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Novel Aspects of Toxicity Mechanisms 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 (29 April 2019) | Viewed by 71411

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Special Issue Editors

Prof. Raimo Pohjanvirta

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Guest Editor

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

Prof. Matti Viluksela

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Co-Guest Editor

School of Pharmacy (Toxicology), University of Eastern Finland, P.O.Box 1627, FI-70211 Kuopio, Finland
Interests: dioxins; persistent organic pollutants; developmental toxicity; risk assessment; developmental origins of health and disease

Special Issue Information

Dear Colleagues,

Dioxins have been the subject of extensive research activities for the past half-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 canonical AH receptor (AHR) signaling in the 1970s and 1980s was a major breakthrough in our understanding of dioxin toxicity mechanisms. The present view is that an inappropriately timed, intense and 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, major 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, for example, the immune system (e.g., regulation of T cell subsets), intestinal microbiota, 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 justified. The first Special Issue on this topic a couple of years ago attracted substantial interest, warranting a renewal now. All manuscripts furthering our current understanding on how dioxins impart their adverse health effects will be considered, be they based on in vivo or in vitro experiments or epidemiological evidence. Of particular interest would be studies on impacts mediated by alternative, non-canonical signaling pathways, or by epigenetic mechanisms. The compounds addressed may be not only PCDD/Fs, but also dioxin-like PCBs, PBDDs and PCNs. In addition to original research papers, full-length and mini-reviews are welcome. As mentioned above, there is still a notable data gap in biochemical steps between modulation of AHR-mediated gene regulation and elicitation of toxic effects by these compounds. Hopefully, this Special Issue will contribute to narrowing that gap.

Prof. Raimo Pohjanvirta
Prof. Matti Viluksela
Guest Editors

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Keywords

Dioxins
TCDD
2,3,7,8-Tetrachlorodibenzo-p-dioxin
Dioxin-like PCBs
Polybrominated dibenzo-p-dioxins
Polychlorinated naphthalenes
Halogenated aromatic hydrocarbons
Aryl hydrocarbon receptor
Persistent organic pollutants
Toxicity mechanisms

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

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Editorial

Jump to: Research, Review

6 pages, 197 KiB

Open AccessEditorial

Novel Aspects of Toxicity Mechanisms of Dioxins and Related Compounds

by Raimo Pohjanvirta and Matti Viluksela

Int. J. Mol. Sci. 2020, 21(7), 2342; https://doi.org/10.3390/ijms21072342 - 28 Mar 2020

Cited by 5 | Viewed by 3146

Abstract

Dioxins and related compounds are common environmental contaminants. Although their levels have gone down, they are still of concern, in particular regarding developmental toxicity. The adverse effects of these compounds are mediated by the aryl hydrocarbon receptor (AHR), whose canonical signaling pathway has been unveiled in fair detail. The alternative (non-genomic) pathways are much more obscure. AHR has also proven to be a master regulator of numerous physiological phenomena, which has led to the search of selective AHR modulators with low toxicity. Papers of this Special Issue address the developmental toxicity of dioxins and related compounds as well as selective modulators of AHR and both its canonical and alternative signaling pathways. In addition, new optical and stereoscopic methods for the detection of dioxins are presented. As a whole, this Special Issue provides an up-to-date view on a wide variety of aspects related to dioxin toxicity mechanisms from both original research articles and reviews. Full article

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

Research

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19 pages, 3068 KiB

Open AccessArticle

Tyroxine Hydroxylase-Positive Neuronal Cell Population is Increased by Temporal Dioxin Exposure at Early Stage of Differentiation from Human Embryonic Stem Cells

by Sailendra Nath Sarma, Reiko Nagano and Seiichiroh Ohsako

Int. J. Mol. Sci. 2019, 20(11), 2687; https://doi.org/10.3390/ijms20112687 - 31 May 2019

