Special Issue "Mechanisms of Toxicity of Dioxins and Related Compounds"
Deadline for manuscript submissions: closed (15 April 2014)
Dr. Raimo Pohjanvirta
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
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
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
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.
- aryl hydrocarbon receptor
- AH receptor
- persistent organic pollutants
- toxicity mechanisms
- transcription factors
- bHLH/PAS proteins
Review: 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; in revised form: 13 June 2014 / Accepted: 17 June 2014 / Published: 1 July 2014| PDF Full-text (970 KB)
Int. J. Mol. Sci. 2014, 15(6), 11100-11110; doi:10.3390/ijms150611100
Received: 16 April 2014; in revised form: 27 May 2014 / Accepted: 7 June 2014 / Published: 19 June 2014| PDF Full-text (1081 KB) | HTML Full-text | XML Full-text
Review: 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; in revised form: 26 March 2014 / Accepted: 27 March 2014 / Published: 5 June 2014| PDF Full-text (484 KB) | HTML Full-text | XML Full-text
Article: 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| PDF Full-text (1011 KB) | HTML Full-text | XML Full-text
Review: 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; in revised form: 16 April 2014 / Accepted: 21 April 2014 / Published: 5 May 2014| PDF Full-text (374 KB) | HTML Full-text | XML Full-text
Article: 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; in revised form: 11 April 2014 / Accepted: 14 April 2014 / Published: 30 April 2014| PDF Full-text (243 KB) | HTML Full-text | XML Full-text
Article: 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; in revised form: 1 February 2014 / Accepted: 7 February 2014 / Published: 16 April 2014| PDF Full-text (748 KB) | HTML Full-text | XML Full-text | Supplementary Files
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Type of Paper: Review
Title: Association between Dioxin and Diabetes: Epidemiological Evidences and New Mechanisms of Beta Cell Dysfunction
Author: Vincenzo De Tata, M.D., Ph.D.
Affiliation: Dept. of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
Abstract: The worldwide explosion of the rates of diabetes and other metabolic diseases in the last 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, low concentration of environmental pollutants (especially the so-called persistent organic pollutants, POPs) within the body might be associated with diabetogenesis. In this review we will summarize the epidemiological evidences suggesting a relationship between dioxin exposure and diabetes incidence and present some recent developments on the possible underlying mechanisms.
Title: Defining Molecular Sensors to Assess Long-term Effects of Pesticides on Carcinogenesis
Authors: Fanny L'Héritier, Maud Marques and Luc Gaudreau
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 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.
Type of Paper: Review
Title: Mammalian Cytochrome P450-dependent Metabolism of Coplanar Polychlorinated Biphenyls (PCBs) and Polychlorinated Dibenzo-p-dioxins (PCDDs)
Authors: Inui H., Itoh T., Yamamoto K., Ikushiro S. and Sakaki T.
Abstract: Coplanar polychlorinated biphenyls (PCBs) show dioxin-like toxicity after bioaccumulation through the food chain from the environment since PCBs are highly hydrophobic and persistent. Rat CYP1A1 metabolized 3,3′,4,4′,5-pentachlorobiphenyl (CB126), which shows the highest toxicity among PCB congeners, to two hydroxylated metabolites, 4-OH-3,3′,4′,5-tetrachlorobiphenyl and 4-OH-3,3′,4′,5,5′-pentachlorobiphenyl. These metabolites are probably less toxic than CB126, due to their higher solubility. In contrast, human CYP1A1 did not metabolize whereas it shows 79% identity in amino acid sequences. Homology models of rat and human CYP1A1s, and its docking studies toward CB126 indicated that differences of two amino acids in the cavity for binding of CB126 were important for metabolism of CB126. These results suggest that toxicity to human should be carefully extrapolated from toxicity data estimated by using the rat as an experimental animal, especially in the case of compounds metabolized by CYP1A1.
We have examined human cytochrome P450-dependent metabolism of polychlorinated dibenzo-p-dioxins (PCDDs). Multiple isoforms of human cytochrome P450 belonging to CYP1 and CYP2 families showed remarkable activities toward low-chlorinated PCDDs. In particular, CYP1A1, 1A2, and 1B1 showed high activities towards mono-, di-, and tri-chloro dibenzo-p-dioxins. As in the case of CB126, rat CYP1A1 showed significantly higher activities towards PCDDs than human CYP1A1. Based on the findings that rat CYP1A1 showed a high activity toward 2,3,7-trichloro-dibenzo-p-dioxin (2,3,7-triCDD) but no detectable activity for 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2,3,7,8-TCDD), we assumed that enlarging the space of substrate-binding pocket of rat CYP1A1 might generate TCDD-metabolizing enzyme. Large-sized amino acids located at putative substrate-recognition sites and F-G loop were substituted for alanine by site-directed mutagenesis. Finally, we successfully generated 2,3,7,8-TCDD-metabolizing enzyme by site-directed mutagenesis of rat CYP1A1.
In this review, we describe the importance of cytochromes P450 in the metabolism of dioxins and PCBs in mammals, and species-based difference between humans and rats. In addition, we demonstrate molecular mechanism of binding modes of dioxin and PCB into the heme-pocket of cytochrome P450.
Type of Paper: Article
Title: Aryl Hydrocarbon Receptor Repressor and ARTD14 (TiPARP) Differentially Repress aryl Hydrocarbon Receptor Transactivation
Authors: Laura MacPherson and Jason Matthews
Affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S1A8, Canada
Abstract: Aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that regulates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Many studies have described how AHR is activated, but far less is known about how activated AHR is repressed. Although the AHR repressor (AHRR), an AHR target gene, is reported to attenuate AHR signalling, its mechanism of inhibition and its role as a repressor of all AHR-mediated response are controversial. We have recently described that the AHR target gene, ADP-ribosyltransferase Diptheria toxin 14 (ARTD14; also known as TCDD inducible poly(ADP-ribose) polymerase [TiPARP]), as a ligand-induced repressor of AHR. To better understand the mechanism(s) of AHR repression we compared AHRR- and ARTD14-mediated inhibition of AHR transactivation. TCDD treatment increased AHRR mRNA levels and recruitment of AHRR to cytochrome P450 1A1 (CYP1A1) and CYP1B1. RNAi-mediated knockdown of ARTD14, but not AHRR, in MCF7 breast carcinoma cells increased TCDD-induced CYP1A1 and CYP1B1 mRNA levels and AHR protein levels. Consistent with ARTD14-/- mouse embryonic fibroblasts (MEFs), immortalized AHRR-/- MEFs exhibited enhanced AHR transactivation. AHRR-/- MEFs had increased basal AHR target mRNA levels. In contrast to ARTD14-/- MEFs, increased AHR protein levels were not observed AHRR-/- MEFs. Overexpression of ARTD14 in AHRR-/- MEFs or AHRR in ARTD14-/- MEFs resulted in reduced TCDD-dependent increases in CYP1A1 mRNA levels, suggesting that both repressors function independently to repress AHR. Cellular localization studies revealed that overexpressed AHRR8, the active form, localized in the cytosol in COS7 and HuH7 cells, but nuclear in MCF7 cells. GFP-ARTD14 exhibited a focal nuclear localization in all cell lines examined. Taken together, AHRR and ARTD14 repress AHR transactivation by independent and distinct mechanisms.
Last update: 31 January 2014