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Objectives: Osteoarthritis (OA) is characterized by a high prevalence, poor prognosis, and a propensity to lead to disability. Despite the availability of standard therapies, they are associated with potential side effects and don't provide a complete cure for patients. Consequently, there is an urgent demand for the development of novel drugs. Method: The gene expression profiles (GSE64394, GSE178557 and GSE215039) of normal and OA chondrocytes samples were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by the ''LIMMA'' R package. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted using the R package clusterProfiler. A protein-protein (PPI) interaction network was performed to identify hub genes by using the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. Small molecule compounds linked to OA were predicted through the NetworkAnalyst platform. Finally, molecular docking was conducted using AutoDock and Pymol software. Results: We identified 98 DEGs primarily implicated in endochondral ossification, extracellular matrix degradation, and Wnt signaling pathways. 23 DEGs were closely associated with OA, and 10 hub genes were found to be potential drug targets for OA. Two new targeted compounds, tetrachlorodibenzodioxin (TCDD) and valproic acid (VPA), were screened. And they both exhibited strong binding affinity to their respective targets. Conclusions: Reducing exposure to TCDD could be a crucial strategy in preventing OA, and VPA has gained recognition as a novel drug candidate for OA treatment.

Copyright of Journal of Faculty of Pharmacy of Ankara University / Ankara Üniversitesi Eczacilik Fakültesi Dergisi is the property of Ankara University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The 2,3,7,8-tetrachlorodibenzodioxin (TCDD), a contaminant in Agent Orange released during the US–Vietnam War, led to a severe environmental crisis. Approximately, 50 years have passed since the end of this war, and vegetation has gradually recovered from the pollution. Soil bacterial communities were investigated by 16S metagenomics in habitats with different vegetation physiognomies in Central Vietnam, namely, forests (S0), barren land (S1), grassland (S2), and developing woods (S3). Vegetation complexity was negatively associated with TCDD concentrations, revealing the reasoning behind the utilization of vegetation physiognomy as an indicator for ecological succession along the gradient of pollutants. Stark changes in bacterial composition were detected between S0 and S1, with an increase in Firmicutes and a decrease in Acidobacteria and Bacteroidetes. Notably, dioxin digesters Arthrobacter, Rhodococcus, Comamonadaceae, and Bacialles were detected in highly contaminated soil (S1). Along the TCDD gradients, following the dioxin decay from S1 to S2, the abundance of Firmicutes and Actinobacteria decreased, while that of Acidobacteria increased; slight changes occurred at the phylum level from S2 to S3. Although metagenomics analyses disclosed a trend toward bacterial communities before contamination with vegetation recovery, non-metric multidimensional scaling analysis unveiled a new trajectory deviating from the native state. Recovery of the bacterial community may have been hindered, as indicated by lower bacterial diversity in S3 compared to S0 due to a significant loss of bacterial taxa and recruitment of fewer colonizers. The results indicate that dioxins significantly altered the soil microbiomes into a state of disorder with a deviating trajectory in restoration. [ABSTRACT FROM AUTHOR]

Copyright of Jornal of Biotechnology Research Center is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The Ah receptor (AhR)-responsive CALUX (chemically activated luciferase expression) cell bioassay is commonly used for rapid screening of samples for the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), dioxin-like compounds, and AhR agonists/antagonists. By increasing the number of AhR DNA recognition sites (dioxin responsive elements), we previously generated a novel third generation (G3) recombinant AhR-responsive mouse CALUX cell line (H1L7.5c3) with a significantly enhanced response to DLCs compared to existing AhR-CALUX cell bioassays. However, the elevated background luciferase activity of these cells and the absence of comparable G3 cell lines derived from other species have limited their utility for screening purposes. Here, we describe the development and characterization of species-specific G3 recombinant AhR-responsive CALUX cell lines (rat, human, and guinea pig) that exhibit significantly improved limit of detection and dramatically increased TCDD induction response. The low background luciferase activity, low minimal detection limit (0.1 pM TCDD) and enhanced induction response of the rat G3 cell line (H4L7.5c2) over the H1L7.5c3 mouse G3 cells, identifies them as a more optimal cell line for screening purposes. The utility of the new G3 CALUX cell lines were demonstrated by screening sediment extracts and a small chemical compound library for the presence of AhR agonists. The improved limit of detection and increased response of these new G3 CALUX cell lines will facilitate species-specific analysis of DLCs and AhR agonists in samples with low levels of contamination and/or in small sample volumes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis by increasing hepatic uptake of dietary and mobilized peripheral fats, inhibiting lipoprotein export, and repressing β-oxidation. In this study, the mechanism of β-oxidation inhibition was investigated by testing the hypothesis that TCDD dose-dependently repressed straight-chain fatty acid oxidation gene expression in mice following oral gavage every 4 days for 28 days. Untargeted metabolomic analysis revealed a dose-dependent decrease in hepatic acyl-CoA levels, while octenoyl-CoA and dicarboxylic acid levels increased. TCDD also dose-dependently repressed the hepatic gene expression associated with triacylglycerol and cholesterol ester hydrolysis, fatty acid binding proteins, fatty acid activation, and 3-ketoacyl-CoA thiolysis while inducing acyl-CoA hydrolysis. Moreover, octenoyl-CoA blocked the hydration of crotonyl-CoA suggesting short chain enoyl-CoA hydratase (ECHS1) activity was inhibited. Collectively, the integration of metabolomics and RNA-seq data suggested TCDD induced a futile cycle of fatty acid activation and acyl-CoA hydrolysis resulting in incomplete β-oxidation, and the accumulation octenoyl-CoA levels that inhibited the activity of short chain enoyl-CoA hydratase (ECHS1). [ABSTRACT FROM AUTHOR]

This study was conducted to determine the effect of α tocopherol (vitamin E) on the number of Leydig cells, levels of testosterone and malondialdehyde (MDA) and Superoxide Desmutase (SOD) activity in rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). A total of 50 rats were divided into 5 groups so that each group consisted of 10 rats. The negative control group (C-) without being given TCDD or α tocopherol, the positive control group (C+) was given TCDD at 700 ng/kgbw/day and without α tocopherol, treatment group 1 (T1) was given TCDD as much as 700 ng/kgbw/day and α tocopherol as much as 77 mg/kgbw/day, treatment group 2 (T2) was given TCDD as much as 700 ng/kgbw/day and α tocopherol as much as 140 mg/kgbw/day and treatment group 3 (T3) was given TCDD as much as 700 ng/kgbw/day and α tocopherol as much as 259 mg/kgbw/day. TCDD and α tocopherol were administered for 45 days. The results showed that giving α tocopherol maintained the number of Leydig cells: 19.14b±1.02 (C-), 12.72c±1.44 (C+), 15.04c±2.75 (T1), 17.89b±1.12 (T2), 18.96b±2.88 (T3); maintained testosterone levels: 37.61b±3.06 (C-), 137.84a ± 12.42 (C+), 30.64c ± 4.46 (T1), 35.48b ± 1.89 (T2), 40.92b ± 2.07 (T3); reduced MDA levels: 3.95b±0.74 (C-), 9.49a±1.78 (C+), 3.29c±0.34 (T1), 4.19b±0.55 (T2), 4.55b±0.23 (T3); and increased SOD activity: 71.08b±9.17 (C-), 32.64a±3.49 (C+), 56.23c±3.42 (T1), 66.04b±2.60 (T2), 68.21b ±6.51 (T3) which were significantly different (p<0.05) compared to the positive control group (C+). [ABSTRACT FROM AUTHOR]

