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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant and a potent aryl hydrocarbon receptor (AHR) ligand, causes delayed intestinal motility and affects the survival of enteric neurons. In this study, we investigated the specific signaling pathways and molecular targets involved in TCDD-induced enteric neurotoxicity. Immortalized fetal enteric neuronal (IM-FEN) cells treated with 10 nM TCDD exhibited cytotoxicity and caspase 3/7 activation, indicating apoptosis. Increased cleaved caspase-3 expression with TCDD treatment, as assessed by immunostaining in enteric neuronal cells isolated from WT mice but not in neural crest cell-specific Ahr deletion mutant mice (Wnt1Cre+/−/Ahrb(fl/fl)), emphasized the pivotal role of AHR in this process. Importantly, the apoptosis in IM-FEN cells treated with TCDD was mediated through a ceramide-dependent pathway, independent of endoplasmic reticulum stress, as evidenced by increased ceramide synthesis and the reversal of cytotoxic effects with myriocin, a potent inhibitor of ceramide biosynthesis. We identified Sptlc2 and Smpd2 as potential gene targets of AHR in ceramide regulation by a chromatin immunoprecipitation (ChIP) assay in IM-FEN cells. Additionally, TCDD downregulated phosphorylated Akt and phosphorylated Ser9-GSK-3β levels, implicating the PI3 kinase/AKT pathway in TCDD-induced neurotoxicity. Overall, this study provides important insights into the mechanisms underlying TCDD-induced enteric neurotoxicity and identifies potential targets for the development of therapeutic interventions. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy flavonoids, known for their anticancer properties, to interact with AHR, both in silico and in vitro, aiming to understand the mechanisms of action and identify selective AHR modulators. A PAS-B domain homology model was constructed to evaluate in silico interactions of chrysin, naringenin, quercetin apigenin and agathisflavone. The EROD activity assay measured the effects of flavonoids on AHR's activity in human breast cancer cells (MCF7). Simulations showed that chrysin, apigenin, naringenin, and quercetin have the highest AHR binding affinity scores (−13.14 to −15.31), while agathisflavone showed low scores (−0.57 and −5.14). All tested flavonoids had the potential to inhibit AHR activity in a dose-dependent manner in the presence of an agonist (TCDD) in vitro. This study elucidates the distinct modulatory effects of flavonoids on AHR, emphasizing naringenin's newly described antagonistic potential. It underscores the importance of understanding flavonoid's molecular mechanisms, which is crucial for developing novel cancer therapies based on these molecules. [ABSTRACT FROM AUTHOR]

Extensive research has been conducted to investigate the toxicological impact of dioxins on mammals, revealing profound effects on the female reproductive system in both humans and animals. Dioxin exposure significantly disrupts the intricate functions of the ovary, a pivotal organ responsible for reproductive and endocrine processes. This disruption manifests as infertility, premature ovarian failure, and disturbances in sex steroid hormone levels. Comprehensive studies, encompassing accidental human exposure and experimental animal data, have raised a wealth of information with consistent yet varied conclusion influenced by experimental factors. This review begins by providing an overarching background on the ovary, emphasizing its fundamental role in reproductive health, particularly in ovarian steroidogenesis and hormone receptor regulation. Subsequently, a detailed examination of the Aryl hydrocarbon Receptor (AhR) and its role in governing ovarian function is presented. The review then outlines the sources and toxicity of dioxins, with a specific focus on AhR involvement in mediating reproductive toxicity in mammals. Within this context, the impact of dioxins, notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on Folliculogenesis and Preimplantation embryos is discussed. Furthermore, the review delves into the disruptions of the female hormonal system caused by TCDD and their ramifications in endometriosis. Notably, variations in the effects of TCDD on the female reproductive and hormonal system are highlighted in relation to TCDD dose, animal species, and age. As a forward-looking perspective, questions arise regarding the potential involvement of molecular mechanisms beyond AhR in mediating the female reproductive toxicity of dioxins. [ABSTRACT FROM AUTHOR]

Parkin regulates protein degradation and mitophagy in dopaminergic neurons. Deficiencies in Parkin expression or function lead to cellular stress, cell degeneration, and the death of dopaminergic neurons, which promotes Parkinson's disease. In contrast, Parkin overexpression promotes neuronal survival. Therefore, the mechanisms of Parkin upregulation are crucial to understand. We describe here the molecular mechanism of AHR-mediated Parkin regulation in human SH-SY5Y neuroblastoma cells. Specifically, we report that the human Parkin gene (PRKN) is transcriptionally upregulated by the aryl hydrocarbon receptor (AHR) through two different selective ligand-dependent pathways. 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), a stress-inducing AHR ligand, indirectly promotes PRKN transcription by inducing ATF4 expression via TCDD-mediated endoplasmic reticulum (ER) stress. In contrast, kynurenine, a nontoxic AHR agonist, induces PRKN transcription by promoting AHR binding to the PRKN promoter without activating ER stress. Our results demonstrate that AHR activation may be a potential pharmacological pathway to induce human Parkin, but such a strategy must carefully consider the choice of AHR ligand to avoid neurotoxic side effects. [Display omitted] • AHR signaling upregulates human PRKN gene in SH-SY5Y neuroblastoma cells. • TCDD-mediated Parkin induction involves ER stress and AHR-dependent ATF4 induction. • Kynurenine-mediated Parkin induction involves the canonic-genomic AHR signaling. • Kynurenine and TCDD induce AHR-dependent Parkin expression by different pathways. [ABSTRACT FROM AUTHOR]

Dimethylmonothioarsinic acid (DMMTAV), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTAV is a minor metabolite in humans and animals, its substantial toxicity raises concerns about potential carcinogenic effects. This toxicity could be attributed to arsenicals' ability to regulate cytochrome P450 1 A (CYP1A) enzymes, pivotal in procarcinogen activation or detoxification. The current study investigates DMMTAV's impact on CYP1A1/2 expression, individually and in conjunction with its inducer, 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). C57BL/6 mice were intraperitoneally injected with 6 mg/kg DMMTAV, alone or with 15 μg/kg TCDD, for 6 and 24 h. Similarly, Hepa-1c1c7 cells were exposed to DMMTAV (0.5, 1, and 2 μM) with or without 1 nM TCDD for 6 and 24 h. DMMTAV hindered TCDD-induced elevation of Cyp1a1 mRNA, both in vivo (at 6 h) and in vitro, associated with reduced CYP1A regulatory element activation. Interestingly, in C57BL/6 mice, DMMTAV boosted TCDD-induced CYP1A1/2 protein and activity, unlike Hepa-1c1c7 cells where it suppressed both. DMMTAV co-exposure increased TCDD-induced Cyp1a2 mRNA. While Cyp1a1 mRNA stability remained unchanged, DMMTAV negatively affected protein stability, indicated by shortened half-life. Baseline levels of CYP1A1/2 mRNA, protein, and catalytic activities showed no significant alterations in DMMTAV-treated C57BL/6 mice and Hepa-1c1c7 cells. Taken together, these findings indicate, for the first time, that DMMTAV differentially modulates the TCDD-mediated induction of AHR-regulated enzymes in both liver of C57BL/6 mice and murine Hepa-1c1c7 cells suggesting that thio-arsenic pentavalent metabolites are extremely reactive and could play a role in the toxicity of arsenic. • DMMTAV differentially modulates the TCDD-inducible expression of CYP1A1/2 enzymes. • DMMTAV potentiates the TCDD-inducible expression of CYP1A1/2 in vivo. • DMMTAV inhibits the TCDD-inducible expression of CYP1A1/2 in vitro. • DMMTAV inhibits the AHR-dependent XRE-driven luciferase reporter activity in transfected Hepa-1c1c7 cells. • DMMTAV decreases the CYP1A1 protein half-life with no effect on the mRNA half-life in vitro. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase 2 (IDO2) is a tryptophan-catabolizing enzyme and a homolog of IDO1 with a distinct expression pattern compared with IDO1. In dendritic cells (DCs), IDO activity and the resulting changes in tryptophan level regulate T-cell differentiation and promote immune tolerance. Recent studies indicate that IDO2 exerts an additional, non-enzymatic function and pro-inflammatory activity, which may play an important role in diseases such as autoimmunity and cancer. Here, we investigated the impact of aryl hydrocarbon receptor (AhR) activation by endogenous compounds and environmental pollutants on the expression of IDO2. Treatment with AhR ligands induced IDO2 in MCF-7 wildtype cells but not in CRISPR-cas9 AhR-knockout MCF-7 cells. Promoter analysis with IDO2 reporter constructs revealed that the AhR-dependent induction of IDO2 involves a short-tandem repeat containing four core sequences of a xenobiotic response element (XRE) upstream of the start site of the human ido2 gene. The analysis of breast cancer datasets revealed that IDO2 expression increased in breast cancer compared with normal samples. Our findings suggest that the AhR-mediated expression of IDO2 in breast cancer could contribute to a pro-tumorigenic microenvironment in breast cancer.

