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PloS One 20222,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the most harmful chemicals showing resistance to biodegradation. The majority of TCDD effects is mediated by the...
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the most harmful chemicals showing resistance to biodegradation. The majority of TCDD effects is mediated by the aryl hydrocarbon receptor (AhR) pathway. TCDD binding to AhR results in the activation of cytochrome P450 enzymes (CYP1A1, CYP1A2, CYP1B1) involved in dioxin biodegradation. The goal of the study was to explore the potential role of CYP1A2 in the metabolism of TCDD. We investigated a molecular structure of CYP1A2 and the binding selectivity and affinity between the pig CYP1A2 and: 1/ DiCDD or TCDD (dioxins differing in toxicity and biodegradability) or 2/ their selected metabolites. pCYP1A2 demonstrated higher affinity towards DiCDD and TCDD than other pCYP1 enzymes. All dioxin-pCYP1A2 complexes were found to be stabilized by hydrophobic interactions. The calculated distances between the heme oxygen and the dioxin carbon nearest to the oxygen, reflecting the hydroxylating potential of CYP1A2, were higher than in other pCYP1 enzymes. The distances between the heme iron and the nearest dioxin carbon exceeded 5 Å, a distance sufficient to allow the metabolites to leave the active site. However, the molecular dynamics simulations revealed that two access channels of CYP1A2 were closed upon binding the majority of the examined dioxins. Moreover, the binding of dioxin metabolites did not promote opening of channel S-an exit for hydroxylated products. It appears that the undesired changes in the behavior of access channels prevail over the hydroxylating potential of CYP1A2 towards TCDD and the favorable distances, ultimately trapping the metabolites at the enzyme's active site.
Topics: Animals; Carbon; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Dioxins; Heme; Oxygen; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Swine
PubMed: 35617319
DOI: 10.1371/journal.pone.0267162 -
Environmental Research Mar 2022Ambient dioxin exposure from industrial sources, excluding exposures from occupations and accidental releases/contamination, may be associated with risk of developing...
Ambient dioxin exposure from industrial sources, excluding exposures from occupations and accidental releases/contamination, may be associated with risk of developing hepatocellular carcinoma (HCC). The objective of this study was to examine the association between county-level ambient dioxin air emissions from industrial sources and HCC risk in the US. We obtained information on 90,359 incident HCC cases diagnosed between 2000 and 2016 from population-based cancer registries across the US in the Surveillance, Epidemiology, and End Results (SEER) database. Dioxin emissions from 1987 to 2007 from a nationwide spatial database of historical dioxin-emitting facilities were linked to the SEER county of residence at diagnosis using a geographic information system (GIS). Poisson regression with robust variance estimation was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between county-level dioxin emissions and HCC rates adjusting for individual-level age at diagnosis, sex, race/ethnicity, year of diagnosis, SEER registry, and county-level information on health conditions, lifestyle factors, and socioeconomic status. There was no association between dioxin emissions based on the number of dioxin-emitting facilities within a county or average annual emissions within a county and HCC risk. In analyses by facility type, there were positive associations between county-level dioxin emissions from coal-fired power plants (adjusted IRR 1.09, 95% CI 1.01-1.17), but not with the number of these facilities. Similarly, positive associations for industrial boilers and sewage sludge incinerators were evident, but not consistent across both exposure metrics. Future research should incorporate individual-level data to further explore the findings suggested by these ecologic analyses.
Topics: Carcinoma, Hepatocellular; Dioxins; Humans; Incidence; Incineration; Liver Neoplasms; United States
PubMed: 34800530
DOI: 10.1016/j.envres.2021.112386 -
International Journal of Molecular... Jan 2021Poisoning by high concentrations of dioxin and its related compounds manifests variable toxic symptoms such as general malaise, chloracne, hyperpigmentation, sputum and... (Review)
Review
Poisoning by high concentrations of dioxin and its related compounds manifests variable toxic symptoms such as general malaise, chloracne, hyperpigmentation, sputum and cough, paresthesia or numbness of the extremities, hypertriglyceridemia, perinatal abnormalities, and elevated risks of cancer-related mortality. Such health hazards are observed in patients with Yusho (oil disease in Japanese) who had consumed rice bran oil highly contaminated with 2,3,4,7,8-pentachlorodibenzofuran, polychlorinated biphenyls, and polychlorinated quaterphenyls in 1968. The blood concentrations of these congeners in patients with Yusho remain extremely elevated 50 years after onset. Dioxins exert their toxicity via aryl hydrocarbon receptor (AHR) through the generation of reactive oxygen species (ROS). In this review article, we discuss the pathogenic implication of AHR in dioxin-induced health hazards. We also mention the potential therapeutic use of herbal drugs targeting AHR and ROS in patients with Yusho.