In studies of hominin adaptations to fire use, the role of the aryl hydrocarbon receptor (AHR) in the evolution of detoxification has been highlighted, including statements that the modern human AHR confers a significantly better capacity to deal with toxic smoke components than the Neanderthal AHR. To evaluate this, we compared the AHR-controlled induction of cytochrome P4501A1 (CYP1A1) mRNA in HeLa human cervix epithelial adenocarcinoma cells transfected with an Altai-Neanderthal or a modern human reference AHR expression construct, and exposed to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). We compared the complete AHR mRNA sequences including the untranslated regions (UTRs), maintaining the original codon usage. We observe no significant difference in CYP1A1 induction by TCDD between Neanderthal and modern human AHR, whereas a 150–1,000 times difference was previously reported in a study of the AHR coding region optimized for mammalian codon usage and expressed in rat cells. Our study exemplifies that expression in a homologous cellular background is of major importance to determine (ancient) protein activity. The Neanderthal and modern human dose–response curves almost coincide, except for a slightly higher extrapolated maximum for the Neanderthal AHR, possibly caused by a 5′-UTR G-variant known from modern humans (rs7796976). Our results are strongly at odds with a major role of the modern human AHR in the evolution of hominin detoxification of smoke components and consistent with our previous study based on 18 relevant genes in addition to AHR , which concluded that efficient detoxification alleles are more dominant in ancient hominins, chimpanzees, and gorillas than in modern humans. [ABSTRACT FROM AUTHOR]

Objectives: Osteoarthritis (OA) is characterized by a high prevalence, poor prognosis, and a propensity to lead to disability. Despite the availability of standard therapies, they are associated with potential side effects and don't provide a complete cure for patients. Consequently, there is an urgent demand for the development of novel drugs., Method: The gene expression profiles (GSE64394, GSE178557 and GSE215039) of normal and OA chondrocytes samples were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by the "LIMMA" R package. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted using the R package clusterProfiler. A protein-protein (PPI) interaction network was performed to identify hub genes by using the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. Small molecule compounds linked to OA were predicted through the NetworkAnalyst platform. Finally, molecular docking was conducted using AutoDock and Pymol software., Results: We identified 98 DEGs primarily implicated in endochondral ossification, extracellular matrix degradation, and Wnt signaling pathways. 23 DEGs were closely associated with OA, and 10 hub genes were found to be potential drug targets for OA. Two new targeted compounds, tetrachlorodibenzodioxin (TCDD) and valproic acid (VPA), were screened. And they both exhibited strong binding affinity to their respective targets., Conclusions: Reducing exposure to TCDD could be a crucial strategy in preventing OA, and VPA has gained recognition as a novel drug candidate for OA treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (©2024PublishedbyElsevierB.V.)

Tetrachlorodibenzodioxin (TCDD) is one of the most famous dioxin families that is hazardous to humans and the environment. Designing cheap and novel catalysts for its detecting and removing is an essential need for the environment. In this work, DFT + VdW is used to investigate the potentiality of proposed catalysts in adsorbing and dissociating TCDD. P-type and N-type charge carrier effects on the adsorption process are modeled by doping of B/Al and N/P atoms in the graphene. Al-doped graphene, with − 1.27 eV adsorption energy, has the highest possibility to adsorb TCDD. P-type dopants have higher interactions with TCDD in comparing with N-type dopants. Introducing positive and negative charges on the studied complexes shows that in all complexes, the driving force of complexation is π-π stacking except for the Al-doped graphene. Dissociative adsorption studies show that unlike literature data, chlorine atoms on the surface of studied catalysts are not dissociated from TCDD, and instead, C–O bonds in TCDD are dissociated symmetrically and asymmetrically. Data show that Al-doped graphene is the best catalyst for symmetrical dissociation, and pure graphene is the best one for asymmetrical dissociation of TCDD. [ABSTRACT FROM AUTHOR]

Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant p-values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AHR) plays a major role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity phenotypes. TCDD bound to AHR elicits both genomic action in which target genes are transcriptionally upregulated and nongenomic action in which cytosolic phospholipase A2α (cPLA2α) is rapidly activated. However, how either of these actions, separately or in combination, induces toxicity phenotypes is largely unknown. In this study, we used AHRnls/nls mice as a model in which AHR was mutated to lack nuclear translocation sequence (NLS), and AHRd/− mice as the corresponding control. Using this model, we studied TCDD-induced alterations in cPLA2α activation and related factors because of the pivotal roles of cPLA2α both in AHR's nongenomic action and in regulation of causative genes of TCDD-induced hydronephrosis. Dams were orally administered TCDD at a dose of 300 µg/kg body weight on postnatal day 1, and pups subsequently exposed to TCDD via milk were examined for gene expression on PND 7 and for histological changes on PND 14. The activation of the AHR genomic action and hydronephrosis onset were observed in the control group but not in the AHRnls/nls group. An ex vivo experiment using peritoneal macrophages exposed to 100 nM TCDD resulted in rapid activation of cPLA2α, an indicator of the nongenomic action, only in the control group but not in the AHRnls/nls group. These results indicated that an NLS is required for the AHR's genomic and nongenomic actions. [ABSTRACT FROM AUTHOR]

Abstract Though increasing reports of deleterious impacts of dioxins and polychlorinated biphenyls (PCBs) on a variety of marine organisms have been described, their effects on the host defense capability of marine bivalve mollusks remain poorly understood. In the present study we used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a representative of dioxins and PCBs to investigate its impacts on the host defense capability of the blood clam, Tegillarca granosa. After exposure of clams to a range (0, 0.01, 0.1, 1, and 10 μg/L) of TCDD for 96 h, the total count, cell type composition, and phagocytic rate of haemocytes were analyzed. In addition, alkaline phosphatase (ALP) activity, cell viability, and the extent of DNA damage of haemocytes were also investigated. Our results showed that exposure to relatively high TCDD concentrations led to significant reductions in the total count and phagocytic activity of haemocytes, which could be accounted by aggravated DNA damage and reduced cell viability. In addition, the percentage of red granulocyte was significantly decreased whereas that of basophil granulocyte was significantly increased upon high doses TCDD exposure (effective concentrations are 1 μg/L and 10 μg/L for red and basophil granulocytes, respectively). Moreover, clams exposed to TCDD had a significant higher activity of ALP, may also indicate an enhanced ability to eliminate pathogens through direct dephosphorylation process whereas a suppressed inflammatory response through indirect regulating of downstream molecular cascade reaction. These findings suggest that TCDD may hamper the host defense capability and therefore render bivalve mollusks more vulnerable to pathogen infections. Highlights • TCDD exposure induced a reduction in total haemocytes counts and phagocytosis. • TCDD exposure caused significant reduction in cell viability whereas aggravation in DNA damage of haemocytes. • Clams exposed to TCDD had a significant higher activity of ALP. [ABSTRACT FROM AUTHOR]