Dynamic economical and industrial expansion lead to environmental contamination and pollution with increasing amounts of harmful agents. Recently, dioxins and dioxin-like compounds (DLCs) have received much attention due to their widespread occurrence, high levels of toxicity, and the significant threat these compounds pose to humans. In this study, we investigated renal toxicity of 2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD) and explained the role of pumpkin seed oil in modulating TCDD toxicity in the kidney of Wister albino rats. Thirty male and female Wister rats were divided into three isolated groups ten animal each. Group 1 (G1) served as normal control, group 2 (G2), rats were received single intraperitoneal dose of TCDD (2μg/kg b.w. dissolved in corn oil), while group 3 (G3), rats were treated with oral pumpkin seed oil (PO) (1.5 ml/kg b.w. day after day) after TCDD treatment (same as group II). Blood samples were collected for biochemical analysis and kidney tissue samples for histological examination. our investigation revealed that, TCDD induced significant increase (P

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) stands as one of the most potent halogenated polycyclic hydrocarbons, known to inflict substantial cytotoxic effects on both animal and human tissues. Its widespread presence and recalcitrance make it an environmental and health concern. Efforts are being intensively channeled to uncover strategies that could mitigate the adverse health outcomes associated with TCDD exposure. In the realm of counteractive agents, boron compounds are emerging as potential candidates. These compounds, which have found applications in a spectrum of industries ranging from agriculture to pharmaceutical and cosmetic manufacturing, are known to modulate several cellular processes and enzymatic pathways. However, the dose–response relationships and protective potentials of commercially prevalent boron compounds, such as boric acid (BA), ulexite (UX), and borax (BX), have not been comprehensively studied. In our detailed investigation, when peripheral blood mononuclear cells (PBMCs) were subjected to TCDD exposure, they manifested significant cellular disruptions. This was evidenced by compromised membrane integrity, a marked reduction in antioxidant defense mechanisms, and a surge in the malondialdehyde (MDA) levels, a recognized marker for oxidative stress. On the genomic front, increased 8-OH-dG levels and chromosomal aberration (CA) frequency suggested that TCDD had the potential to cause DNA damage. Notably, our experiments have revealed that boron compounds could act as protective agents against these disruptions. They exhibited a pronounced ability to diminish the cytotoxic, genotoxic, and oxidative stress outcomes instigated by TCDD. Thus, our findings shed light on the promising role of boron compounds. In specific dosages, they may not only counteract the detrimental effects of TCDD but also serve as potential chemopreventive agents, safeguarding the cellular and genomic integrity of PBMCs. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals (EDCs) might contribute to the increase in female-specific cancers in Western countries. 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) is considered the "prototypical toxicant" to study EDCs' effects on reproductive health. Epigenetic regulation by small noncoding RNAs (sncRNAs), such as microRNAs (miRNA), is crucial for controlling cancer development. The aim of this study was to analyze transcriptional activity and sncRNA expression changes in the KGN cell line after acute (3 h) and chronic (72 h) exposure to 10 nM TCDD in order to determine whether sncRNAs' deregulation may contribute to transmitting TCDD effects to the subsequent cell generations (day 9 and day 14 after chronic exposure). Using Affymetrix GeneChip miRNA 4.0 arrays, 109 sncRNAs were found to be differentially expressed (fold change < −2 or >2; p-value < 0.05) between cells exposed or not (control) to TCDD for 3 h and 72 h and on day 9 and day 14 after chronic exposure. Ingenuity Pathway Analysis predicted that following the acute and chronic exposure of KGN cells, sncRNAs linked to cellular development, growth and proliferation were downregulated, and those linked to cancer promotion were upregulated on day 9 and day 14. These results indicated that TCDD-induced sncRNA dysregulation may have transgenerational cancer-promoting effects. [ABSTRACT FROM AUTHOR]

Extensive research has been conducted to investigate the toxicological impact of dioxins on mammals, revealing profound effects on the female reproductive system in both humans and animals. Dioxin exposure significantly disrupts the intricate functions of the ovary, a pivotal organ responsible for reproductive and endocrine processes. This disruption manifests as infertility, premature ovarian failure, and disturbances in sex steroid hormone levels. Comprehensive studies, encompassing accidental human exposure and experimental animal data, have raised a wealth of information with consistent yet varied conclusion influenced by experimental factors. This review begins by providing an overarching background on the ovary, emphasizing its fundamental role in reproductive health, particularly in ovarian steroidogenesis and hormone receptor regulation. Subsequently, a detailed examination of the Aryl hydrocarbon Receptor (AhR) and its role in governing ovarian function is presented. The review then outlines the sources and toxicity of dioxins, with a specific focus on AhR involvement in mediating reproductive toxicity in mammals. Within this context, the impact of dioxins, notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on Folliculogenesis and Preimplantation embryos is discussed. Furthermore, the review delves into the disruptions of the female hormonal system caused by TCDD and their ramifications in endometriosis. Notably, variations in the effects of TCDD on the female reproductive and hormonal system are highlighted in relation to TCDD dose, animal species, and age. As a forward-looking perspective, questions arise regarding the potential involvement of molecular mechanisms beyond AhR in mediating the female reproductive toxicity of dioxins.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant and a potent aryl hydrocarbon receptor (AHR) ligand, causes delayed intestinal motility and affects the survival of enteric neurons. In this study, we investigated the specific signaling pathways and molecular targets involved in TCDD-induced enteric neurotoxicity. Immortalized fetal enteric neuronal (IM-FEN) cells treated with 10 nM TCDD exhibited cytotoxicity and caspase 3/7 activation, indicating apoptosis. Increased cleaved caspase-3 expression with TCDD treatment, as assessed by immunostaining in enteric neuronal cells isolated from WT mice but not in neural crest cell-specific Ahr deletion mutant mice (Wnt1Cre+/−/Ahrb(fl/fl)), emphasized the pivotal role of AHR in this process. Importantly, the apoptosis in IM-FEN cells treated with TCDD was mediated through a ceramide-dependent pathway, independent of endoplasmic reticulum stress, as evidenced by increased ceramide synthesis and the reversal of cytotoxic effects with myriocin, a potent inhibitor of ceramide biosynthesis. We identified Sptlc2 and Smpd2 as potential gene targets of AHR in ceramide regulation by a chromatin immunoprecipitation (ChIP) assay in IM-FEN cells. Additionally, TCDD downregulated phosphorylated Akt and phosphorylated Ser9-GSK-3β levels, implicating the PI3 kinase/AKT pathway in TCDD-induced neurotoxicity. Overall, this study provides important insights into the mechanisms underlying TCDD-induced enteric neurotoxicity and identifies potential targets for the development of therapeutic interventions.

The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy flavonoids, known for their anticancer properties, to interact with AHR, both in silico and in vitro, aiming to understand the mechanisms of action and identify selective AHR modulators. A PAS-B domain homology model was constructed to evaluate in silico interactions of chrysin, naringenin, quercetin apigenin and agathisflavone. The EROD activity assay measured the effects of flavonoids on AHR’s activity in human breast cancer cells (MCF7). Simulations showed that chrysin, apigenin, naringenin, and quercetin have the highest AHR binding affinity scores (−13.14 to −15.31), while agathisflavone showed low scores (−0.57 and −5.14). All tested flavonoids had the potential to inhibit AHR activity in a dose-dependent manner in the presence of an agonist (TCDD) in vitro. This study elucidates the distinct modulatory effects of flavonoids on AHR, emphasizing naringenin’s newly described antagonistic potential. It underscores the importance of understanding flavonoid’s molecular mechanisms, which is crucial for developing novel cancer therapies based on these molecules.