Topics: Animals; Dioxins; Humans; Porphyrias; Reactive Oxygen Species; Receptors, Aryl Hydrocarbon; Rice Bran Oil
PubMed: 33445793
DOI: 10.3390/ijms22020708 -
Journal of Neurochemistry Sep 2021Acetylcholinesterase (AChE, EC 3.1.1.7) plays important roles in cholinergic neurotransmission and has been widely recognized as a biomarker for monitoring pollution by... (Review)
Review
Acetylcholinesterase (AChE, EC 3.1.1.7) plays important roles in cholinergic neurotransmission and has been widely recognized as a biomarker for monitoring pollution by organophosphate (OP) and carbamate pesticides. Dioxin is an emerging environmental AChE disruptor and is a typical persistent organic pollutant with multiple toxic effects on the nervous system. Growing evidence has shown that there is a significant link between dioxin exposure and neurodegenerative diseases and neurodevelopmental disorders, most of which involve AChE and cholinergic dysfunctions. Therefore, an in-depth understanding of the effects of dioxin on AChE and the related mechanisms of action might help to shed light on the molecular bases of dioxin impacts on the nervous system. In the past decade, the effects of dioxins on AChE have been revealed in cultured cells of different origins and in rodent animal models. Unlike OP and carbamate pesticides, dioxin-induced AChE disturbance is not due to direct inhibition of enzymatic activity; instead, dioxin causes alterations of AChE expression in certain models. As a widely accepted mechanism for most dioxin effects, the aryl hydrocarbon receptor (AhR)-dependent pathway has become a research focus in studies on the mechanism of action of dioxin-induced AChE dysregulation. In this mini-review, the effects of dioxin on AChE and the diverse roles of the AhR pathway in AChE regulation are summarized. Additionally, the involvement of AhR in AChE regulation during different neurodevelopmental processes is discussed. These AhR-related findings might also provide new insight into AChE regulation triggered by diverse xenobiotics capable of interacting with AhR.
Topics: Acetylcholinesterase; Animals; Brain; Cells, Cultured; Dioxins; Humans; Neurodegenerative Diseases; Neurons; Receptors, Aryl Hydrocarbon
PubMed: 33278027
DOI: 10.1111/jnc.15261 -
The Kaohsiung Journal of Medical... Jul 2012The aim of the present study is to describe recent issues with Yusho disease in Japan, describe the state of dioxin accumulation and the intake of dioxin via food in... (Review)
Review
The aim of the present study is to describe recent issues with Yusho disease in Japan, describe the state of dioxin accumulation and the intake of dioxin via food in Japan, and introduce the Japan Environment and Children's Study. Yusho disease manifested in western Japan in 1968. The causes of Yusho are believed to be dioxin-related compounds, mainly polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs), via the ingestion of rice oil produced in February 1968. As of March 31, 2011, there were 1961 registered Yusho cases, but of these 539 are deceased. A retrospective cohort study on registered Yusho cases reported that the standardized mortality ratios (SMRs) for the major causes of death were not significantly elevated, with the exception of all-cancer (SMR=1.26; 95% confidence interval [CI]: 1.03-1.53) and lung cancer mortality (SMR=1.56; 95% CI: 1.03-2.27) in males. The results of the Yusho mortality study show that the SMR for liver cancer in males tends to decrease over time. In 2011, the Ministry of the Environment of Japan reported that the average concentration of dioxins in the blood (2002-2010) of the Japanese people was 19 pg-TEQ/g-fat, demonstrating a range of 0.10-130 pg-TEQ/g-fat, and that the average dioxin intake from food (2002-2010) was 0.82 pg-TEQ/kg-body weight/day, demonstrating a range of 0.031-6.2 pg-TEQ/kg-body weight/day according to 2006 WHO TEFs. The Japan Environment and Children's Study Project was launched in 2011 and is supported by the Ministry of the Environment of Japan. In this project, 100,000 mother and child pairs will be recruited over 3 years from designated study areas. Follow-up examinations will be carried out from pregnancy until the children are 13 years of age (a so-called birth-cohort study). This project will be implemented by the National Center at the National Institute for Environmental Studies and is supported by the Medical Support Center at the National Center for Child Health and Development. Field operations will be performed at 15 designated regional centers nationwide.