Feed control is essential for the safety of animal-origin food. It is estimated that more than 80% of human exposure to dioxins and related compounds comes from the consumption of animal-origin food, and farm animals are exposed to dioxins mainly through the feed. A monitoring programme for dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)) and dioxin-like polychlorinated biphenyls (DL-PCBs) was conducted in the Polish feed market between 2004 and 2017. Using two complementary ISO 17025-accredited analytical methods (bioassay and high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS)), 2919 samples of plant, animal and minerals origin were analysed. The total number of samples exceeding the maximum limit (ML) was 52, which is 1.8% of all tested samples. They all contained PCDD/Fs in concentrations over the ML, and in 16 samples the limit for the sum of PCDD/F/DL-PCBs was also exceeded. The highest dioxins level was found in feedstuffs derived from Baltic fish; the fish oil was followed by fish meal. Low-chlorinated furans (2.3,7,8 TCDF, 2,3,4,7,8-PCDF and 1,2,3,7,8-PeCDF) were dominant and these congeners accounted for the toxicity expressed in WHO toxic equivalents (WHO-TEQ). In this category, 155 out of the 498 samples (32%) exceeded the action threshold (AT) for PCDD/Fs and in 10 samples (2.0%) for DL-PCBs. Non-compliant fish meals were found in 34 (5.6%) of the tested samples, in 0.7% of compound feeds, and in 1.5% of plant-origin materials. Seven dried plant-derived materials contained PCDD/F level above ML, including alfalfa, maize, apple, basil and beet pulp pellets containing molasses. The dry vegetable materials were mostly contaminated by the 2,3,7,8-furans, the congeners arising from a faulty drying process. No significant time trend can be seen. From the obtained results, it can be concluded that concentrations of PCDD/Fs and DL-PCBs in Polish feed materials were sufficiently low to ensure low concentrations in animal-derived products. [ABSTRACT FROM AUTHOR]

Interactions between regulatory pathways allow organisms to adapt to their environment and respond to stress. One interaction that has been recently identified occurs between the aryl hydrocarbon receptor (AHR) and the nuclear factor erythroid-2 related factor (NRF) family. Each transcription factor regulates numerous downstream genes involved in the cellular response to toxicants and oxidative stress; they are also implicated in normal developmental pathways. The zebrafish model was used to explore the role of AHR regulation of nrf genes during development and in response to toxicant exposure. To determine if AHR1b is responsible for transcriptional regulation of 6 nrf genes during development, a loss-of-function experiment using morpholino-modified oligonucleotides was conducted followed by a chromatin immunoprecipitation study at the beginning of the pharyngula period (24 h postfertilization). The expression of nrf1a was AHR1b dependent and its expression was directly regulated through specific XREs in its cis -promoter. However, nrf1a expression was not altered by exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a toxicant and prototypic AHR agonist. The expression of nrf1b, nrf2a, and nfe2 was induced by TCDD, and AHR1b directly regulated their expression by binding to cis -XRE promoter elements. Last, nrf2b and nrf3 were neither induced by TCDD nor regulated by AHR1b. These results show that AHR1b transcriptionally regulates nrf genes under toxicant modulation via binding to specific XREs. These data provide a better understanding of how combinatorial molecular signaling potentially protects embryos from embryotoxic events following toxicant exposure. [ABSTRACT FROM AUTHOR]

2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared with the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Abstract 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) is the most difficult to biodegradate and the most toxic dioxin congener. Previously, we demonstrated in silico the ability of pig CYP1A1 to hydroxylate 2,7-dichlorodibenzo- p -dioxin (DiCDD), but not TCDD. To increase our knowledge concerning the low effectiveness of TCDD biodegradability, we analyzed in silico the binding selectivity and affinity between pig CYP1B1 and the two dioxins by means of molecular modeling. We also compared the effects of TCDD and DiCDD on CYP1B1 gene expression (qRT-PCR) and catalytic (EROD) activity in porcine granulosa cells. It was found that DiCDD and TCDD were stabilized within the pig CYP1B1 active site by hydrophobic interactions. The analysis of substrate channel availability revealed that both dioxins opened the exit channel S, allowing metabolites to leave the enzyme active site. Moreover, DiCDD and TCDD increased the CYP1B1 gene expression and catalytic activity in porcine granulosa cells. On the other hand, TCDD demonstrated higher than DiCDD calculated affinity to pig CYP1B1, hindering TCDD exit from the active site. The great distance between CYP1B1's heme and TCDD also might contribute to the lower hydroxylation effectiveness of TCDD compared to that of DiCDD. Moreover, the narrow active site of pig CYP1B1 may immobilize TCDD molecule, inhibiting its hydroxylation. The results of the access channel analysis and the distance from pig CYP1B1's heme to TCDD suggest that the metabolizing potential of pig CYP1B1 is higher than that of pig CYP1A1. However, this potential is probably not sufficiently high to considerably improve the slow TCDD biodegradation. Graphical abstract Unlabelled Image Highlights • Two PCDDs differing in toxicity and ability to undergo degradation were studied. • DiCDD and TCDD increased the catalytic activity of pCYP1B1 in granulosa cells. • pCYP1B1 demonstrated a potential to metabolize dioxins. • Hydrophobic interactions stabilized both dioxins within the pCYP1B1 active site. • TCDD low biodegradability may result from its high affinity and distance to pCYP1B1. [ABSTRACT FROM AUTHOR]

Highlights • White-Rot Fungi are efficient degraders of organic pollutants such as organo-halogens. • Fungal Lignolytic enzymes, like laccase, break open aromatic ring structures. • White-Rot fungus FMD21 breaks down TCDD, the most toxic and stable dioxin congener. • Dioxins are persistent environmental pollutants which end up in agricultural biomass. • Fungal bioremediation of dioxins can help alleviate effects caused by these pollutants. Abstract Ligninolytic fungi contain a number of representative strains consisting of mainly white-rot fungi (WRF) that produce lignin-modifying enzymes (LME) such as laccases and manganese peroxidases. Lignin-modifying enzymes are multipurpose enzymes which have potential for application in various fields such as, for example, bioremediation and biomass conversion. Because of the non-specific nature of these enzymes, they are also capable of biodegradation and removal of xenobiotic pollutants. In this study we used a tiered screening process where we screened over 70 Vietnamese WRF fungal isolates for LME activity and subsequently for the ability to breakdown the dioxin TCDD. After the initial screening we selected four fungal strains, which belong to the order of Polyporales, which excreted high laccase enzyme levels. The most active fungus being isolate FMD21, a species of Rigidoporus , which was isolated from a forest in the South of Vietnam and which produced both laccase and manganese peroxidase. In the optimized PDSRb medium, FMD21 laccase levels reaced activities of 238800 U/L after 10 days while MnP activity showed the highest activity at day 4 of aproximately 40 U/L. 2,3,7,8-TCDD, which is the most toxic dioxin congener, is a persistent organic pollutant of which few organisms are known that break it down. After the final screening, FMD21 was the only fungus capable of degrading TCDD and was able to reach a breakdown percentage of 73% after 28 days culture with a start concentration of 0.5 pg TEQ/μL TCDD. Co-cultivation experiments of up to three fungi were performed to test for a synergistic breakdown effect of TCDD but such an effect was not observed. FMD21 is a fungus that shows a potential to be used as a bioremediation agent to clean up dioxin contamination in the environment. [ABSTRACT FROM AUTHOR]

A jaw lesion reported in mink exposed to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and TCDD‐like chemicals is considered a potential indicator of exposure to these chemicals. Many of the effects of TCDD‐like chemicals are induced through interaction with the aryl hydrocarbon receptor. The present study indicates that mink dosed with β‐naphthoflavone, which is an aryl hydrocarbon receptor ligand but not a TCDD‐like chemical, also develop the lesion. Environ Toxicol Chem 2019;38:460–463. © 2018 SETAC [ABSTRACT FROM AUTHOR]

