficiency in response to TCDD. This result was verified by mutation analysis, suggesting that the conserved DRE at site -981 could represent a significant and universal AhR regulatory element for CYP1A1. The reversed substituted intolerant core sequence (5'-GCGTG-3' or 5'-CACGC-3') of seven DREs reduced the transcriptional efficiency, which illustrated that the adjacent sequences of DRE played a vital role in activating transcription. The core DRE sequence (5'-TNGCGTG-3') tends to show a higher transcriptional level than that of the core DRE sequence (5'-CACGCNA-3') triggered by TCDD. Furthermore, in the core DRE (5'-TNGCGTG-3') sequence, when “N” is thymine or cytosine (T or C), the transcription efficiency was stronger compared with that of the other nucleotides. The effects of DRE orientation, DRE adjacent sequences and the nucleotide “N” in the core DRE (5'-TNGCGTG-3') sequence on the AhR-regulated CYP1A1 transcription in response to TCDD were studied systematically, and our study laid a good foundation for further investigation into the AhR-dependent transcriptional regulation triggered by dioxin and dioxin-like compounds. Full article

(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)

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