Previously, we showed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) ligand and a potent and persistent toxicant and carcinogenic agent, induces high levels of murine myeloid-derived suppressor cell (MDSC) when injected into mice. In the current study, we demonstrate that Resveratrol (3,4,5-trihydroxy-trans-stilbene; RSV), an AhR antagonist, reduces TCDD-mediated MDSC induction. RSV decreased the number of MDSCs induced by TCDD in mice but also mitigated the immunosuppressive function of TCDD-induced MDSCs. TCDD caused a decrease in F4/80+ macrophages and an increase in CD11C+ dendritic cells, while RSV reversed these effects. TCDD caused upregulation in CXCR2, a critical molecule involved in TCDD-mediated induction of MDSCs, and Arginase-1 (ARG-1), involved in the immunosuppressive functions of MDSCs, while RSV reversed this effect. Transcriptome analysis of Gr1+ MDSCs showed an increased gene expression profile involved in the metabolic pathways in mice exposed to TCDD while RSV-treated mice showed a decrease in such pathways. The bio-energetic profile of these cells showed that RSV treatment decreased the energetic demands induced by TCDD. Overall, the data demonstrated that RSV decreased TCDD-induced MDSC induction and function by altering the dynamics of various myeloid cell populations involving their numbers, phenotype, and immunosuppressive potency. Because MDSCs play a critical role in tumor growth and metastasis, our studies also support the potential use of RSV to attenuate the immunosuppressive properties of MDSC. [ABSTRACT FROM AUTHOR]

The toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is generally believed to be mediated by aryl hydrocarbon receptor (AhR), but some evidence suggests that the effects of TCDD can also be produced through AhR-independent mechanisms. In previous experiments, we found that mainly AhR-dependent mechanism was involved in the migration inhibition of glioblastoma U87 cells by TCDD. Due to the heterogeneity of glioblastomas, not all tumor cells have significant AhR expression. The effects and mechanisms of TCDD on the migration of glioblastomas with low AhR expression are still unclear. We employed a glioblastoma cell line A172 with low AhR expression as a model, using wound healing and Transwell® assay to detect the effect of TCDD on cell migration. We found that TCDD can inhibit the migration of A172 cells without activating AhR signaling pathway. Further, after being pre-treated with AhR antagonist CH223191, the inhibition of TCDD on A172 cells migration was not changed, indicating that the effect of TCDD on A172 cells is not dependent on AhR activation. By transcriptome sequencing analysis, we propose dysregulation of the expression of certain migration-related genes, such as IL6, IL1B, CXCL8, FOS, SYK, and PTGS2 involved in cytokines, MAPK, NF-κB, and IL-17 signaling pathways, as potential AhR-independent mechanisms that mediate the inhibition of TCDD migration in A172 cells.

الديوكسينات هي مجموعة من الملوثات العضوية واسعة الانتشار بيئياً، ذات أثرٍ ضارٍ على العديد من الكائنات الحية، ويعدُ مركب رباعي كلورو ثنائي بنزو بارا ديوكسين 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)، المركب الأكثر أهمية من مجموعة الديوكسينات كونه شديد السُميّة، وذو معامل مكافئ سُمي يعادل 1.0. لذا يمكن أن يؤثر على خصوبة إناث الثدييات من خلال احداثه لتغيرات على مستوى التوازن الهرموني الدقيق المطلوب لحدوث الإباضة، والتي تؤثر على الصحة الإنجابية عند النساء، وهنا تبرز أهمية معرفة مدى قدرة هذا المركب على تغيير التعبير المورثي للعديد من المورثات المسؤولة عن نقل واستقلاب الكولسترول الضروري لتركيب الهرمونات الجنسية. حيث يؤدي أنزيم P450scc (CYP11A1) الدور الرئيس في تحويل الكولسترول إلى هرمون البريغنينولون pregnenolone، والموجود في الخلايا الغمدية للمبيض وقشرة الغدة الكظرية. هدفت الدراسة إلى تحري الأثر السمي لمركب TCDD على خلايا المبيض والغدة الكظرية، باستكشاف التأثيرات المُعتمدة على كمية جرعة TCDD، من خلال التغير النسبي في التعبير المورثي عن المورثة CYP11A1 المرمزة لأنزيم P450scc ضمن الأعضاء المذكورة وذلك باستعمال تقانة التفاعل السلسلي للبوليميراز الكمي في الزمن الحقيقي RT-qPCR. حيث قمنا في هذه الدراسة بتجريع إناث فئران بالغة من السلالة BALB/c بجرعة واحدة فموياً وهي بعمر 10 أسابيع بتركيزين مختلفين، 25 و50 ميكروغرام/كيلوغرام من مركب TCDD، مقارنةً بمجموعة الشاهد. بيَّنت النتائج وجود فروقات في التعبير المورثي للعينات المدروسة وذلك تِبعاً لاختلاف نوع العضو وكمية الجرعة المعطاة، ففي المبيض وجدنا انخفاضاً في التعبير عن المورثة CYP11A1، في جميع المجموعات المُعاملة مقارنةً بمجموعة الشاهد، حيث لوحظ انخفاضاً في التعبير المورثي في الجرعة المنخفضة 25 ميكروغرام/كيلوغرام بشكل أكبر عن الجرعة المرتفعة50 ميكروغرام/كيلوغرام. وعلى خلاف ذلك أظهرت نتائجنا بالنسبة للغدة الكظرية، ارتفاعاً في التعبير عن المورثة CYP11A1، في جميع المجموعات المُعاملة مقارنةً بمجموعة الشاهد، حيث وجدنا زيادة في التعبير المورثي في الجرعة المرتفعة 50 ميكروغرام/كيلوغرام بشكل أكبر عنه في الجرعة المنخفضة 25 ميكروغرام/كيلوغرام. توصلت نتائج دراستنا إلى أن لمركب TCDD قدرة على تغيير التعبير المورثي للمورثة CYP11A1 في المبيض والغدة الكظرية وبشكل معتمد على الجرعة، وبالتالي إمكانية تغير مستويات الأنزيمات الصانعة للستيروئيدات، وما لذلك من أثر على اصطناع الهرمونات الستيروئيدية، الأمر الذي يمكن أن يؤدي في النهاية إلى اضطرابات في الخصوبة عند إناث الفئران.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant found widely across the world. While animal and human studies have shown that exposure to TCDD may cause significant alterations in the reproductive tract, the effect of TCDD on the expression of miRNA in the reproductive organs has not been previously tested. In the current study, we exposed adult female or male mice to TCDD or vehicle and bred them to study the impact on reproduction. The data showed that while TCDD treatment of females caused no significant change in litter size, it did alter the survival of the pups. Also, TCDD exposure of either the male or female mice led to an increase in the gestational period. While TCDD did not alter the gross morphology of the ovaries and testes, it induced significant alterations in the miRNA expression. The ovaries showed the differential expression of 426 miRNAs, of which 315 miRNAs were upregulated and 111 miRNA that were downregulated after TCDD exposure when compared to the vehicle controls. In the testes, TCDD caused the differential expression of 433 miRNAs, with 247 miRNAs upregulated and 186 miRNAs downregulated. Pathway analysis showed that several of these dysregulated miRNAs targeted reproductive functions. The current study suggests that the reproductive toxicity of TCDD may result from alterations in the miRNA expression in the reproductive organs. Because miRNAs also represent one of the epigenetic pathways of gene expression, our studies suggest that the transgenerational toxicity of TCDD may also result from dysregulation in the miRNAs.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) stands as one of the most potent halogenated polycyclic hydrocarbons, known to inflict substantial cytotoxic effects on both animal and human tissues. Its widespread presence and recalcitrance make it an environmental and health concern. Efforts are being intensively channeled to uncover strategies that could mitigate the adverse health outcomes associated with TCDD exposure. In the realm of counteractive agents, boron compounds are emerging as potential candidates. These compounds, which have found applications in a spectrum of industries ranging from agriculture to pharmaceutical and cosmetic manufacturing, are known to modulate several cellular processes and enzymatic pathways. However, the dose–response relationships and protective potentials of commercially prevalent boron compounds, such as boric acid (BA), ulexite (UX), and borax (BX), have not been comprehensively studied. In our detailed investigation, when peripheral blood mononuclear cells (PBMCs) were subjected to TCDD exposure, they manifested significant cellular disruptions. This was evidenced by compromised membrane integrity, a marked reduction in antioxidant defense mechanisms, and a surge in the malondialdehyde (MDA) levels, a recognized marker for oxidative stress. On the genomic front, increased 8-OH-dG levels and chromosomal aberration (CA) frequency suggested that TCDD had the potential to cause DNA damage. Notably, our experiments have revealed that boron compounds could act as protective agents against these disruptions. They exhibited a pronounced ability to diminish the cytotoxic, genotoxic, and oxidative stress outcomes instigated by TCDD. Thus, our findings shed light on the promising role of boron compounds. In specific dosages, they may not only counteract the detrimental effects of TCDD but also serve as potential chemopreventive agents, safeguarding the cellular and genomic integrity of PBMCs.