Cited by 4 | Viewed by 3631

Abstract

Background: The neurological effects of short-term dioxin exposure during the fetal period is an important health risk in humans. Here, we investigated the effects of dioxin on neural differentiation using human embryonic stem cells (hESCs) to evaluate human susceptibility to dioxin. Methods: Using an enzymatic bulk passage, neural differentiation from human ESCs was carried out. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was added to various stages of culture. The expression levels of the neuronal markers microtubule-associated protein 2 (MAP2) and thyroxine hydroxylase (TH) were measured by RT-qPCR and image analysis of immunostaining. Results: Although early-stage neuronal cells are quite resistant to TCDD, the numbers of neural rosettes and increases in mRNA expression levels and the number of cells positive for MAP2 and TH were significant by temporal exposure at embryoid body stage (Day9-exposure group). In contrast, the TCDD exposures against ESCs (Day0-exposure group) and differentiated neural cells (Day35-exposure group) were not affected at all. The increment was similarly observed by continuous exposure of TCDD from Day9 through Day60. Conclusions: These results indicated that dioxin exposure during the early stage of differentiation from hESCs increases the contents of neuronal cells, especially TH-positive neuronal cells. Regulations of aryl hydrocarbon receptor (AHR) signaling in an early stage of embryogenesis should be investigated extensively to understand the mechanism underlying the increase in neuronal cell populations and to apply the knowledge to regenerative medicine. Full article

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

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10 pages, 893 KiB

Open AccessCommunication

Role of NF-kB RelB in Aryl Hydrocarbon Receptor-Mediated Ligand Specific Effects

by Yasuhiro Ishihara, Sarah Y. Kado, Christiane Hoeper, Shelly Harel and Christoph F. A. Vogel

Int. J. Mol. Sci. 2019, 20(11), 2652; https://doi.org/10.3390/ijms20112652 - 30 May 2019

Cited by 45 | Viewed by 5063

Abstract

Here, we investigate the role of RelB in the regulation of genes which were identified to be induced in an aryl hydrocarbon receptor (AhR)-dependent manner and critically involved in regulation of immune responses. We analyzed the expression of genes of the AhR gene battery, cytokines, and immune regulatory enzymes in bone marrow-derived macrophages (BMM) and thymus of B6 wildtype (wt) mice and RelB knockout (RelB^−/−) mice after treatment with various AhR ligands. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced expression of indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 was significantly repressed in thymus of RelB^−/− mice but not in BMM derived from RelB^−/− mice. Interestingly, the induced and basal expression of the cytokines interleukin (IL)-17A, IL-22, and CCL20 required the functional expression of RelB. The RelB-dependent expression of CCL20 was induced by the AhR ligands TCDD and 6-formylindolo[3,2-b]carbazole (FICZ), whereas indole-3-carbinol (I3C) suppressed CCL20 in lipopolysaccharide (LPS)-activated wt BMM. The LPS-induced expression of IL-6 and IL-10 was enhanced by TCDD and FICZ, whereas I3C significantly suppressed these cytokines in BMM. The exposure to FICZ led to higher increases of IL-17A and IL-22 mRNA compared to the effect of TCDD or I3C in thymus of wt mice. On the other hand, TCDD was the strongest inducer of CYP1A1, AhR Repressor (AhRR), and IDO2. In summary, these findings provide evidence for the important role of RelB in the transcriptional regulation of cytokines and enzymes induced by AhR ligands. Full article

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

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26 pages, 6512 KiB

Open AccessArticle

Coupling Genome-wide Transcriptomics and Developmental Toxicity Profiles in Zebrafish to Characterize Polycyclic Aromatic Hydrocarbon (PAH) Hazard

by Prarthana Shankar, Mitra C. Geier, Lisa Truong, Ryan S. McClure, Paritosh Pande, Katrina M. Waters and Robert L. Tanguay

Int. J. Mol. Sci. 2019, 20(10), 2570; https://doi.org/10.3390/ijms20102570 - 25 May 2019

