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- 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression. [Journal Article]
- CTCardiovasc Toxicol 2019 May 21
- 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribut…
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction. TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.
- The potential therapeutic benefit of resveratrol on Th17/Treg imbalance in immune thrombocytopenic purpura. [Journal Article]
- IIInt Immunopharmacol 2019 May 15; 73:181-192
- CONCLUSIONS: This study revealed that resveratrol reversed the Th17/Treg imbalance by a mechanism involving the suppression of the AhR pathway. Since ITP is characterized by a Th17/Treg imbalance, resveratrol might be beneficial for the treatment of this condition.
- Effects of perinatal dioxin exposure on development of children: a 3-year follow-up study of China cohort. [Journal Article]
- ESEnviron Sci Pollut Res Int 2019 May 18
- The purpose of this study was to investigate the longitudinal effects of perinatal exposure to dioxin on physical growth in a 3-year follow-up study. In 2015, 27 mother-infant pairs living in an elec…
The purpose of this study was to investigate the longitudinal effects of perinatal exposure to dioxin on physical growth in a 3-year follow-up study. In 2015, 27 mother-infant pairs living in an electronic waste (e-waste) dismantling region and 35 pairs living in a control region were enrolled in the present study. Breast milk samples were collected at 4 weeks after birth. Physical growth, including weight, height, and head and chest circumferences, was measured at 6 months and 3 years of age. Dioxin levels in the breast milk were measured by gas chromatography/high-resolution mass spectrometry. Levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin and toxic equivalency values in maternal breast milk of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCDDs/PCDFs were significantly higher in women residing in the e-waste dismantling region. In 3-year-old boys, inverse associations were found between height and PCDDs-TEQ. In girls, positive associations were found between height and 2,3,7,8-TetraCDD, PCDDs-TEQ, and PCDDs/PCDFs-TEQ, and for weight and PCDDs-TEQ and PCDDs/PCDFs-TEQ at 3 years of age. In this study, sex-specific differences were observed in children, in whom dioxin exposure decreased growth in boys but increased growth in girls during the first 3 years of life.
- Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on acetylcholinesterase during myogenic differentiation of contractile rat primary skeletal muscle cells. [Journal Article]
- CBChem Biol Interact 2019 May 14
- Emerging data indicate that prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could interfere with myogenic differentiation in vivo. Acetylcholinesterase (EC22.214.171.124; AChE), an enzyme cr…
Emerging data indicate that prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could interfere with myogenic differentiation in vivo. Acetylcholinesterase (EC126.96.36.199; AChE), an enzyme critical for cholinergic neurotransmission, is abundantly expressed in neurons and mature myotubes, and we recently found that muscle AChE expression was suppressed in parallel with the inhibition of myogenic differentiation upon TCDD treatment in mouse C2C12 cells. This TCDD-induced suppression of muscle AChE was proposed to involve an aryl hydrocarbon receptor (AhR)-independent mechanism, but the precise underlying mechanism remains unclear. Considering the widely recognized role of muscular activity in AChE expression and its potential crosstalk with the AhR signaling pathway, we sought to investigate the effect of TCDD on muscle AChE expression in the presence of muscular activity. Therefore, we employed a highly contractile rat primary skeletal muscle culture system in which AChE activity and the expression of genes related to it (AChE T subunit and collagen Q (ColQ)) were increased during the myogenic differentiation process. Although TCDD treatment successfully induced the expression of genes regulated by AhR activation, the treatment exerted no notable effects on myogenic differentiation. Moreover, muscle AChE enzymatic activity and mRNA level remained unchanged following TCDD treatment, and only ColQ mRNA expression was slightly increased after 4-day treatment with TCDD (10-10 M). The compensatory role of muscle-contraction-related signaling pathways in this newly identified unresponsiveness of muscle AChE to TCDD warrants further investigation.
- Interleukin 33 expression induced by aryl hydrocarbon receptor in macrophages. [Journal Article]
- TSToxicol Sci 2019 May 15
- Polycyclic aromatic hydrocarbons (PAHs) contained in airborne particulate matter have been identified as a contributing factor for inflammation in the respiratory tract. Recently, interleukin-33 (IL-…
Polycyclic aromatic hydrocarbons (PAHs) contained in airborne particulate matter have been identified as a contributing factor for inflammation in the respiratory tract. Recently, interleukin-33 (IL-33) is strongly suggested to be associated with airway inflammation. Aryl hydrocarbon receptor (AhR) is a receptor for PAHs to regulates several metabolic enzymes, but the relationships between AhR and airway inflammation are still unclear. In this study, we examined the role of AhR in the expression of interleukin-33 (IL-33) in macrophages. THP-1 macrophages mainly expressed IL-33 variant 5, which in turn was strongly induced by the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and kynurenine (KYN). AhR antagonist CH223191 suppressed the increase in IL-33 expression. Promoter analysis revealed that the IL-33 promoter has two dioxin response elements (DREs). AhR was recruited to both DREs after treatment with TCDD or KYN as assessed by gel shift and chromatin immunoprecipitation assays. A luciferase assay showed that one of the DREs was functional and involved in the expression of IL-33. Macrophages isolated from AhR-null mice expressed only low levels of IL-33 even in response to treatment with AhR ligands compared with wild-type cells. The treatment of THP-1 macrophages with diesel particulate matter and particle extracts increased the mRNA and protein expression of IL-33. Taken together, the results show that ligand-activated AhR mediates the induction of IL-33 in macrophages via a DRE located in the IL-33 promoter region. AhR-mediated IL-33 induction could be involved in the exacerbation and/or prolongation of airway inflammation elicited by toxic chemical substances.