Endocrine-disrupting chemicals (EDCs) might contribute to the increase in female-specific cancers in Western countries. 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) is considered the “prototypical toxicant” to study EDCs’ effects on reproductive health. Epigenetic regulation by small noncoding RNAs (sncRNAs), such as microRNAs (miRNA), is crucial for controlling cancer development. The aim of this study was to analyze transcriptional activity and sncRNA expression changes in the KGN cell line after acute (3 h) and chronic (72 h) exposure to 10 nM TCDD in order to determine whether sncRNAs’ deregulation may contribute to transmitting TCDD effects to the subsequent cell generations (day 9 and day 14 after chronic exposure). Using Affymetrix GeneChip miRNA 4.0 arrays, 109 sncRNAs were found to be differentially expressed (fold change < −2 or >2; p-value < 0.05) between cells exposed or not (control) to TCDD for 3 h and 72 h and on day 9 and day 14 after chronic exposure. Ingenuity Pathway Analysis predicted that following the acute and chronic exposure of KGN cells, sncRNAs linked to cellular development, growth and proliferation were downregulated, and those linked to cancer promotion were upregulated on day 9 and day 14. These results indicated that TCDD-induced sncRNA dysregulation may have transgenerational cancer-promoting effects.

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This study provides the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in blood profile and pathological changes of liver albino in male rats, the aims of present study were detected the influence of TCDD in the male rats, the present study was include (118 albino male rats) divided into three groups, their age ranged from 8-9 week, the LD50 of TCDD (70.7 μg /kg) and the period of this study 90 days. The hematological examination showed increased in WBCs while decreased in RBCs, Hb., platelets in 2nd & 3rd group, the pathological examination revealed in 2nd & 3rd group in liver enlargement and pale in color, the histopathological changes in liver showed extensive necrosis, cirrhosis, dilation in sinusoid, increased cellularity, granulomatous reaction and sever infiltration of inflammatory cells, acute cellular swelling with mild sinusoid and infiltration of neutrophils, moderate infiltration of inflammatory cells, sinusoid dilation with extensive hemorrhage, fibroblast cells aggregation with midzone areas of necrosis. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor, classically associated with the regulation of xenobiotic metabolism in response to environmental toxins. In recent years, transgenic rodent models have implicated AhR in aging and longevity. Moreover, several AhR ligands, such as resveratrol and quercetin, are compounds proven to extend the lifespan of model organisms. In this paper, we first review AhR biology with a focus on aging and highlight several AhR ligands with potential anti-aging properties. We outline how AhR-driven expression of xenobiotic metabolism genes into old age may be a key mechanism through which moderate induction of AhR elicits positive benefits on longevity and healthspan. Furthermore, via integration of publicly available datasets, we show that liver-specific AhR target genes are enriched among genes subject to epigenetic aging. Changes to epigenetic states can profoundly affect transcription factor binding and are a hallmark of the aging process. We suggest that the interplay between AhR and epigenetic aging should be the subject of future research and outline several key gaps in the current literature. Finally, we recommend that a broad range of non-toxic AhR ligands should be investigated for their potential to promote healthspan and longevity. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxicological effects of an AhR lacking the entire PASB structurally diverse chemicals, including halogenated aromatic hydrocarbons. Ligand-dependent transformation of the AhR into its DNA binding form involves a ligand-dependent conformational change, heat shock protein 90 (hsp90), dissociation from the AhR complex and AhR dimerization with the AhR nuclear translocator (ARNT) protein. The mechanism of AhR transformation was examined using mutational approaches and stabilization of the AhR:hsp90 complex with sodium molybdate. Insertion of a single mutation (F281A) in the hsp90-binding region of the AhR resulted in its constitutive (ligand-independent) transformation/DNA binding in vitro. Mutations of AhR residues within the Arg-Cys-rich region (R212A, R217A, R219A) and Asp371 (D371A) impaired AhR transformation without a significant effect on ligand binding. Stabilization of AhR:hsp90 binding with sodium molybdate decreased transformation/DNA binding of the wild type AhR but had no effect on constitutively active AhR mutants. Interestingly, transformation of the AhR in the presence of molybdate allowed detection of an intermediate transformation ternary complex containing hsp90, AhR, and ARNT. These results are consistent with a stepwise transformation mechanism in which binding of ARNT to the liganded AhR:hsp90 complex results in a progressive displacement of hsp90 and conversion of the AhR into its high affinity DNA binding form. The available molecular insights into the signaling mechanism of other Per-ARNT-Sim (PAS) domains and structural information on hsp90 association with other client proteins are consistent with the proposed transformation mechanism of the AhR.

BackgroundIn animal studies, perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters thyroid homoeostasis and thyroid hormone concentrations; epidemiologic evidence is limited.ObjectivesWe aimed to determine the association of prenatal exposure to TCDD with thyroid hormone concentrations in the Seveso Second Generation Study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 chemical factory explosion in Seveso, Italy.MethodsWe included 570 children (288 female, 282 male) with complete follow-up data, including a fasting blood draw. Serum levels of total and free thyroxine (T4), free triiodothyronine (T3), and thyroid stimulating hormone (TSH) were measured using immunoassays. We defined prenatal TCDD exposure as: 1) maternal initial TCDD concentration measured in serum collected soon after the explosion and 2) maternal TCDD estimated at pregnancy.ResultsCompared to the lowest quartile (Q1), maternal initial serum TCDD was associated with lower free T3 (Q2: adj-β = -0.13, 95%CI -0.26, 0.00; Q3: adj-β = -0.22, 95%CI -0.35, -0.09; Q4: adj-β = -0.14, 95%CI -0.28, 0.00; p-trend = 0.02). In participants with high thyroid antibody status, inverse associations between maternal initial serum TCDD and free T3 were significantly stronger than in participants with normal antibody status (p-interaction = 0.02). We also observed a positive association between maternal initial serum TCDD and TSH concentrations in participants with high thyroid antibody status (Q2: adj-β = 11.4%, 95%CI -25.2, 66.1; Q3: adj-β = 49.0%, 95%CI 3.0, 115.5; Q4: adj-β = 105.5, 95%CI 36.6, 209.2; p-trend

There is strong evidence that exposure to fine particulate matter (PM2.5) and a high-fat diet (HFD) increase the risk of mortality from atherosclerotic cardiovascular diseases. Recent studies indicate that PM2.5 generated by combustion activates the Aryl Hydrocarbon Receptor (AHR) and inflammatory cytokines contributing to PM2.5-mediated atherogenesis. Here we investigate the effects of components of a HFD on PM-mediated activation of AHR in macrophages. Cells were treated with components of a HFD and AHR-activating PM and the expression of biomarkers of vascular inflammation was analyzed. The results show that glucose and triglyceride increase AHR-activity and PM2.5-mediated induction of cytochrome P450 (CYP)1A1 mRNA in macrophages. Cholesterol, fructose, and palmitic acid increased the PM- and AHR-mediated induction of proinflammatory cytokines in macrophages. Treatment with palmitic acid significantly increased the expression of inflammatory cytokines and markers of vascular injury in human aortic endothelial cells (HAEC) after treatment with PM2.5. The PM2.5-mediated activation of the atherogenic markers C-reactive protein (CRP) and S100A9, a damage-associated molecular pattern molecule, was found to be AHR-dependent and involved protein kinase A (PKA) and a CCAAT/enhancer-binding protein (C/EBP) binding element. This study identified nutritional factors interacting with AHR signaling and contributing to PM2.5-induced markers of atherogenesis and future cardiovascular risk.