Although epidemiologic studies have suggested a possible association between occupational exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the risk of development of multiple myeloma, definitive evidence in support of this association is lacking. In the present study, we employed the Vk*Myc mouse model of multiple myeloma to assess the impact of TCDD exposure on multiple myeloma pathogenesis. TCDD induced splenomegaly and multiple peripheral blood abnormalities, including anemia and high serum IgG levels. In addition, TCDD triggered bone lytic lesions, as well as renal tubular casts, a phenomenon associated with human myeloma kidney disease. Even in wild-type C57BL/6 mice, TCDD increased serum IgG levels, induced anemia, and increased plasma cell presence in the spleen and bone marrow, hallmarks of benign monoclonal gammopathy. Lastly, TCDD induced AKT activation and the DNA damage response, key pathogenic events in myeloma pathogenesis, in animal spleen and/or bone marrow. These data indicate that TCDD accelerates monoclonal gammopathy development and promotes progression to multiple myeloma in genetically-predisposed mice. This work offers the first direct experimental evidence establishing TCDD as an environmental risk factor for monoclonal gammopathy of undetermined significance and multiple myeloma. [ABSTRACT FROM AUTHOR]

Highlights • Gestational TCDD exposure altered prostate development in male rats. • Maternal resveratrol intake reduced disorders induced by TCDD on both early and late prostate development. • Resveratrol was able to prevent hiperplastic processes in the prostate of adults exposed to TCDD in utero. Abstract This study evaluated the protective effects of resveratrol on the prostate development of rats exposed to TCDD. Pregnant rats received TCDD (1 μg/kg) at GD15 and/or RES (20 mg/kg/day) from GD10 to PND21. Newborn and adult males from Control, TCDD, TCDD + RES and RES groups were euthanized and the prostate was excised. On PND1, there was a reduction in the number of prostatic buds, AR-positive mesenchymal cells and proliferation index in epithelial and mesenchymal cells in TCDD group, but restored by RES. AhR immunoreactivity was greater in TCDD group than the other groups. On PND90, there was higher frequency of functional hyperplasia in the distal area of the prostate acini in TCDD group, but restored by RES. AhRR expression was higher in the TCDD while NRF2 was higher in the TCDD + RES compared to the other groups. Resveratrol was able to reduce the adverse effects of TCDD on prostate development and its long-term repercussions. [ABSTRACT FROM AUTHOR]

Abstract Background Persistent organic pollutants (POPs) are known to accumulate in adipose tissues (AT). This storage may be beneficial by diverting POPs from other sensitive tissues or detrimental because of chronic release of pollutants as indirectly suggested during weight loss. The aim is to study the biological and/or toxic effects that chronic POP release from previously contaminated grafted AT could exert in a naïve mouse. Methods C57BL/6J male mice were exposed intraperitoneally to 2,3,7,8-tetrachlorodibenzo- p -doxin (TCDD); their epididymal fat pads were collected and grafted on the back skin of uncontaminated recipient mice whose brain, liver, and epididymal ATs were analyzed (TCDD concentration, relevant gene expression). Kinetics of release and redistribution were modeled using Physiologically Based PharmacoKinetics (PBPK). Results The grafts released TCDD over a period of 10 weeks with different kinetics of distribution in the three organs studied. A PBPK model was used to simulate the AT releasing process and the incorporation of TCDD into the major organs. At three weeks post-graft, we observed significant changes in gene expression in the liver and the host AT with signatures reminiscent of inflammation, gluconeogenesis and fibrosis as compared to the control. Conclusions This study confirms that AT-stored TCDD can be released and distributed to the organs of the recipient hence leading to distinct changes in gene expression. This original model provides direct evidence of the potential toxic-relevant effects when endogenous sources of contamination are present. Highlights • A new model to study the release and distribution of POPs • Introduction of a new PBPK model to study the effects of POPs • Internal release of TCDD activates signatures of inflammation & fibrosis. • Internal stores of POPs could play a significant role in long term toxicity. [ABSTRACT FROM AUTHOR]

Highlights • The Tg(cy p1 a-12DRE:EGFP) zebrafish has higher stability inducing EGFP expression (nearly to 100%) than other transgenic zebrafish lines. • The TCDD-induced EGFP expression was observed in the head cartilages, gut, eye, otic vesicle and pectoral fin bud of larvae. • The lowest observed effective concentration of TCDD was estimated to be about 1 ng/L. • The Tg(cy p1 a-12DRE:EGFP) zebrafish was capable to report risk of cranial malformation caused by toxic organic compounds. Abstract Dioxin-like compounds (DLCs) are extremely stable toxic organic compounds and can cause serious health risks. To develop a convenient biomonitoring tool for the detection of DLCs in the environment, we generated a transgenic line— Tg(cy p1 a-12DRE:EGFP) —with a zebrafish cy p1 a promoter recombined with multiple dioxin-responsive elements (DREs) that drive EGFP expression. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced EGFP expression was observed in the head cartilage (most sensitive), gut, otic vesicle, pectoral fin bud and eye of larvae. The lowest observed effect concentration of TCDD was estimated to be approximately 1 ng/L. Compared with existing zebrafish lines, our transgenic fish displayed comparable or even higher detection sensitivity to DLCs and could serve as an improved and rapid assay in an in vivo context. The Tg(cy p1 a-12DRE:EGFP) transgenic zebrafish line also had higher stability for inducing EGFP expression (nearly 100% of our zebrafish induced EGFP at approximately 1 ng/L TCDD) than other lines. In addition, Tg(cy p1 a-12DRE:EGFP) zebrafish could serve as a convenient and straightforward tool to assess potential cranial malformations and related health effects. [ABSTRACT FROM AUTHOR]

Abstract 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) is an endocrine disrupting chemical (EDC) with high persistency. Even a low amount can pass the placental barrier during gestational exposure. Exposure to TCDD exposure can impair the development of the nervous system in children, leading to impaired learning ability in later-life. But the changes in neurobehavioral developments in infancy and childhood caused by TCDD are unknown. Pregnant Sprague-Dawley rats were given a consecutive daily dose of TCDD (200 or 800 ng/day/kg) or an equivalent volume of vehicle by gavage on gestational days 8–14 (GD 8–14) as the prenatal TCDD exposure model. In the offspring, early neurobehavioral development was assessed at postnatal day 5 (PND5) and eye-opening was monitored from PND10 onwards. Adult male offspring was tested by Morris Water Maze for spatial memory and learning ability evaluation. Hippocampus Nissl's staining and astrocyte GFAP immunohistochemistry were used to evaluate the activity of astrocytes. The results of the behavioral tests showed that gestational TCDD exposure induced premature motor activity and earlier eyes-opening, but lead to serious deficits of spatial memory and learning ability in the adult male offspring. Morphology and number of neurons in the hippocampus CA1 region was not affected, while the activity of astrocytes in the same region was significantly reduced. These data indicate that perinatal TCDD exposure induced premature neurobehavioral development but impaired the spatial learning and memory in adult male rat offspring. The decreased activity of astrocytes in the hippocampus may play a role in these adverse effects. Graphical abstract Image 1 Highlights • Perinatal exposure to TCDD advanced sensory-motor development in the early life stages of F1 male rats. • Perinatal exposure to TCDD impairs the ability of spatial learning and memory in adulthood. • The activity of hippocampal astrocytes in the adult male offspring was inhibited after perinatal TCDD exposure. • The decreased activity of astrocyte may play a role in the impairment of the spatial learning and memory in adulthood. [ABSTRACT FROM AUTHOR]