Topics: Animals; Dioxins; Food Contamination; History, 20th Century; History, 21st Century; Humans; Japan; Neoplasms; Porphyrias
PubMed: 22871602
DOI: 10.1016/j.kjms.2012.05.010 -
Scientific Reports Jul 2022Epithelial development starts with stem cell commitment to ectoderm followed by differentiation to the basal keratinocytes. The basal keratinocytes, first committed in...
Epithelial development starts with stem cell commitment to ectoderm followed by differentiation to the basal keratinocytes. The basal keratinocytes, first committed in embryogenesis, constitute the basal layer of the epidermis. They have robust proliferation and differentiation potential and are responsible for epidermal expansion, maintenance and regeneration. We generated basal epithelial cells in vitro through differentiation of mouse embryonic stem cells (mESCs). Early on in differentiation, the expression of stem cell markers, Oct4 and Nanog, decreased sharply along with increased ectoderm marker keratin (Krt) 18. Later on, Krt 18 expression was subdued when cells displayed basal keratinocyte characteristics, including regular polygonal shape, adherent and tight junctions and Krt 14 expression. These cells additionally expressed abundant Sca-1, Krt15 and p63, suggesting epidermal progenitor characteristics. Using Map3k1 mutant mESCs and environmental dioxin, we examined the gene and environment effects on differentiation. Neither Map3k1 mutation nor dioxin altered mESC differentiation to ectoderm and basal keratinocytes, but they, individually and in combination, potentiated Krt 1 expression and basal to spinous differentiation. Similar gene-environment effects were observed in vivo where dioxin exposure increased Krt 1 more substantially in the epithelium of Map3k1 than wild type embryos. Thus, the in vitro model of epithelial differentiation can be used to investigate the effects of genetic and environmental factors on epidermal development.
Topics: Animals; Cell Differentiation; Dioxins; Epidermal Cells; Epidermis; Keratinocytes; MAP Kinase Kinase Kinase 1; Mice; Mouse Embryonic Stem Cells; Mutation
PubMed: 35798792
DOI: 10.1038/s41598-022-15760-z -
European Review For Medical and... 2015Endometriosis is a common, benign, estrogen-dependent gynecological disease that represents one of the main causes of hospitalization in industrialized countries. It is... (Review)
Review
Endometriosis is a common, benign, estrogen-dependent gynecological disease that represents one of the main causes of hospitalization in industrialized countries. It is well established that a large amount of natural and man-made chemicals are present in the environment and both humans and animals are exposed to them. Dioxin and dioxin-like compounds have long biological half-life, can accumulate within the organism and could negatively affect several physiological processes. The purpose of this review is to provide an overview of the possible relationship between these chemicals and the pathogenesis of endometriosis.