BackgroundExposure to endocrine disrupting compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during susceptible developmental windows may alter risk of metabolic disease later in life. Animal studies of in utero and lactational TCDD exposure report associations with alterations in insulin sensitivity and energy homeostasis, but epidemiologic evidence is limited. We examined the relationship of prenatal TCDD exposure with markers of glucose homeostasis in the Seveso Second Generation study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 explosion in Seveso, Italy.MethodsWe included 426 children who were 18 years or older with complete follow-up data including a fasting blood draw. Insulin and glucose were measured and the updated homoeostatic model assessment was used to estimate insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B). Prenatal TCDD exposure was defined in two ways, as initial maternal serum TCDD concentration and TCDD estimated at pregnancy.ResultsThe children (222 female, 204 male) averaged 28.6 (±6.0) years. We found a 10-fold increase in TCDD estimated at pregnancy was inversely associated with insulin (adj-β = -1.24 μIU/mL, 95% confidence interval (CI): -2.38, -0.09) and HOMA2-B (adj-β = -10.2% decrease, 95% CI: -17.8, -1.9) among daughters, but not sons (insulin: adj-β = 0.57 μIU/mL, 95% CI: -0.84, 1.98, P for interaction = 0.04; and HOMA2-B: adj-β = 0.8% increase, 95% CI -10.7, 13.9, P for interaction = 0.11). Similar effect modification was observed for TCDD estimated at pregnancy and HOMA2-IR (P for interaction = 0.13). The models for initial maternal serum TCDD showed similar effect modification by child sex. The observed associations in daughters showed evidence of mediation by body mass index, which we have previously found to be associated with prenatal TCDD exposure in female offspring.ConclusionThese results suggest prenatal exposure to TCDD is associated with lower insulin resistance and beta compensation in female offspring, and show evidence of mediation by body mass index.

Despite progress describing the effects of persistent organic pollutants (POPs) on the central nervous system, the effect of POPs on enteric nervous system (ENS) function remains underexplored. We studied the effects of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), a POP, and a potent aryl hydrocarbon receptor (AHR) ligand, on the ENS and intestinal motility in mice. C57Bl/6J mice treated with TCDD (2.4 µg/kg body weight) for 8 weeks (once per week) exhibited significant delay in intestinal motility as shown by reduced stool frequency, prolonged intestinal transit time, and a persistence of dye in the jejunum compared to control mice with maximal dye retention in the ileum. TCDD significantly increased Cyp1a1 expression, an AHR target gene, and reduced the total number of neurons and affected nitrergic neurons in cells isolated from WT mice, but not Ahr−/− mice. In immortalized fetal enteric neuronal cells, TCDD-induced nuclear translocation of AHR as well as increased Cyp1a1 expression. AHR activation did not affect neuronal proliferation. However, AHR activation resulted in enteric neuronal toxicity, specifically, nitrergic neurons. Our results demonstrate that TCDD adversely affects nitrergic neurons and thereby contributes to delayed intestinal motility. These findings suggest that AHR signaling in the ENS may play a role in modulating TCDD-induced gastrointestinal pathophysiology. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is widely considered as the most toxic and common carcinogen in the world. Exposure to TCDD causes liver lipid metabolism disorder and steatosis. However, the molecular mechanism of TCDD-induced liver lipid accumulation is not completely clear. Here, we found that a 5 μg/kg TCDD exposure for 3 weeks induced hepatocyte lipid deposition, increased CD36 expression, and promoted AMP-activated protein kinase (AMPK) ɑ phosphorylation in the liver of C57BL/6J mice. Furthermore, sulfo-N-succinimidyl oleate, a CD36 inhibiter, blunted TCDD-induced lipid deposition in Huh7 cells, confirming the critical role of CD36 in TCDD-induced hepatic steatosis. In terms of molecular mechanisms, we found that TCDD exposure increased reactive oxygen species (ROS) levels in Huh7 cells, which activated AMPK. Moreover, the activated AMPK upregulated CD36 expression. Therefore, we can see that the increase in CD36 expression induced by TCDD was regulated by ROS/AMPK/CD36 signaling pathway. Our results help to clarify the molecular mechanism of TCDD-induced hepatic steatosis. [ABSTRACT FROM AUTHOR]

The impact of exposure to multiple chemicals raises concerns for human and environmental health. The adverse outcome pathway method offers a framework to support mechanism-based assessment in environmental health starting by describing which mechanisms are triggered upon interaction with different stressors. The identification of the molecular initiating event and the molecular interaction between a chemical and a protein target is still a challenge for the development of adverse outcome pathways. The cellular response to chemical exposure studied with omics could not directly identify the protein targets. However, recent mass spectrometry-based methods are offering a proteome-wide identification of protein targets interacting with s but unrevealing a molecular initiating event from a set of targets is still dependent on available knowledge. Here, we directly coupled the target identification findings from the proteome integral solubility alteration assay with an analytical hierarchy process for the prediction of a prioritized molecular initiating event. We demonstrate the applicability of this combination of methodologies with a test compound (TCDD), and it could be further studied and integrated into AOPs. From the eight protein targets identified by the proteome integral solubility alteration assay after analyzing 2824 human hepatic proteins, the analytical hierarchy process can select the most suitable protein for an AOP. Our combined method solves the missing links between high-throughput target identification and prediction of the molecular initiating event. We anticipate its utility to decipher new molecular initiating events and support more sustainable methodologies to gain time and resources in chemical assessment. [ABSTRACT FROM AUTHOR]

Various circular RNAs (circRNAs) are novel class of non-coding RNAs, which are pervasively transcribed in the genome. CircRNAs play important roles in human, animals and plants. Up to now, there was no report regarding circRNAs of cleft palate by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) induce. The present study screened identification and characterization of differential expressed-circRNAs in TCDD-induced cleft palate. 6903 circRNAs candidates came from cleft palates. Among them, 3525 circRNAs are up-regulation, and 3378 circRNAs are down-regulation by TCDD induce. The cluster and GO analysis found that circRNAs involved in biological process, cellular component, and molecular function. Through the analysis of KEGG Pathway, circRNAs made functions via classical signaling pathway in cleft palate, such as TGF-beta signaling pathway, BMP signal pathway, MAPK signaling pathway. In addition, we found down-regulated circRNA224, circRNA3302 and up-regulated circRNA5021 targeted tgfbr3, but up-regulated circRNA4451 targeted tgfbr2. circRNA4451 may make functions through TGF-beta signaling pathway. These results suggested that many different circRNAs may make important role in TCDD-induced cleft palate, which provided a theoretical basis for further research. [ABSTRACT FROM AUTHOR]

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener of dioxins, has a proven reproductive toxicity. Due to the lack of evidence on the multigenerational female reproductive toxicity of TCDD through the maternal exposure, the current study aims to evaluate, on the one hand, the acute reproductive toxicity of TCDD on adult female pre-gestational exposed to a critical single dose of TCDD (25 μg/kg) for a week (group referred to as AFnG; adult female/non-gestation). On the other hand, the transcription, hormonal and histological effects of TCDD on the females of two generations F1 and F2, were also investigated after the exposure of pregnant females to TCDD on gestational day 13 (GD13) (group referred to as AFG; adult female/gestation). First, our data showed alternations in the ovarian expressional pattern of certain key genes involved in the detoxification of TCDD as well as in the biosynthesis of steroidal hormones. The expression of Cyp1a1 was highly induced in TCDD-AFnG group, but reduced in both F1 and F2. While the transcripts levels of Cyp11a1 and 3βhsd2 were decreased, Cyp19a1 transcripts were increased as a function of TCDD exposure. This was synchronized with a dramatic increase in the level of estradiol hormone in the females of both experimental groups. Beside a significant reduce in their size and weight, ovaries of TCDD-exposed females showed serious histological alterations marked by atrophy of the ovary, congestion in the blood vessels, necrosis in the layer of granular cells, dissolution of the oocyte and nucleus of ovarian follicles. Finally, the female fertility was dramatically affected across generations with a reduced maleemale ratio. Our data indicate that the exposure of pregnant female to TCDD has serious negative effects in the female productive system across generations and suggest the use of hormonal alternation as biomarker to monitor and assess the indirect exposure of these generations to TCDD.