- [Expression of gamma-aminobutyric acid type A receptor beta3 subunit in murine cleft palate induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin]. [Journal Article]
- ZKZhonghua Kou Qiang Yi Xue Za Zhi 2019 May 09; 54(5):328-334
- CONCLUSIONS: TCDD delayed palatal shelf elevation and eventually led to cleft palate may be associated with a decrease in GABRB3. GABRB3 may play an important role in the elevation and fusion phases of the palate development.
- A comprehensive review on hepatoprotective and nephroprotective activities of chrysin against various drugs and toxic agents. [Review]
- CBChem Biol Interact 2019 May 11; 308:51-60
- Chrysin belongs to the flavonoids and has been used as traditional medicine from ancient and has been reported to exhibit a wide range of pharmacological properties. The biochemical and molecular mec…
Chrysin belongs to the flavonoids and has been used as traditional medicine from ancient and has been reported to exhibit a wide range of pharmacological properties. The biochemical and molecular mechanisms involved in the hepato- and nephroprotective activities of chrysin were discussed in this review. Chrysin exhibited hepatoprotective activity against 2,3,7,8-tetrachlorodibenzo-p-dioxin, carbon tetrachloride, cisplatin, d-galactosamine, doxorubicin, ethanol, lipopolysaccharide/d-galactosamine, methotrexate, ammonium chloride, paracetamol, diethylnitrosamine, streptozotocin, tert-butyl hydroperoxide, thioacetamide, 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), ischemia/reperfusion-induced hepatotoxicity and nephroprotective activity against cisplatin, doxorubicin, paracetamol, gentamicin, streptazotocin, N-nitrosodiethyl amine, 5-fluorouracil, adenine, carbon tetrachloride, copper, 2,3,7,8-tetrachlorodibenzo- p-dioxin, colistin, Nω-nitro-l-arginine-methylester and ethanol in various animal models due to its antioxidant, anti-apoptotic activities. In this review, we provide an overview of the possible mechanisms by which chrysin reduced the hepatotoxicity and nephrotoxicity of different toxicants. This will help the toxicologists, pharmacologists and chemists to develop new safer pharmaceutical products with chrysin and other toxicants.
- 3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice. [Journal Article]
- IJInt J Mol Sci 2019 May 10; 20(9)
- TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit…
TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.
- Kinetic and mechanistic insight into the OH-initiated atmospheric oxidation of 2,3,7,8-tetrachlorodibenzo-p-dioxin via OH-addition and hydrogen abstraction pathways: A theoretical investigation. [Journal Article]
- STSci Total Environ 2019 May 07; 679:106-114
- The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic polychlorinated dibenzo-p-dioxin. The OH-initiated oxidation of TCDD has been studied using the density functional, canonical transiti…
The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic polychlorinated dibenzo-p-dioxin. The OH-initiated oxidation of TCDD has been studied using the density functional, canonical transition state, and canonical Rice-Ramsperger-Kassel-Marcus theories. The kinetic data were corrected for quantum tunneling by the Wigner and Eckart models. All OH addition and hydrogen atom abstraction channels were thermodynamically exergonic. The kinetic and thermodynamic data analysis at the reliable level MPWB1K/MG3S//M06-2X/MG3S indicate that the addition of OH to the carbon atom adjacent to the oxygen atom in dioxin ring leads to the formation of predominant adduct. The calculated bimolecular rate constant for the formation of predominant adduct was ~5.97-6.75 × 10-13 cm3 molecule-1 s-1, its branching ratio was ~0.955, and the overall rate constant for the OH-initiated oxidation of TCDD was ~6.25-7.08 × 10-13 cm3 molecule-1 s-1. The atmospheric lifetime of TCDD determined by OH was ~8.17-9.26 days indicating the TCDD can be categorized as medium lifetime organic pollutant.
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- Assessment of the carcinogenic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin using mouse embryonic stem cells to form teratoma in vivo. [Journal Article]
- TLToxicol Lett 2019 May 10; 312:139-147
- As the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has gained lots of concerns, due to its diverse deleterious effects. However, the knowledge on carcinogenic risk of TCDD during ea…
As the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has gained lots of concerns, due to its diverse deleterious effects. However, the knowledge on carcinogenic risk of TCDD during early stage of development remains scarce. The in vivo teratoma formation model based on the transplantation of embryonic stem cells (ESCs) in immunodeficient mice is appealing for studying pluripotency and tumorigenicity in developmental biology, and also shows promise in environmental toxicology, especially in carcinogenesis researches. In this study, the malignant transformation of mouse embryonic stem cells (mESCs) pretreated with TCDD was investigated during their in vivo differentiation using teratoma formation model. Based on characterization of the pluripotency and differentiation capabilities of mESCs, evil changes in teratomas derived from TCDD-exposed mESCs were systematically studied. The results showed that TCDD significantly up-regulated CYP1A1 transcriptional levels in mESCs, elevated the incidence of malignant change in mESC-derived teratomas, and caused indefinite proliferation capabilities in sequential cultures of tumor tissues. The findings suggested that TCDD could exert carcinogenic effect on mESCs during their differentiation into teratoma in vivo, and more attention should be paid to the adverse health effects of this chemical during gestation or early developmental period.