Cited by 44 | Viewed by 5595

Abstract

Polycyclic Aromatic Hydrocarbons (PAHs) are diverse environmental pollutants associated with adverse human health effects. Many studies focus on the carcinogenic effects of a limited number of PAHs and there is an increasing need to understand mechanisms of developmental toxicity of more varied yet environmentally relevant PAHs. A previous study characterized the developmental toxicity of 123 PAHs in zebrafish. Based on phenotypic responses ranging from complete inactivity to acute mortality, we classified these PAHs into eight bins, selected 16 representative PAHs, and exposed developing zebrafish to the concentration of each PAH that induced 80% phenotypic effect. We conducted RNA sequencing at 48 h post fertilization to identify gene expression changes as a result of PAH exposure. Using the Context Likelihood of Relatedness algorithm, we inferred a network that links the PAHs based on coordinated gene responses to PAH exposure. The 16 PAHs formed two broad clusters: Cluster A was transcriptionally more similar to the controls, while Cluster B consisted of PAHs that were generally more developmentally toxic, significantly elevated cyp1a transcript levels, and induced Ahr2-dependent Cyp1a protein expression in the skin confirmed by gene-silencing studies. We found that cyp1a transcript levels were associated with transcriptomic response, but not with PAH developmental toxicity. While all cluster B PAHs predominantly activated Ahr2, they also each enriched unique pathways like ion transport signaling, which likely points to differing molecular events between the PAHs downstream of Ahr2. Thus, using a systems biology approach, we have begun to evaluate, classify, and define mechanisms of PAH toxicity. Full article

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

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15 pages, 6042 KiB

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3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice

by Tiffany E. Cho, Debbie Bott, Shaimaa Ahmed, David Hutin, Alvin Gomez, Laura Tamblyn, Angela C. Zhou, Tania H. Watts, Denis M. Grant and Jason Matthews

Int. J. Mol. Sci. 2019, 20(9), 2312; https://doi.org/10.3390/ijms20092312 - 10 May 2019

Cited by 7 | Viewed by 4857

Abstract

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp^−/− mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp^−/− mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp^−/− or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP’s role as a repressor of AHR signaling, 3MC-treated Tiparp^−/− mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp^−/− mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp^−/− mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp^−/− mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp^−/− mice. Our study reveals that Tiparp^−/− mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome. Full article

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

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15 pages, 2231 KiB

Open AccessArticle

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

by Stephenie D. Prokopec, Raimo Pohjanvirta, Selma Mahiout, Lars Pettersson and Paul C. Boutros

Int. J. Mol. Sci. 2019, 20(6), 1370; https://doi.org/10.3390/ijms20061370 - 19 Mar 2019

Cited by 4 | Viewed by 4253

Abstract

IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population. Full article

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

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12 pages, 1435 KiB

Open AccessArticle

Upregulation of FLG, LOR, and IVL Expression by Rhodiola crenulata Root Extract via Aryl Hydrocarbon Receptor: Differential Involvement of OVOL1

by Akiko Hashimoto-Hachiya, Gaku Tsuji, Mika Murai, Xianghong Yan and Masutaka Furue

Int. J. Mol. Sci. 2018, 19(6), 1654; https://doi.org/10.3390/ijms19061654 - 4 Jun 2018

Cited by 48 | Viewed by 5688

Abstract

Rhodiola species are antioxidative, salubrious plants that are known to inhibit oxidative stress induced by ultraviolet and γ-radiation in epidermal keratinocytes. As certain phytochemicals activate aryl hydrocarbon receptors (AHR) or OVO-like 1 (OVOL1) to upregulate the expression of epidermal barrier proteins such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL), we investigated such regulation by Rhodiola crenulata root extract (RCE). We demonstrated that RCE induced FLG and LOR upregulation in an AHR-OVOL1-dependent fashion. However, RCE-mediated IVL upregulation was AHR-dependent but OVOL1-independent. Coordinated upregulation of skin barrier proteins by RCE via AHR may be beneficial in the management of barrier-disrupted inflammatory skin diseases such as atopic dermatitis. Full article

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

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20 pages, 3817 KiB

Open AccessArticle

Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling

by Bendik C. Brinchmann, Eric Le Ferrec, Normand Podechard, Dominique Lagadic-Gossmann, Kenji F. Shoji, Aubin Penna, Klara Kukowski, Alena Kubátová, Jørn A. Holme and Johan Øvrevik