تُعرف الديوكسينات بأنها سموم عضوية هالوجينية مثابرة وعالية السُّمية وتشمل عائلتين هما الديوكسينات ثنائية البنزن عديدة التكلور Polychlorinated Dibenzo-p-Dioxins (PCDDs) والفورانات ثنائية البنزن عديدة التكلور Polychlorinated Dibenzo Furans (PCDFs). ويتواسط المستقبل Aryl-hydrocarbon Receptor (AhR) سُميِة الديوكسينات، ويُعرف المركب 2,3,7,8 رباعي كلورو ثنائي بنزو بارا ديوكسين 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) بأنه الأعلى سُميِّة من بين جميع الديوكسينات والأعلى ألفة للمستقبل AhR وذو عامل مُكافئ سُمِّي يعادل 1.0.. ونظراً لطبيعتها المُحبة للدسم، تُعرف الديوكسينات بقدرتها على التراكم في النسج المدخرة للدسم وبشكل خاص الكبد الذي يلعب دوراً رئيساً في نزع سُميِّة الديوكسينات بما يمتلكه من منظومة إنزيمية معقدة؛ عائلة السيتوكرومات P450 (CYPs)، وعُضيات متخصصة هي القطيرات اللبيدية Lipid Droplets (LDs). وهنا تبرز أهمية تحري أثر التعرض لِـTCDD على LDs الكبدية مورفولوجياً وجزيئياً لدى نموذج حيواني كفئران BALB/c. فقد تم في هذا العمل تجريع إناث فئران BALB/c فموياً بجرعة واحدة من زيت الذرة الحاوي على 15 ميكروغرام/كيلوغرام من TCDD، بالمقارنة مع الفئران الشاهدة المُجرّعة فموياً بزيت الذرة فقط. ووفق أربع فواصل زمنية من زمن التجريع، عُزلت LDs الكبدية ووُصفت مجهرياً. ودُرس التغير النسبي في التعبير المورثي عن أهم المورثات المسؤولة عن نزع السُميّة واصطناع الأوكسيلبينات وLDs باستعمال تقانة التفاعل السلسلي للبوليميراز الكمي في الزمن الحقيقي RT-qPCR، أظهرت النتائج وجود فروقات في التعبير المورثي في العينات المدروسة باختلاف النقاط الزمنية للدراسة، وتبدو الفروقات جليّة في عينات الزمن P3 وP4 إذ توجد زيادة في التعبير المورثي في كل من مورثتي AhR وARNT وCYP1A1 وذلك بالمقارنة مع P1 وP2. وتُظهر أيضاً زيادة واضحة في التعبير المورثي لكلٍ من مورثتي LOX15 وCOX2، وكذلك ارتفاعاً في التعبير عن مورثات Plin5 وCideC وPpara وPparg. وعلى خلاف ذلك، لُوحظ انخفاضاَ في التعبير المورثي للمورثات المدروسة عدا AhR، في الزمن P1، أما في الزمن P2 فلُوحظ انخفاضاً في التعبير المورثي في كلا مورثتي AhR وARNT، وعلى العكس ارتفاعاً طفيفاً في CYP1A1، وعدم وجود فروقات تُذكر في باقي المورثات. أما على مستوى LDs، فقد تمَّ التأكد من نقاوتها وسلامة شكلها مجهرياً، وكذلك تلوينها بصبغة Blue Nile وتصويرها باستعمال مجهر الفلورة. لُوحظ ارتفاع بسيط في أعداد LDs وتراكيز البروتينات المرتبطة في كل من النقاط الزمنية الأربعة بالمقارنة مع الشاهد، إلا أنه لم يكن هناك اختلافات ملحوظة بحجم LDs، إذ كانت أحجامها متقاربة في جميع عينات الدراسة. تخلص نتائج دراستنا لوجود مؤشرات أولية للتعرض لِـ TCDD على مستوى التعبير المورثي لمورثات مسؤولة عن نزع السُّميِّة واصطناع الأوكسيلبينات وLDs بشكل معتمد على الزمن. وهنا تبدو أهمية التركيز على سُمية هذا المركب وقدرته على التراكم ضمن LDs وتأثيره على تعدادها وعلى تركيبها ومحتواها اللبيدي والبروتيني من خلال تعديل منظومة التعبير المورثي، الأمر الذي يتطلب مزيداً من البحث.

Previously, we showed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) ligand and a potent and persistent toxicant and carcinogenic agent, induces high levels of murine myeloid-derived suppressor cell (MDSC) when injected into mice. In the current study, we demonstrate that Resveratrol (3,4,5-trihydroxy-trans-stilbene; RSV), an AhR antagonist, reduces TCDD-mediated MDSC induction. RSV decreased the number of MDSCs induced by TCDD in mice but also mitigated the immunosuppressive function of TCDD-induced MDSCs. TCDD caused a decrease in F4/80+ macrophages and an increase in CD11C+ dendritic cells, while RSV reversed these effects. TCDD caused upregulation in CXCR2, a critical molecule involved in TCDD-mediated induction of MDSCs, and Arginase-1 (ARG-1), involved in the immunosuppressive functions of MDSCs, while RSV reversed this effect. Transcriptome analysis of Gr1+ MDSCs showed an increased gene expression profile involved in the metabolic pathways in mice exposed to TCDD while RSV-treated mice showed a decrease in such pathways. The bio-energetic profile of these cells showed that RSV treatment decreased the energetic demands induced by TCDD. Overall, the data demonstrated that RSV decreased TCDD-induced MDSC induction and function by altering the dynamics of various myeloid cell populations involving their numbers, phenotype, and immunosuppressive potency. Because MDSCs play a critical role in tumor growth and metastasis, our studies also support the potential use of RSV to attenuate the immunosuppressive properties of MDSC.

The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR's functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.

BackgroundExposure to endocrine-disrupting chemicals (EDCs) during sensitive developmental windows, such as in utero, may influence disease later in life but direct measurement of fetal hormones is not feasible. The ratio of the length of the second finger digit to the fourth digit (2D:4D), a sexually dimorphic trait, is a biomarker of androgen levels and the androgen/estrogen balance in utero. However, it is unclear whether in utero EDC exposure might alter 2D:4D ratio.AimsWe examined 2D:4D ratio in Seveso children in relation to in utero exposure to a potent EDC, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using linear regression.Study designThe Seveso Women's Health Study (SWHS) is a historical cohort study, following the health of women exposed to TCDD during a 1976 explosion in Seveso, Italy. Individual-level TCDD was measured for SWHS in serum collected soon after the accident. In 2014, the SWHS children born after the explosion were enrolled in the Seveso Second Generation Study.Subjects594 SWHS children born post-explosion to 397 mothers.Outcome measuresRight hand 2D:4D ratio.ResultsOn average, 2D:4D ratio for males was significantly lower than for females (p

BackgroundPrenatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure has been shown to alter sexual differentiation of the brain in animal models, impacting pubertal development, behavior, cortical dominance, and cognition. The effects of early life exposure to dioxin-like compounds on human neurodevelopment, however, are less clear and warrant further investigation.MethodsThe Seveso Women's Health Study (SWHS), initiated in 1996, is a well-characterized cohort of 981 Italian women who lived in proximity to an industrial accident in July 1976 that resulted in one of the highest residential TCDD exposures on record. In 2014-2016, we enrolled offspring born after the accident into the Seveso Second Generation Health Study. Children aged 7-17 years old (n = 161) completed a neuropsychological assessment spanning executive function and reverse learning (Wisconsin Card Sort), non-verbal intelligence (Raven's Progressive Matrices), attention and hyperactivity (Connor's Continuous Performance (CPT), and memory (Rey's Auditory Verbal Learning). We used multivariate regression with robust standard error estimates accounting for clustering of siblings to model the associations between these outcomes and prenatal exposure defined as TCDD measured in maternal serum collected soon after the explosion and estimated to pregnancy.ResultsThe children (82 male, 79 female) averaged 13.1 (±2.9) years of age. Adjusting for covariates, a 10-fold increase in maternal serum TCDD was not adversely associated with reverse learning/set-shifting, memory, attention/impulsivity, or non-verbal intelligence. In sex-stratified models, prenatal TCDD was associated with more non-perseverative errors in boys but not in girls (pint = 0.04). TCDD was also associated with attention deficits on the CPT but only among children with the shortest breastfeeding histories.ConclusionsWhile overall, there were no significant associations, the observed differential neurotoxic sensitivities to TCDD by sex and lactation history may warrant confirmation in future studies.