Abstract Based on chemical fingerprinting and other lines of scientific evidence, a former pesticide manufacturing plant in Newark, New Jersey (U.S.A.) has been implicated in numerous journal articles as the major source of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in the sediments of the Lower Passaic River (LPR). Although the site has been extensively studied for over three decades, no previous study has identified a pathway capable of discharging an amount of 2,3,7,8-TCDD comparable to the mass estimates made for 2,3,7,8-TCDD in the sediments of the LPR and Newark Bay, or examined the timing of specific manufacturing processes at the site in relation to 2,3,7,8-TCDD concentrations in dated sediment cores. A reconstruction of the historical operations at this site was performed, supporting it as the major source of 2,3,7,8-TCDD to the LPR. A 2,4,5-trichlorophenol purification process, utilized prior to September 1954, was specifically identified as a significant source of 2,3,7,8-TCDD to the LPR. This purification process generated a dioxin-rich sludge that was discharged to the river prior to September 1954. Annual 2,4,5-trichlorophenol production, coupled with modeling to predict concentrations of 2,3,7,8-TCDD, indicate that 2,3,7,8-TCDD discharges to the LPR from this one process (20–80 kg) are consistent with mass estimates of 2,3,7,8-TCDD in the river (30–50 kg). 2,3,7,8-TCDD and cesium-137 data from nearby sediment cores support this purification process as a major pathway by which 2,3,7,8-TCDD entered the river. Graphical abstract Image 1 Highlights • 2,4,5-TCP operations at a former pesticide plant in Newark, NJ, were reviewed. • Waste sludge containing 2,3,7,8-TCDD was discharged to Lower Passaic River (LPR). • Estimated 2,3,7,8-TCDD mass discharge is similar to mass of 2,3,7,8-TCDD in the LPR. • 2,3,7,8-TCDD and Cs-137 sediment data support a major discharge pathway to the LPR. • The findings supported this plant as the major source of 2,3,7,8-TCDD to the LPR. [ABSTRACT FROM AUTHOR]

Abstract 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) is a toxic man-made chemical compound contaminating the environment. The exposure of living organisms to TCDD may result in numerous disorders, including reproductive pathologies. By employing two-dimensional fluorescence difference gel electrophoresis we aimed to identify proteins potentially involved in the mechanism of TCDD action and toxicity in porcine granulosa cells. The porcine granulosa cells were treated with TCDD (100 nM) for 3, 12 or 24 h, and afterwards, cytoplasmic proteins were isolated and labeled with cyanines. Next, samples were separated by isoelectric focusing and SDS-PAGE. Proteins of interest were identified by MALDI-TOF/TOF MS analysis. A total of 75 differentially expressed protein spots (p < 0.05 and fold change ≥2.0) were found in granulosa cells treated with TCDD. After 3, 12 and 24 h of TCDD treatment, we were able to identify 29, 34 and 12 spots, respectively. Functional analysis showed that cytoskeletal proteins formed the largest class of proteins significantly affected by TCDD in all time points. We also demonstrated that most of the identified proteins were associated with the "structural constituent of cytoskeleton" and "chaperone binding" Gene Ontology categories. Based on the analysis of the porcine granulosa cell proteome, we demonstrated that TCDD may affect the ovarian follicle fate by the rearrangement of the cytoskeleton and extracellular matrix as well as the modulation of proteins important for the cellular response to stress. The results of the current study present an extended insight into the TCDD mechanism of action in porcine granulosa cells, providing new directions for future functional studies. Highlights • TCDD effect on the porcine granulosa cell proteome was studied for the first time. • 75 proteins with altered abundance were identified after TCDD treatment. • TCDD affected cytoskeletal proteins and proteins involved in response to stress. [ABSTRACT FROM AUTHOR]

Bien Hoa airbase is located in Dong Nai Province (Southern Vietnam). Several sites within the airbase are highly contaminated by Agent Orange/Dioxin, and thus, they are also commonly named as an Agent Orange/Dioxin hotpot. In the present study, 36 maternal milk samples were collected from primiparas who have lived at least 5 years in four wards, Buu Long, Quang Vinh, Trung Dung and Tan Phong, which are closed to Bien Hoa airbase in order to investigate the level and distribution of Agent Orange/Dioxin exposure in different local communities. The mean concentrations of PCDD/PCDFs in four investigated wards range from 6.4 to 13.6 pgTEQ/g lipid. The highest mean TEQ of PCDD/PCDFs was observed in Buu Long ward (13.6 pgTEQ/g lipid), followed by Tan Phong ward (12.3 pgTEQ/g lipid), and the lowest value was observed in Trung Dung ward (6.4 pgTEQ/g lipid). The mean concentration of 2,3,7,8-TCDD in Buu Long (7.6 pg/g lipid) was approximately 2-6 times higher than those in Tan Phong (3.9 pg/g lipid), Quang Vinh (2.3 pg/g lipid), or Trung Dung (1.2 pg/g lipid). These results imply site-specific exposure to PCDD/PCDFs in different local communities living around Bien Hoa airbase. The mean values of daily intake of dioxin estimated for the breast fed infants living in Buu Long, Quang Vinh, Trung Dung and Tan Phong were about 80, 37.5, 31.7 and 58 pg TEQ/kg bw/day, respectively. [ABSTRACT FROM AUTHOR]

Abstract Trace metal ions such as cadmium (Cd2+) and trace organics typified by 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) are common co-contaminants in the environment and cause toxic effects in aquatic organisms that pose serious health risks. We studied the effects of Cd2+ on the regulation of cytochrome P450 1A1 (cyp1a1) gene-induction by TCDD using zebrafish embryos and larvae and adult zebrafish tissues. Our results showed that TCDD induced the cyp1a1 gene in all developmental stages and tissues of zebrafish, and the induction was higher in females than males. However, for the upstream genes (ahr2 and arnt2b) that mediate cyp1a1 gene induction in the zebrafish liver cell line was not induced by TCDD similar to the pattern of cyp1a1 in all investigated groups. After co-treatment with Cd2+, induction of the aryl hydrocarbon receptor pathway by TCDD was inhibited in the zebrafish larvae and the livers, intestines, kidneys and gills of adult zebrafish, but not in the embryos or brains of adult zebrafish, indicating that the toxicological effects of Cd2+ on TCDD are dependent on the developmental stages and tissue types. The present study confirms that Cd2+ blocks the TCDD-induced cyp1a1 gene in vivo but emphasizes that the effects are specific to the developmental stage, type of tissue and sex. The combined effects of Cd2+ and TCDD must be taken into consideration together with these parameters to accurately predict and assess cadmium and TCDD-induced toxicity in fish and carcinogenesis in animals in general. Graphical abstract Image 1 Highlights • Combined effects of Cd2+ and TCDD on zebrafish were studied in vivo. • Zebrafish embryo, larvae, and adults were investigated. • Inhibitory effects of Cd2+ on TCDD-induced genes in larvae and some adult organs. • Female fish are more sensitive than males to show cyp1a inductions. [ABSTRACT FROM AUTHOR]

For the first time, the levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were characterized in the tissues of wild small mammals living in contaminated sites near a municipal solid waste landfill (Moscow, Russia). The Ural field mice Sylvaemus uralensis, the bank voles Clethrionomys glareolus, and the common shrews Sorex araneus were trapped at 1- and 5-km distances from the landfield “Salariyevo.” High-resolution chromatography-mass spectrometry was used to measure the levels of 17 PCDD/Fs congeners in the animal organisms and natural objects (soils, bottom sediments). The values of the total toxic equivalencies (WHO-TEQ05) for animals were many times higher than those for soils and bottom sediments. The octo-substituted congeners dominated in the samples from the habitat, whereas the highly toxic 2,3,7,8-substituted ones — in the mammalian tissues. The levels of WHO-TEQ05 were comparable in the soil samples collected at 1- and 5-km distances from the dump body. The levels of WHO-TEQ05 in tissues of mammals caught 1 km from the dump were much higher than those of the distant territory inhabitants. The maximum WHO-TEQ05 levels were found in the shrews, and this has been considered in terms of nutrition characteristics. The data obtained will be used to assess the risks of chronic exposure to low doses of PCDD/Fs contaminating the environment near landfills. [ABSTRACT FROM AUTHOR]

