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Special Issue "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)

Special Issue Editor

Guest Editor
Dr. Raimo Pohjanvirta (Website)

Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, FI-00014 University of Helsinki, Finland
Interests: dioxins; AH receptor; estrogenic and genotoxic chemicals in foodstuffs

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

Submission

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF.

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

Published Papers (13 papers)

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Research

Jump to: Review

Open AccessArticle TCDD Induces the Hypoxia-Inducible Factor (HIF)-1α Regulatory Pathway in Human Trophoblastic JAR Cells
Int. J. Mol. Sci. 2014, 15(10), 17733-17750; doi:10.3390/ijms151017733
Received: 14 August 2014 / Revised: 19 September 2014 / Accepted: 22 September 2014 / Published: 30 September 2014
Cited by 1 | PDF Full-text (2435 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] Read more.
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)
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
Int. J. Mol. Sci. 2014, 15(8), 13938-13966; doi:10.3390/ijms150813938
Received: 14 May 2014 / Revised: 24 July 2014 / Accepted: 29 July 2014 / Published: 12 August 2014
Cited by 7 | PDF Full-text (3273 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Open AccessArticle Epigenetic Determinants of CYP1A1 Induction by the Aryl Hydrocarbon Receptor Agonist 3,3',4,4',5-Pentachlorobiphenyl (PCB 126)
Int. J. Mol. Sci. 2014, 15(8), 13916-13931; doi:10.3390/ijms150813916
Received: 4 June 2014 / Revised: 6 August 2014 / Accepted: 7 August 2014 / Published: 11 August 2014
Cited by 2 | PDF Full-text (1069 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] Read more.
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)
Open AccessArticle Aryl Hydrocarbon Receptor Repressor and TiPARP (ARTD14) Use Similar, but also Distinct Mechanisms to Repress Aryl Hydrocarbon Receptor Signaling
Int. J. Mol. Sci. 2014, 15(5), 7939-7957; doi:10.3390/ijms15057939
Received: 9 April 2014 / Accepted: 23 April 2014 / Published: 6 May 2014
Cited by 9 | PDF Full-text (1011 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Open AccessArticle The Relationship between Dioxin Congeners in the Breast Milk of Vietnamese Women and Sister Chromatid Exchange
Int. J. Mol. Sci. 2014, 15(5), 7485-7499; doi:10.3390/ijms15057485
Received: 14 March 2014 / Revised: 11 April 2014 / Accepted: 14 April 2014 / Published: 30 April 2014
Cited by 2 | PDF Full-text (243 KB) | HTML Full-text | XML Full-text
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) [...] Read more.
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)
Figures

Open AccessArticle Functional Analysis of the Dioxin Response Elements (DREs) of the Murine CYP1A1 Gene Promoter: Beyond the Core DRE Sequence
Int. J. Mol. Sci. 2014, 15(4), 6475-6487; doi:10.3390/ijms15046475
Received: 3 January 2014 / Revised: 1 February 2014 / Accepted: 7 February 2014 / Published: 16 April 2014
Cited by 2 | PDF Full-text (748 KB) | HTML Full-text | XML Full-text | Supplementary Files
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 [...] Read more.
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)

Review

Jump to: Research

Open AccessReview Intersection of AHR and Wnt Signaling in Development, Health, and Disease
Int. J. Mol. Sci. 2014, 15(10), 17852-17885; doi:10.3390/ijms151017852
Received: 15 August 2014 / Revised: 4 September 2014 / Accepted: 18 September 2014 / Published: 3 October 2014
Cited by 10 | PDF Full-text (11229 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Open AccessReview Defining Molecular Sensors to Assess Long-Term Effects of Pesticides on Carcinogenesis
Int. J. Mol. Sci. 2014, 15(9), 17148-17161; doi:10.3390/ijms150917148
Received: 3 July 2014 / Revised: 11 September 2014 / Accepted: 22 September 2014 / Published: 25 September 2014
Cited by 1 | PDF Full-text (1146 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Open AccessReview Mammalian Cytochrome P450-Dependent Metabolism of Polychlorinated Dibenzo-p-dioxins and Coplanar Polychlorinated Biphenyls
Int. J. Mol. Sci. 2014, 15(8), 14044-14057; doi:10.3390/ijms150814044
Received: 13 May 2014 / Revised: 8 July 2014 / Accepted: 16 July 2014 / Published: 13 August 2014
Cited by 5 | PDF Full-text (1429 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Figures

Open AccessReview Interplay between Dioxin-Mediated Signaling and Circadian Clock: A Possible Determinant in Metabolic Homeostasis
Int. J. Mol. Sci. 2014, 15(7), 11700-11712; doi:10.3390/ijms150711700
Received: 22 April 2014 / Revised: 13 June 2014 / Accepted: 17 June 2014 / Published: 1 July 2014
Cited by 4 | PDF Full-text (970 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Open AccessReview Coactivator Recruitment of AhR/ARNT1
Int. J. Mol. Sci. 2014, 15(6), 11100-11110; doi:10.3390/ijms150611100
Received: 16 April 2014 / Revised: 27 May 2014 / Accepted: 7 June 2014 / Published: 19 June 2014
Cited by 3 | PDF Full-text (1081 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Open AccessReview The Role of AhR in Autoimmune Regulation and Its Potential as a Therapeutic Target against CD4 T Cell Mediated Inflammatory Disorder
Int. J. Mol. Sci. 2014, 15(6), 10116-10135; doi:10.3390/ijms150610116
Received: 17 February 2014 / Revised: 26 March 2014 / Accepted: 27 March 2014 / Published: 5 June 2014
Cited by 2 | PDF Full-text (484 KB) | HTML Full-text | XML Full-text
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 [...] Read more.
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)
Open AccessReview Association of Dioxin and Other Persistent Organic Pollutants (POPs) with Diabetes: Epidemiological Evidence and New Mechanisms of Beta Cell Dysfunction
Int. J. Mol. Sci. 2014, 15(5), 7787-7811; doi:10.3390/ijms15057787
Received: 19 February 2014 / Revised: 16 April 2014 / Accepted: 21 April 2014 / Published: 5 May 2014
Cited by 7 | PDF Full-text (374 KB) | HTML Full-text | XML Full-text
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, [...] Read more.
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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