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

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

Multipotent mesenchymal stem cells (MSCs) maintain the ability to differentiate into adipogenic, chondrogenic, or osteogenic cell lineages. There is increasing concern that exposure to environmental agents such as aryl hydrocarbon receptor (AhR) ligands, may perturb the osteogenic pathways responsible for normal bone formation. The objective of the current study was to evaluate the potential of the prototypic AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to disrupt osteogenic differentiation of human bone-derived MSCs (hBMSCs) in vitro. Primary hBMSCs from three donors were exposed to 10 nM TCDD and differentiation was interrogated using select histological, biochemical, and transcriptional markers of osteogenesis. Exposure to 10 nM TCDD resulted in an overall consistent attenuation of alkaline phosphatase (ALP) activity and matrix mineralization at terminal stages of differentiation in primary hBMSCs. At the transcriptional level, the transcriptional regulator DLX5 and additional osteogenic markers (ALP, OPN, and IBSP) displayed attenuated expression; conversely, FGF9 and FGF18 were consistently upregulated in each donor. Expression of stem cell potency markers SOX2, NANOG, and SALL4 decreased in the osteogenic controls, whereas expression in TCDD-treated cells resembled that of undifferentiated cells. Coexposure with the AhR antagonist GNF351 blocked TCDD-mediated attenuation of matrix mineralization, and either fully or partially rescued expression of genes associated with osteogenic regulation, extracellular matrix, and/or maintenance of multipotency. Thus, experimental evidence from this study suggests that AhR transactivation likely attenuates osteoblast differentiation in multipotent hBMSCs. This study also underscores the use of primary human MSCs to evaluate osteoinductive or osteotoxic potential of chemical and pharmacologic agents in vitro.

This article, titled "Editorial: Linking environmental exposure to toxicants and chronic disease," discusses the relationship between environmental exposure to toxicants and the development of chronic diseases. The authors highlight the increasing mortality rates caused by non-communicable diseases (NCDs) and emphasize the role of environmental toxicants in contributing to these diseases. The article presents research on various NCDs, including neurodegenerative, respiratory, in utero, molecular, and oncological diseases, and explores the impact of environmental toxicants on their development. The authors call for further research in this area and emphasize the need to identify biomarkers for assessing previous exposure to environmental contaminants. The article also discusses the effects of inflammation induced by toxicants on respiratory health, the associations between grandparental exposures and asthma in grandchildren, and the impact of in utero exposure to toxicants on birth abnormalities. Additionally, the article examines the effects of specific toxicants, such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and talc, on reproductive toxicity and potential transgenerational effects. The authors conclude that further research is needed to understand the long-term effects of environmental toxicant exposure and its potential impact on future generations. [Extracted from the article]

A 1976 chemical factory explosion near Seveso, Italy exposed residents to high levels of 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD or dioxin). Dioxin is a known human carcinogen and potent endocrine disruptor. It is highly lipophilic and has a long half-life in humans. Much of what we know and can learn about the risks of dioxin exposure on human health arose from the tragic circumstances of Seveso. This review aims to describe the Seveso accident, summarize the results of 40 years of research on the health of the Seveso population since the accident, and discuss next-stage research on the health of Seveso residents, their children, and grandchildren.

Background2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant that can bioaccumulate in humans, cross the placenta, and cause immunological effects in children, including altering their risk of developing allergies. On July 10, 1976, a chemical explosion in Seveso, Italy, exposed nearby residents to a high amount of TCDD. In 1996, the Seveso Women's Health Study (SWHS) was established to study the effects of TCDD on women's health. Using data from the Seveso Second Generation Health Study, we aim to examine the effect of prenatal exposure to TCDD on the risk of atopic conditions in SWHS children born after the explosion.MethodsIndividual-level TCDD was measured in maternal serum collected soon after the accident. In 2014, we initiated the Seveso Second Generation Health Study to follow-up the children of the SWHS cohort who were born after the explosion or who were exposed in utero to TCDD. We enrolled 677 children, and cases of atopic conditions, including eczema, asthma, and hay fever, were identified by self-report during personal interviews with the mothers and children. Log-binomial and Poisson regressions were used to determine the association between prenatal TCDD and atopic conditions.ResultsA 10-fold increase in 1976 maternal serum TCDD (log10TCDD) was not significantly associated with asthma (adjusted relative risk (RR) = 0.93; 95% CI: 0.61, 1.40) or hay fever (adjusted RR = 0.99; 95% CI: 0.76, 1.27), but was significantly inversely associated with eczema (adjusted RR = 0.63; 95% CI: 0.40, 0.99). Maternal TCDD estimated at pregnancy was not significantly associated with eczema, asthma, or hay fever. There was no strong evidence of effect modification by child sex.ConclusionsOur results suggest that maternal serum TCDD near the time of explosion is associated with lower risk of eczema, which supports other evidence pointing to the dysregulated immune effects of TCDD.

2,3,7,8-tet-rachlorodibenzo-p-dioxin (TCDD) and α-endosulfan are two typical persistent organic pollutants (POPs), both of which accumulate in the liver and have potential carcinogenic hepatic effects. The underlying molecular mechanisms of pathogenesis of hepatocellular carcinoma (HCC) remain elusive when exposure to POPs. The aim of this study is to explore the key genes involved in HCC when exposure to TCDD and α-endosulfan by weighted gene co-expression network analysis (WGCNA). First, we performed co-expressed analysis on HCC and normal condition, based on WGCNA. In results, seven co-expressed modules were identified from 56 human liver samples, and the brown module correlated with five stages of HCC. Subsequently, we predicted that human five liver diseases were associated with exposure to TCDD and/or α-endosulfan by Nextbio analysis. Functional enrichment analysis showed that the brown module enriched in oxidation-reduction process, DNA replication, oxidoreductase activity and aging, which were the same as the results when exposure to the mixture of TCDD and α-endosulfan. Lastly, based on the protein-protein interaction network, we identified three novel genes including HK2, EXO1 and PFKP as key genes in HCC associated with exposure to TCDD and α-endosulfan mixture. In addition, survival analysis of key genes in Kaplan-Meier plotter demonstrated that aberrant expression levels of all the three key genes were associated with poor prognosis of HCC. Finally, Western blot analysis confirmed that protein expression levels of PFKP and HK2 in the three exposed groups were significantly elevated, while EXO1 were significantly upregulated when exposure to TCDD and α-endosulfan mixture in HepaRG cells. This study provides a new perspective to the understanding of the genetic mechanism of HCC when exposure to POPs.