Int. J. Mol. Sci. 2018, 19(5), 1429; https://doi.org/10.3390/ijms19051429 - 10 May 2018

Cited by 25 | Viewed by 4937

Abstract

Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca²⁺]_i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca²⁺]_i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca²⁺]_i increases in HMEC-1. n-Hex-EOM triggered [Ca²⁺]_i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca²⁺]_i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca²⁺]_i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca²⁺]_i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca²⁺]_i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca²⁺]_i increase. Full article

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

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Review

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37 pages, 1496 KiB

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Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity

by Carolyn Klocke and Pamela J. Lein

Int. J. Mol. Sci. 2020, 21(3), 1013; https://doi.org/10.3390/ijms21031013 - 4 Feb 2020

Cited by 77 | Viewed by 7081

Abstract

Despite being banned from production for decades, polychlorinated biphenyls (PCBs) continue to pose a significant risk to human health. This is due to not only the continued release of legacy PCBs from PCB-containing equipment and materials manufactured prior to the ban on PCB production, but also the inadvertent production of PCBs as byproducts of contemporary pigment and dye production. Evidence from human and animal studies clearly identifies developmental neurotoxicity as a primary endpoint of concern associated with PCB exposures. However, the relative role(s) of specific PCB congeners in mediating the adverse effects of PCBs on the developing nervous system, and the mechanism(s) by which PCBs disrupt typical neurodevelopment remain outstanding questions. New questions are also emerging regarding the potential developmental neurotoxicity of lower chlorinated PCBs that were not present in the legacy commercial PCB mixtures, but constitute a significant proportion of contemporary human PCB exposures. Here, we review behavioral and mechanistic data obtained from experimental models as well as recent epidemiological studies that suggest the non-dioxin-like (NDL) PCBs are primarily responsible for the developmental neurotoxicity associated with PCBs. We also discuss emerging data demonstrating the potential for non-legacy, lower chlorinated PCBs to cause adverse neurodevelopmental outcomes. Molecular targets, the relevance of PCB interactions with these targets to neurodevelopmental disorders, and critical data gaps are addressed as well. Full article

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

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22 pages, 715 KiB

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Multigenerational and Transgenerational Effects of Dioxins

by Matti Viluksela and Raimo Pohjanvirta

Int. J. Mol. Sci. 2019, 20(12), 2947; https://doi.org/10.3390/ijms20122947 - 17 Jun 2019

Cited by 41 | Viewed by 6734

Abstract

Dioxins are ubiquitous and persistent environmental contaminants whose background levels are still reason for concern. There is mounting evidence from both epidemiological and experimental studies that paternal exposure to the most potent congener of dioxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), can lower the male/female ratio of offspring. Moreover, in laboratory rodents and zebrafish, TCDD exposure of parent animals has been reported to result in reduced reproductive performance along with other adverse effects in subsequent generations, foremost through the paternal but also via the maternal germline. These impacts have been accompanied by epigenetic alterations in placenta and/or sperm cells, including changes in methylation patterns of imprinted genes. Here, we review recent key studies in this field with an attempt to provide an up-to-date picture of the present state of knowledge to the reader. These studies provide biological plausibility for the potential of dioxin exposure at a critical time-window to induce epigenetic alterations across multiple generations and the significance of aryl hydrocarbon receptor (AHR) in mediating these effects. Currently available data do not allow to accurately estimate the human health implications of these findings, although epidemiological evidence on lowered male/female ratio suggests that this effect may take place at realistic human exposure levels. Full article

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

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19 pages, 2932 KiB

Open AccessReview

Dioxin and Related Compound Detection: Perspectives for Optical Monitoring

by Barbara Patrizi, Mario Siciliani de Cumis, Silvia Viciani and Francesco D’Amato

Int. J. Mol. Sci. 2019, 20(11), 2671; https://doi.org/10.3390/ijms20112671 - 30 May 2019