Topics: Animals; Dioxins; Endometriosis; Environmental Exposure; Female; Humans; Polychlorinated Biphenyls
PubMed: 26125255
DOI: No ID Found -
Revista Da Associacao Medica Brasileira... 2011Endometriosis represents a common gynecological condition affecting 5%-15% of childbearing age women and up to 3% 5% of post-menopausal women. This disease is defined by... (Review)
Review
Endometriosis represents a common gynecological condition affecting 5%-15% of childbearing age women and up to 3% 5% of post-menopausal women. This disease is defined by the presence of stromal and/or endometrial glandular epithelium implants in extra-uterine locations possibly compromising several sites. Humans and animals are daily exposed to chemical pollutants that could adversely influence physiological processes and potentially cause diseases, including endometriosis. In this review, the authors aimed at settling the influence of environmental and dietary factors on endometriosis pathogenesis. The mechanism by which dioxin and its similes (TCDD/PCBs) act changing the endometrial physiology remains uncertain and is speculative due to the difficulty in assessing the exposure over intrauterine life, childhood and adulthood and its actual consequences, in addition to the limitations to its in vitro reproducibility. We need to better understand the mechanism of action of these environmental pollutants, not only on reproductive health, but also on overall health of individuals and so prevention strategies, including not only population education, but setting exposure limits, less polluting techniques and a better use of our natural resources, could be promoted.
Topics: Diet; Dioxins; Endometriosis; Environment; Environmental Pollutants; Female; Humans; Risk Factors
PubMed: 21876930
DOI: 10.1590/s0104-42302011000400022 -
Environment International Aug 2023Children and consumers are exposed to increasingly complex mixtures of known and as-yet-unknown toxic chemicals from toys and products. However traditional chemical...
BACKGROUND
Children and consumers are exposed to increasingly complex mixtures of known and as-yet-unknown toxic chemicals from toys and products. However traditional chemical analysis methods only evaluate a small number of chemicals at a time thereby restricting consumer awareness of the full range of potentially harmful chemicals in products.
METHODS
We used high-throughput effect-based non-animal methods to investigate exposures to complex chemical mixtures of several kinds of brominated flame retardants (BFRs) for their dioxin- and thyroid hormone-like activities in various kinds of consumer products and toys from 26 different countries, on four continents (Africa, America, Asia and Europe) in combination with chemical analysis of various polybrominated flame retardants (BFRs) and their impurities (such as polyhalogenated PCDD/Fs and PBDD/Fs).
RESULTS
We found high levels of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in toys and now, for the first time, also in consumer products that are manufactured from black plastics containing certain brominated flame retardants (BFRs). The presence of PBDD/PBDFs as well as other BFRs in various black plastic materials from additional countries as well as additional kinds of consumer products as confirmed by effect-based in vitro reporter gene DR CALUX and TTR-TRβ CALUX assays as well as congener-specific chemical analysis. We compared total Toxicity Equivalent (TEQ) levels of PBDD/F-TEQs analysed by chemical analysis to by CALUX bioassay measured Biological equivalence (BEQ) concentrations (for further info see at ISO 23196, ISO, 2022). In the case of TBBPA, both chemical and TTR-TRβ CALUX analysis measure direct the amount of TBBPA. Finally, the daily ingestion of 2,3,7,8-TCDD equivalents from PBDD/Fs-contaminated plastic toys by child mouthing habits have been related to our earlier study (Budin et al., 2020).
CONCLUSIONS
Interaction of children with such contaminated plastics may significantly contribute to the daily uptake of dioxin- and thyroid hormone transport disrupting-like compounds. Effect-based bioassays for dioxin- and thyroid hormone-like activities are relevant to pick-out such complex mixtures of known and yet unknown (and therefore not regulated) substances for safer and more sustainable plastics. Low POPs Content Levels and other mechanisms set under the Basel and Stockholm Conventions are set far too high to prevent a significant flow of BFRs and PBDD/Fs into consumer products.
Topics: Child; Humans; Polychlorinated Dibenzodioxins; Dioxins; Dibenzofurans; Flame Retardants; Complex Mixtures; Plastics; Thyroid Hormones
PubMed: 37453209
DOI: 10.1016/j.envint.2023.108079 -
International Journal of Molecular... Jun 2019Dioxins are ubiquitous and persistent environmental contaminants whose background levels are still reason for concern. There is mounting evidence from both... (Review)
Review
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--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.
Topics: Animals; Biomarkers; Dioxins; Environmental Pollutants; Environmental Pollution; Epigenesis, Genetic; Female; Humans; Male; Maternal Exposure; Maternal Inheritance; Paternal Inheritance; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 31212893
DOI: 10.3390/ijms20122947