2,3,7,8-tetrachlorodibenzo-[p]-dioxin (TCDD) is a persistent global pollutant that exhibits a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. Epidemiological studies have associated AHR agonist exposure with multiple human neuropathologies. Consistent with the human data, research studies using laboratory models have linked pollutant-induced AHR activation to disruptions in learning and memory as well as motor impairments. Our understanding of endogenous AHR functions in brain development is limited and, correspondingly, scientists are still determining which cell types and brain regions are sensitive to AHR modulation. To identify novel phenotypes resulting from pollutant-induced AHR activation and ahr2 loss of function, we utilized the optically transparent zebrafish model. Early embryonic TCDD exposure impaired embryonic brain morphogenesis, resulted in ventriculomegaly, and disrupted neural connectivity in the optic tectum, habenula, cerebellum, and olfactory bulb. Altered neural network formation was accompanied by reduced expression of synaptic vesicle 2. Loss of ahr2 function also impaired nascent network development, but did not affect gross brain or ventricular morphology. To determine whether neural AHR activation was sufficient to disrupt connectivity, we used the Gal4/UAS system to express a constitutively active AHR specifically in differentiated neurons and observed disruptions only in the cerebellum; thus, suggesting that the phenotypes resulting from global AHR activation likely involve multiple cell types. Consistent with this hypothesis, we found that TCDD exposure reduced the number of oligodendrocyte precursor cells and their derivatives. Together, our findings indicate that proper modulation of AHR signaling is necessary for the growth and maturation of the embryonic zebrafish brain. [ABSTRACT FROM AUTHOR]

Simple Summary: The aryl hydrocarbon receptor (AhR) is expressed in breast cancer cells and tumors and in some studies, the AhR is a negative prognostic factor for patient survival. Structurally diverse AhR ligands have been extensively investigated as anticancer agents in breast cancer cells and tumors and show efficacy in both estrogen receptor (ER)-positive and ER -negative breast cancer cells. Moreover, synthetic AhR ligands are being developed and have been in clinical trials for treating breast cancer. In contrast, other reports show that AhR ligands enhance mammary carcinogenesis and in a few studies opposite results are observed for the same AhR ligands in comparable breast cancer cells lines. This paper attempts to provide an extensive, unbiased review of the contrasting effects of AhR ligands in breast cancer and points out that future research will be required to resolve these conflicting results. Breast cancer is a complex disease which is defined by numerous cellular and molecular markers that can be used to develop more targeted and successful therapies. The aryl hydrocarbon receptor (AhR) is overexpressed in many breast tumor sub-types, including estrogen receptor -positive (ER+) tumors; however, the prognostic value of the AhR for breast cancer patient survival is not consistent between studies. Moreover, the functional role of the AhR in various breast cancer cell lines is also variable and exhibits both tumor promoter- and tumor suppressor- like activity and the AhR is expressed in both ER-positive and ER-negative cells/tumors. There is strong evidence demonstrating inhibitory AhR-Rα crosstalk where various AhR ligands induce ER degradation. It has also been reported that different structural classes of AhR ligands, including halogenated aromatics, polynuclear aromatics, synthetic drugs and other pharmaceuticals, health promoting phytochemical-derived natural products and endogenous AhR-active compounds inhibit one or more of breast cancer cell proliferation, survival, migration/invasion, and metastasis. AhR–dependent mechanisms for the inhibition of breast cancer by AhR agonists are variable and include the downregulation of multiple genes/gene products such as CXCR4, MMPs, CXCL12, SOX4 and the modulation of microRNA levels. Some AhR ligands, such as aminoflavone, have been investigated in clinical trials for their anticancer activity against breast cancer. In contrast, several publications have reported that AhR agonists and antagonists enhance and inhibit mammary carcinogenesis, respectively, and differences between the anticancer activities of AhR agonists in breast cancer may be due in part to cell context and ligand structure. However, there are reports showing that the same AhR ligand in the same breast cancer cell line gives opposite results. These differences need to be resolved in order to further develop and take advantage of promising agents that inhibit mammary carcinogenesis by targeting the AhR. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the protective role of capsaicin in a rat model of 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD)-induced toxicity. Exposure to TCDD which is an environmental toxicant causes severe toxic effects in the animal and human tissues. Therefore, the potential protective effect of capsaicin in TCDD-induced organ damage was investigated in rats by measuring thiobarbituric acid reactive substances (TBARS) level, superoxide dismutase (SOD) activity, and glutathione (GSH) level in the heart, liver, and kidney tissues for oxidant/antioxidant balance. Thirty-two healthy adults (250–300 g weight and 3–4 months old) male Wistar albino rats were randomly distributed into four equal groups (n = 8): Control, CAP, TCDD, TCDD + CAP. A dose of 2 μg/kg TCDD or a dose of 25 mg/kg capsaicin were dissolved in corn oil and orally administered to the rats for 30 days. The results indicated that TCDD-induced oxidative stress by increasing the level of TBARS and by decreasing the levels of GSH, and SOD activity in the tissues of rats. However, capsaicin treatment was significantly decreased TBARS levels and was significantly increased GSH level and SOD activity (p < 0.05). In addition, capsaicin (25 mg/kg) significantly attenuated TCDD-induced histopathological alteration associated with oxidative stress in the heart, liver, and kidney tissues (p < 0.05). As capsaicin regulates oxidative imbalance and attenuates histopathological alterations in the rat tissues, it may be preventing agents in TCDD toxicity. [ABSTRACT FROM AUTHOR]

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) regulates cellular detoxification, proliferation and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-sequencing to identify the signature of the AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGRF1 and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression was elevated in a subset of colon cancer patient samples, which also contained elevated ß-catenin levels. Remarkably, SCIN expression promoted nuclear translocation of ß-catenin and activates the WNT pathway. Our study identifies a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of ß-catenin. [ABSTRACT FROM AUTHOR]

Humoral responses to respiratory viruses, such as influenza viruses, develop over time and are central to protection from repeated infection with the same or similar viruses. Epidemiological and experimental studies have linked exposures to environmental contaminants that bind the aryl hydrocarbon receptor (AHR) with modulated antibody responses to pathogenic microorganisms and common vaccinations. Other studies have prompted investigation into the potential therapeutic applications of compounds that activate AHR. Herein, using two different AHR ligands [2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) and 2-(1 H -Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE), to modulate the duration of AHR activity, we show that the humoral response to viral infection is dependent upon the duration and timing of AHR signaling, and that different cellular elements of the response have different sensitivities. When AHR activation was initiated prior to infection with influenza A virus, there was suppression of all measured elements of the humoral response (i.e., the frequency of T follicular helper cells, germinal center B cells, plasma cells, and circulating virus-specific antibody). However, when the timing of AHR activation was adjusted to either early (days −1 to +5 relative to infection) or later (days +5 onwards), then AHR activation affected different aspects of the overall humoral response. These findings highlight the importance of considering the timing of AHR activation in relation to triggering an immune response, particularly when targeting the AHR to manipulate disease processes. • The duration of AHR signaling influences antibody responses to viral infection. • AHR activation by TCDD or ITE suppresses humoral immune response. • The initial days after infection are a key window for AHR activation to influence anti-viral humoral immunity. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic persistent organic pollutant (POP) that can induce DNA damage within cells. Although oxidative stress is one of the primary mechanisms causing DNA damage, its role in the process of TCDD-induced DNA damage remains unclear. In this study, the TCDD-induced production of reactive oxygen species (ROS) and the occurrence of DNA damage at the AP site were monitored simultaneously. Further investigation revealed that TCDD impaired the activities of superoxide dismutase (SOD) and catalase (CAT), compromising the cellular antioxidant defense system. Consequently, this led to an increase in the production of O 2 .− and NO, thus inducing DNA damage at the AP site under oxidative stress. Our findings were further substantiated by the upregulation of key genes in the base excision repair (BER) pathway and the absence of DNA AP site damage after inhibiting O 2 .− and NO. In addition, transcriptome sequencing revealed that TCDD induces DNA damage by upregulating genes associated with oxidative stress in the mitogen-activated protein kinase (MAPK), cyclic adenosine monophosphate (cAMP), and breast cancer pathways. This study provides important insights into the toxicity mechanisms of TCDD. [Display omitted] • TCDD disrupts the activities of SOD and CAT in antioxidant defense system. • TCDD induces an increase of ROS in cells leading to AP sites DNA damage. • TCDD induced AP sites damage promotes the expression of key genes in BER pathway. • TCDD affects oxidative stress levels in MAPK, cAMP and breast cancer pathways. • TCDD affects cell cycle, apoptosis, inflammatory response and oxidative stress. [ABSTRACT FROM AUTHOR]