Purpose Patients with Yusho, a condition caused by exposure to dioxins and dioxin-like compounds, have diverse mental and physical complaints. However, the relationship between dioxins and sleep disorders has not yet been examined. This cross-sectional study was designed to investigate problems associated with sleep among patients with Yusho. Methods A total of 140 participants (52.9% men, average age: 67.1 ± 12.2 years) were examined using questionnaires and medical interviews by an expert on sleep medicine. Demographic and clinical characteristics, including blood concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), which is the major cause of Yusho, were obtained from the results of recent surveys conducted by the Yusho Study Group. Results Moderate to severe symptoms of insomnia were present in 51.8% of the patients. The median Pittsburgh Sleep Quality Index global score (PSQI GS) was 8 (interquartile range: 5–11). The prevalence of restless legs syndrome/Willis–Ekbom disease (RLS/WED) was 30.7%; 24.3% of patients had severe RLS/WED (distressing symptoms with a frequency ≥ 1day per week). A higher blood concentration of 2,3,4,7,8-PeCDF (≥72.27 pg/g lipid) and severe RLS/WED were associated with higher odds of a PSQI GS ≥8, after adjusting for covariates (odds ratio [95% confidence interval]: 4.84 [1.10–21.25] and 4.15 [1.53–11.28], respectively). Conclusions Symptoms of insomnia were frequent, and the prevalence of RLS/WED was high in patients with Yusho. In addition to the presence of RLS/WED, a higher blood concentration of 2,3,4,7,8-PeCDF was associated with lower subjective sleep quality. [ABSTRACT FROM AUTHOR]

We have previously reported that a cell-free extract prepared from Geobacillus thermodenitrificans UZO 3 reductively cleaves diaryl ether bonds of 2,3,7,8-tetrachlorodibenzo- p -dioxin (2,3,7,8-TCDD), a dioxin with the highest toxicity, in a sequential fashion producing 3′,4′,4,5-tetrachloro-2-hydroxydiphenyl ether (TCDE) as the intermediate, and 3,4-dichlorophenol (DCP) as the final reaction product. The detection of TCDE implicated the discovery of an unprecedented dioxin-degrading enzyme that reductively cleaves the diaryl ether bonds. In this study, we report the cloning and sequencing of the dioxin reductive etherase gene dreE which codes for the 2,3,7,8-TCDD-degrading enzyme. We showed that dreE was expressed in Escherichia coli and that the product of the expression could reductively cleave diaryl ether bonds of 2,3,7,8-TCDD to produce TCDE. Furthermore, we established that the amino acid sequence encoded by dreE was homologous to an enzyme with yet unknown function that is encoded by a gene located in the riboflavin (vitamin B2) biosynthesis operon in Bacillus subtilis. We also showed that the amino acid sequence possesses a coenzyme A (CoA) binding site that is conserved in the N-acyltransferase superfamily. For the first time, the degradation of 2,3,7,8-TCDD at the molecular level using a enzyme of bacterial origin has been demonstrated. A novel mechanism model for the reductive cleavage of diaryl ether bond of 2,3,7,8-TCDD was also proposed. [ABSTRACT FROM AUTHOR]

Abstract The mediator of dioxin toxicity, aryl hydrocarbon receptor (AHR), has also important physiological functions. Selective AHR modulators (SAHRMs) share some effects of dioxins, except for their marked toxicity. We recently characterised toxicologically two novel SAHRMs, prodrugs IMA-08401 and IMA-07101 in rats, demonstrating that they are far less deleterious than the most toxic AHR-agonist, TCDD. Here, we analysed the in vitro toxicity and in silico AHR binding of the respective active, deacetylated metabolites, IMA-06201 (N-ethyl- N -phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-06504 (N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). In H4IIE rat hepatoma cells, IMA-06201 and IMA-06504 induced CYP1A1 with comparable potencies and efficacies to those of TCDD. They had little effect on cell viability as assessed by LDH leakage and MTT reduction assays, and were not mutagenic in the Ames test, but IMA-06504 elicited a maximally 2.7-fold increase in micronuclei. Molecular docking simulations showed that similar to TCDD, they occupy the central region of AHR ligand binding cavity. Hence, while showing low to negligible in vitro toxicity, these novel SAHRMs bind to the AHR qualitatively in a similar fashion to TCDD, and appear comparably powerful AHR agonists. Combined with our earlier results demonstrating that they seem considerably less toxic in vivo than TCDD, these compounds are thus highly interesting new SAHRMs. Highlights • IMA-06201 and IMA-06504 are selective AHR modulators. • As CYP1A1 inducers, they appear comparable to TCDD in potency and efficacy. • They also show low to negligible cytotoxicity and mutagenicity in vitro. • Based on in silico modelling, their binding to the AHR resembles that of TCDD. • Therefore, they have potential as drug compound candidates and research tools. [ABSTRACT FROM AUTHOR]

Dioxin is a highly toxic and caustic substance, which widely existed in the atmosphere, soil and water with tiny particles. Dioxin pollution has become a major problem that concerns the survival of mankind, which must be strictly controlled. The bond length, bond angle, energy, dipole moment, orbital energy level distribution of dioxin under the external field are investigated using DFT (density functional theory) on basis set level of B3LYP/6-31G (d, p). The results indicate that with the increase of the electric field, the length of one Carbon-Oxygen bond increases while another Carbon-Oxygen bond decreases. The energy gradually decreases with the electric field, while the change of the dipole moment has an opposite trend. In the infrared spectra, the vibration frequency decreases with the electric field increasing and shows an obvious red shift. Moreover, the ultraviolet-visible absorption spectra under different electric fields are analyzed with TD-DFT (time-dependent density functional theory) method. The wavelength of the strongest absorption peak increases and occurs red shift with the increase of the electric field. All the above results can provide reference for further research on the properties of dioxin under different external electric field. [ABSTRACT FROM AUTHOR]

The article discusses the bad effects of dioxin in the health of people exposed to it. Dioxin is used in the production of Agent Orange which was used by the U.S. forces in the program of defoliation and crop destruction in areas of major Viet Cong activity, during the war in South Vietnam. Some of the symptoms of dioxin poisoning are hands and feet numbness, depression, irritation, and difficulty in concentrating or remembering things. Dioxin is also believed to cause cancer, and deformities among the children of exposed men.

Analyses were conducted of reproductive outcomes for conceptions of participants of the Air Force Heath Study. Participants were male Air Force veterans of the Vietnam War. Conceptions were categorized into conceived before and after the start of the participant's Vietnam War service. Analyses accounted for correlation between outcomes for multiple conceptions for each participant. For each of three non-sparsely occurring outcomes, including not live born, miscarriage, and preterm, the probability of occurrence increased substantially when conceived after compared to before the start of Vietnam War service. These results support the conclusion of an adverse effect due to Vietnam War service on these reproductive outcomes. Data for conceptions after the start of Vietnam War service for participants with measured dioxin values were used to estimate dose-response curves for the effect of dioxin exposure on the occurrence of each of the three non-sparsely occurring outcomes. These curves were assumed to be constant up to a threshold and then monotonic after that threshold. For each of the three non-sparsely occurring outcomes, the estimated dose-response curves increased nonlinearly after associated thresholds. These results support the conclusion that the adverse effect due to conception after the start of Vietnam War service is attributable to high enough exposures to dioxin, a toxic contaminant of Agent Orange used for herbicide spraying in the Vietnam War. Sensitivity analyses supported the conclusion that dioxin results were not substantially affected by the assumption of monotonicity, decay due to elapsed time from exposure to measurement, and available covariates. • Vietnam service adversely affected reproductive outcomes for male veterans. • Adverse effects were attributable to increased dioxin exposures. • Results held for occurrence of not live born, miscarriage, and preterm conceptions. • Adverse effects for participants with measured dioxin likely hold more generally. • A variety of limitations may have affected these conclusions. [ABSTRACT FROM AUTHOR]

ABSTRACT PURPOSE: To determine the toxic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on reproductive system and the beneficial effects of Montelukast (ML) with histological and biochemical analysis. METHODS: Rats were randomly divided into four equal groups (control, TCDD, ML and TCDD+ML). Tissue samples were collected on day 60 and oxidative status and histological alterations were analyzed. RESULTS: The results showed a significant increase in oxidative and histological damage on uterine and ovarian tissues. Otherwise, the oxidative and histological damages caused by TCDD were prevented with ML treatment. CONCLUSION: The toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on female reproductive system were reversed with Montelukast treatment. Therefore, we claimed that ML treatment might be useful for TCDD toxicity.