Cited by 10 | Viewed by 5813

Abstract

Dioxins and related compounds are environmental xenobiotics that are dangerous to human life, due to the accumulation and persistence in the environment and in the food chain. Cancer, reproductive and developmental issues, and damage to the immune system and endocrine system are only a few examples of the impact of such substances in everyday life. For these reasons, it is fundamental to detect and monitor these molecules in biological samples. The consolidated technique for analytical evaluation is gas chromatography combined with high-resolution mass spectrometry. Nowadays, the development of mid-infrared optical components like broadband laser sources, optical frequency combs, high performance Fourier-transform infrared spectroscopy, and plasmonic sensors open the way to new techniques for detection and real time monitoring of these organic pollutants in gaseous or liquid phase, with sufficient sensitivity and selectivity, and in short time periods. In this review, we report the latest techniques for the detection of dioxins, furans and related compounds based on optical and spectroscopic methods, looking at future perspectives. Full article

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

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16 pages, 263 KiB

Open AccessReview

Mechanisms of Developmental Toxicity of Dioxins and Related Compounds

by Wataru Yoshioka and Chiharu Tohyama

Int. J. Mol. Sci. 2019, 20(3), 617; https://doi.org/10.3390/ijms20030617 - 31 Jan 2019

Cited by 43 | Viewed by 5899

Abstract

Dioxins and related compounds induce morphological abnormalities in developing animals in an aryl hydrocarbon receptor (AhR)-dependent manner. Here we review the studies in which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is used as a prototypical compound to elucidate the pathogenesis of morphological abnormalities. TCDD-induced cleft palate in fetal mice involves a delay in palatogenesis and dissociation of fused palate shelves. TCDD-induced hydronephrosis, once considered to be caused by the anatomical obstruction of the ureter, is now separated into TCDD-induced obstructive and non-obstructive hydronephrosis, which develops during fetal and neonatal periods, respectively. In the latter, a prostaglandin E₂ synthesis pathway and urine concentration system are involved. TCDD-induced abnormal development of prostate involves agenesis of the ventral lobe. A suggested mechanism is that AhR activation in the urogenital sinus mesenchyme by TCDD modulates the wingless-type MMTV integration site family (WNT)/β-catenin signaling cascade to interfere with budding from urogenital sinus epithelium. TCDD exposure to zebrafish embryos induces loss of epicardium progenitor cells and heart malformation. AHR2-dependent downregulation of Sox9b expression in cardiomyocytes is a suggested underlying mechanism. TCDD-induced craniofacial malformation in zebrafish is considered to result from the AHR2-dependent reduction in SRY-box 9b (SOX9b), probably partly via the noncoding RNA slincR, resulting in the underdevelopment of chondrocytes and cartilage. Full article

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

15 pages, 524 KiB

Open AccessReview

TCDD Toxicity Mediated by Epigenetic Mechanisms

by Barbara Patrizi and Mario Siciliani de Cumis

Int. J. Mol. Sci. 2018, 19(12), 4101; https://doi.org/10.3390/ijms19124101 - 18 Dec 2018

Cited by 54 | Viewed by 7575

Abstract

Dioxins are highly toxic and persistent halogenated organic pollutants belonging to two families i.e., Polychlorinated Dibenzo-p-Dioxins (PCDDs) and Polychlorinated Dibenzo Furans (PCDFs). They can cause cancer, reproductive and developmental issues, damage to the immune system, and can deeply interfere with the endocrine system. Dioxins toxicity is mediated by the Aryl-hydrocarbon Receptor (AhR) which mediates the cellular metabolic adaptation to these planar aromatic xenobiotics through the classical transcriptional regulation pathway, including AhR binding of ligand in the cytosol, translocation of the receptor to the nucleus, dimerization with the AhR nuclear translocator, and the binding of this heterodimeric transcription factor to dioxin-responsive elements which regulate the expression of genes involved in xenobiotic metabolism. 2,3,7,8-TCDD is the most toxic among dioxins showing the highest affinity toward the AhR receptor. Beside this classical and well-studied pathway, a number of papers are dealing with the role of epigenetic mechanisms in the response to environmental xenobiotics. In this review, we report on the potential role of epigenetic mechanisms in dioxins-induced cellular response by inspecting recent literature and focusing our attention on epigenetic mechanisms induced by the most toxic 2,3,7,8-TCDD. Full article

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

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