We investigated changes in rat liver tissues following administration of thymoquinone (TQ) against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hepatotoxicity. Fifty rats were assigned randomly to five groups of 10 as follows: control, corn oil, TCDD, TQ and TCDD + TQ. Biochemical and histopathological analyses were conducted on liver tissue. We found that 30 day TCDD administration caused histopathological changes in liver including thickening of Glisson’s capsule, intracytoplasmic vacuolization in hepatocytes, sinusoidal dilation, vascular and sinusoidal congestion and inflammatory cell infiltration. TCDD administration increased malondialdehyde (MDA), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels in rat liver tissue and reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) levels compared to all other groups. In the TQ treated group, GSH, SOD, CAT and TAS levels increased compared to all other groups. MDA, TOS, ALT, AST, ALP levels decreased compared to all other groups. Our histological findings were consistent with the biochemical findings. The oxidative and histologic effects of TCDD were eliminated by TQ treatment. TCDD administration caused oxidative stress in rat liver and TQ administered with TCDD prevented TCDD induced hepatotoxicity. TQ could be considered an alternative anti-TCDD toxicity agent. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract TCDD-mediated toxicity of human individuals together with animal studies led to identification of the aryl hydrocarbon receptor (AHR). It was characterized as multifunctional ligand-activated transcription factor and environmental sensor. Comparison of human toxic responses and animal models provide hints to physiologic AHR functions including chemical and microbial defense, homeostasis of stem/progenitor cells and modulation of the immune system in barrier organs such as skin and the gastrointestinal tract. Extrapolation from animals to humans is difficult due to marked species differences and dependence of AHR function on the cellular context. Nevertheless, therapeutic possibilities of AHR agonists and antagonists are in development. The AHR remains challenging and fascinating. [ABSTRACT FROM AUTHOR]

The occurrence and human dietary exposure of 12 dioxin-like polychlorinated biphenyls (DL-PCBs) in 41 marine fish samples from Shandong Province of China were investigated. The DL-PCB congeners were extracted using automated Soxhlet extraction, purified via a composite column clean-up procedure and analysed by gas chromatography-triple quadrupole mass spectrometry. DL-PCB congeners were found in all analysed samples, with a mean concentration of 0.887 ng/g ww (wet weight). The TEQ concentrations of DL-PCBs in individual fish samples ranged from 0.011 to 9.214 pg WHO TEQ/g ww. The mean dietary intake for all fish species was 36.5 pg TEQ/kg bw/month, which was lower than the provisional tolerable monthly intake of 70 pg TEQ/kg bw/month set by the Joint FAO/WHO Expert Committee on Food Additives. To monitor the trend of DL-PCBs in fish for food safety control, it is necessary to maintain a surveillance programme. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD), the classic aryl hydrocarbon receptor (AhR) agonist, is a potent environmental toxicant and endocrine-disrupting chemical (EDC) with known developmental toxicity in humans, rodents, and fish. Early life exposure to some EDCs, including TCDD, is linked to the occurrence of adult-onset and multigenerational disease. Previous work exposing juvenile F0 zebrafish (Danio rerio) to 50 ppt (parts per trillion) TCDD during reproductive development has shown male-mediated transgenerational decreases in fertility (F0–F2) and histologic and transcriptomic alterations in F0 testes. Here, we analyzed male germline alterations in F1 and F2 adult fish, looking for changes in testicular histology and gene expression inherited through the male lineage that could account for decreased reproductive capacity. Testes of TCDD-lineage F1 fish displayed an increase in spermatogonia (immature germ cells) and decrease in spermatozoa (mature germ cells). No histological changes were present in F2 fish. Transcriptomic analysis of exposed F1 and F2 testes revealed alterations in lipid and glucose metabolism, oxidation, xenobiotic response, and sperm cell development and maintenance genes, all of which are implicated in fertility outcomes. Overall, we found that differential expression of reproductive genes and reduced capacity of sperm cells to mature could account for the reproductive defects previously seen in TCDD-exposed male zebrafish and their descendants, providing insight into the distinct multigenerational effects of toxicant exposure. [ABSTRACT FROM AUTHOR]

Dioxins are endocrine-disrupting chemicals, and their effects on reproductive functions are well-documented. The aim of the present study was to measure the levels of reproductive hormones in 42 men residing near a dioxin-contaminated area in Vietnam. We measured levels of 17 2,3,7,8-substituted congeners of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) and four non-ortho polychlorinated biphenyls (PCBs) in blood. Levels of follicle-stimulating hormone, luteinizing hormone, progesterone, prolactin, estradiol, and total testosterone were measured in serum. Blood dioxin levels were elevated; the levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin was 7.3 pg/g fat. Seven of the men had testosterone levels below 250 ng/dL, and nine men had prolactin levels above 9.7 ng/mL. Four PCDD congeners, two PCDF congeners, one PCB congener, and the sum TEQ of PCDDs, PCDDs/Fs, and PCDDs/Fs/PCBs were positively and significantly correlated with prolactin levels. Two PCDD congeners, six PCDF congeners, two PCB congeners, and the TEQs of PCDFs and PCBs were negatively and significantly correlated with testosterone levels. There were no significant correlations between dioxin congeners and follicle-stimulating hormone, luteinizing hormone, or progesterone levels. [ABSTRACT FROM AUTHOR]

Composite surface soil samples were collected at 0, 25, and 50 cm from the base of 12 utility poles on the Kenai National Wildlife Refuge in Alaska, to assess the extent to which pentachlorophenol, polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo furans may have leached from pentachlorophenol-treated poles. Six pairs of utility poles were included, consisting of an “old” pole manufactured in 1959 or 1963, a “new” pole manufactured within the past 20 years, and a suitable background soil sample from the same vicinity. Old poles had greater concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents (TEQs) near the pole base and at 25 cm than “new” poles did. For all 12 poles combined, the mean pentachlorophenol levels in soil were 1810, 157, and 17.8 ppm dry weight (d.w.) near the pole bases, at 25 and 50 cm from the poles, respectively, while the mean total TEQ levels in soil were 15,200, 5170, and 1510 parts per trillion d.w. at those distances. Surface soil levels of pentachlorophenol and TCDD-TEQs exceeded both human health and ecological risk-based screening levels. The design and results of this study were similar to another project in Montreal, Quebec in Canada. Together the results are cause for concern, indicating that millions of similarly treated utility poles in North America may be point sources of pentachlorophenol and dioxins/furans to soil. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a well-known environmental contaminant that exerts its toxicity through a variety of signaling mechanisms. The present study evaluated the effects of 27-deoxyactein, one of the major constituents isolated from Cimicifuga racemosa, on TCDD-induced toxicity in osteoblastic MC3T3-E1 cells. TCDD reduced cell survival, markedly increased apoptosis, and enhanced autophagy activity. However, pre-treatment with 27-deoxyactein attenuated all TCDD-induced effects and significantly decreased intracellular calcium (Ca2+) concentrations, the collapse of the mitochondrial membrane potential (MMP), the level of reactive oxygen species (ROS), and cardiolipin peroxidation compared to the TCDD-treated controls. Additionally, TCDD-induced increases in the levels of aryl hydrocarbon receptor (AhR), cytochrome P450 1A1 (CYP1A1), and extracellular signal-regulated kinase (ERK) were significantly inhibited by 27-deoxyactein. The mRNA levels of superoxide dismutase (SOD), ERK1, and nuclear factor kappa B (NF-κB) were also effectively restored by pre-treatment with 27-deoxyactein. Furthermore, 27-deoxyactein significantly increased the expressions of genes associated with osteoblast differentiation, including alkaline phosphatase (ALP), osteocalcin, bone sialoprotein (BSP), and osterix. Taken together, the present findings demonstrate the preventive effects of 27-deoxyactein on TCDD-induced damage in osteoblasts. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) agonists have been shown to regulate bone development and remodeling in a species-, ligand-, and age-specific manner, however the underlying mechanisms remain poorly understood. In this study, we characterized the effect of 0.01–30 μg/kg TCDD on the femoral morphology of male and female juvenile mice orally gavaged every 4 days for 28 days and used RNA-Seq to investigate gene expression changes associated with the resultant phenotype. Micro-computed tomography revealed that TCDD dose-dependently increased trabecular bone volume fraction (BVF) 2.9- and 3.3-fold in male and female femurs, respectively. Decreased serum tartrate-resistant acid phosphatase (TRAP) levels, combined with a reduced osteoclast surface to bone surface ratio and repression of femoral proteases (cathepsin K, matrix metallopeptidase 13), suggests that TCDD impaired bone resorption. Increased osteoblast counts at the trabecular bone surface were consistent with a reciprocal reduction in the number of bone marrow adipocytes, suggesting AhR activation may direct mesenchymal stem cell differentiation towards osteoblasts rather than adipocytes. Notably, femoral expression of transmembrane glycoprotein NMB ( Gpnmb ; osteoactivin), a positive regulator of osteoblast differentiation and mineralization, was dose-dependently induced up to 18.8-fold by TCDD. Moreover, increased serum levels of 1,25-dihydroxyvitamin D 3 were in accordance with the renal induction of 1α-hydroxylase Cyp27b1 and may contribute to impaired bone resorption. Collectively, the data suggest AhR activation tipped the bone remodeling balance towards bone formation, resulting in increased bone mass with reduced marrow adiposity. [ABSTRACT FROM AUTHOR]

Infectious agents are a significant risk factor for preterm birth (PTB); however, the simple presence of bacteria is not sufficient to induce PTB in most women. Human and animal data suggest that environmental toxicant exposures may act in concert with other risk factors to promote PTB. Supporting this “second hit” hypothesis, we previously demonstrated exposure of fetal mice (F1 animals) to the environmental endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to an increased risk of spontaneous and infection-mediated PTB in adult animals. Surprisingly, adult F1males also confer an enhanced risk of PTB to their control partners. Herein, we used a recently established model of ascending group B Streptococcus (GBS) infection to explore the impact of a maternal versus paternal developmental TCDD exposure on infection-mediated PTB in adulthood. Group B Streptococcus is an important contributor to PTB in women and can have serious adverse effects on their infants. Our studies revealed that although gestation length was reduced in control mating pairs exposed to low-dose GBS, dams were able to clear the infection and bacterial transmission to pups was minimal. In contrast, exposure of pregnant F1females to the same GBS inoculum resulted in 100% maternal and fetal mortality. Maternal health and gestation length were not impacted in control females mated to F1males and exposed to GBS; however, neonatal survival was reduced compared to controls. Our data revealed a sex-dependent impact of parental TCDD exposure on placental expression of Toll-like receptor 2 and glycogen production, which may be responsible for the differential impact on fetal and maternal outcomes in response to GBS infection. [ABSTRACT FROM AUTHOR]

Open combustion of solid waste is one of the main sources of the emission of dioxin and dioxin-like compounds (DLCs). Ambient dioxin will eventually undergo depositions on soils and tree leaves. Pine trees have shown an ability to store dioxin in their needles allowing biomonitoring of dioxin atmospheric concentrations. Infiltration can transport dioxin to greater depths into the ground, on one hand, while vaporization can allow dioxin to return back to the atmosphere on the other. Several studies evaluated the migration of dioxin between two compartments; however, few studies have attempted to understand the fate of non-conservative PCDDs and PCDFs in an unsteady state system of more than two mediums. This study focused on the transportation of dioxin between polluted trees and the underlying soil through the effect of rain water. For approximately 10 years, pine trees in this study have been exposed to emissions generated by the open combustion of municipal solid waste (MSW) from a fixed location. Soil samples located further from the point source had generally lower dioxin concentrations. Dioxin concentrations were correlated to distance from the source using least square regression. Soil samples below contaminated trees had dioxin concentrations 10-35% greater than the calculated measurements for the same spots using the regression model. By detecting these spikes in concentrations, it was possible to identify pools of dioxin found directly under the contaminated trees—indicating a rinsing effect of rain water on the stored dioxin on the trees’ needles. [ABSTRACT FROM AUTHOR]

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cleft palate formation in mice. This TCDD treatment, which may be considered an environmental factor in cleft palate formation, is associated with alterations in DNA methylation. However, the underlying molecular mechanisms of DNA methylation produced by TCDD in mouse embryos are poorly understood. DNA methyltransferases (DNMTs) and methyl‑CpG binding domain proteins (MBDs) are thought to be closely associated with the actions of DNA methylation. Therefore, the present study tested the hypothesis that this cleft palate inducing effect of TCDD will alter the expression levels of DNMTs and various MBDs in palate tissue of fetal mice. Pregnant C57BL/6J mice were treated with either TCDD (64 µg/kg) or corn oil (control) at embryonic day 10.5 (E10.5) and fetal palates were harvested for structural and molecular analyses at E13.5, E14.5, E15.5 and E17.5. Expression levels of DNMTs and MBDs were assayed using reverse transcription‑quantitative polymerase chain reaction and western blotting. The incidence of cleft palates in the TCDD group was 98.24%, whereas no cases of cleft palate were observed in the control group. Expression levels of DNMTs and MBDs were significantly increased in the TCDD group compared with the control. The results demonstrate clear alterations in DNMTs and MBDs, as induced by TCDD, and suggest that such alterations are important in cleft palate formation in fetal mice. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic agent and has disruptive effects on reproductive tissues in females. TCDD disrupts the hormonal regulation of the body and decreases the production of melatonin. In this study, we investigated the protective effects of melatonin supplements against the toxic effects of TCDD on ovaries of female rats. TCDD caused a significant decrease in the average number of corpora lutea and follicles per tissue section (2.1±0.7; 2.3±0.8, respectively), whereas these numbers were maintained in the melatonin supplemented group (5.0 ± 0.8; 5.1 ± 0.8, respectively) and were similar to the control group (5.3±1.0; 5.9±0.9, respectively). Electron microscopic analysis showed that the disruption of ultrastructure components such as cell membrane and organelles due to TCDD exposure was inhibited by melatonin supplements. This study suggested that melatonin has a protective and a possible ameliorative effect over histopathological damage of rat ovaries exposed to TCDD. [ABSTRACT FROM AUTHOR]