Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms

Safe, Stephen; Wang, F; Porter, Weston W.; Duan, Renqin; McDougal, Andrew

doi:10.1016/s0378-4274(98)00331-2

Cited by 221 publications

(104 citation statements)

References 11 publications

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“…TCDD (>99.5% pure) was obtained from Cambridge Isotope Laboratory (Andover, MA). [6, H]E 2 and [6,7-3 H]E 1 (specific activities of 51 and 58 Ci/ mmol, respectively) and [4][5][6][7][8][9][10][11][12][13][14] C]E 2 (specific activities of 55.1 mCi/mmol) were purchased from PerkinElmer Life Science Products (Boston, MA). All the organic solvents used in this study were of HPLC grade or better, and were obtained from Fisher Scientific (Atlanta, GA).…”

Section: Chemicalsmentioning

confidence: 99%

“…The reaction mixture consisted of liver microsomal protein (1 mg/mL), [4][5][6][7][8][9][10][11][12][13][14] C]E 2 (dissolved in 2 μL ethanol), 2 mM NADPH and 5 mM ascorbic acid in a final volume of 1.0 mL TrisHCl (100 mM)/HEPES (50 mM) buffer, pH 7.4. The reaction was initiated by addition of microsomal protein and lasted for 30 min at 37°C with constant mild shaking.…”

Section: Assay Of the Nadph-dependent 2-and 4-hydroxylation Of E 2 Bymentioning

confidence: 99%

“…Contamination of TCDD in the environment is widespread, and its resistance to biodegradation results in its presence in the environment [1] and in human body for long periods of time [2]. TCDD is a developmental and reproductive toxicant and causes immunotoxicity, dermal and hepatic toxicity, and a plethora of endocrine-disrupting effects [3][4][5][6][7][8]. In addition, TCDD is also considered a carcinogen, increasing the incidence of a variety of cancers in humans as well as in laboratory animals [4,[9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Zhu

Gallo

Burger

et al. 2008

Toxicology and Applied Pharmacology

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We studied the effect of administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by i.p. injection once every two weeks in combination with a high-fat (HF) diet for 8 or 16 weeks on the body and organ weight changes as well as on the hepatic enzyme activity for estrogen metabolism in C3H/HeN female mice. Administration of TCDD at 100 μg/kg b.w. once every two weeks for 8 weeks increased the body weight by 46% in the HF diet-fed animals, but not in the regular diet-fed animals. This is the first observation suggesting that TCDD, a potent Ah receptor agonist, may have an obesity-inducing effect in animals fed a HF diet. While TCDD increased liver weight and decreased thymus weight in animals, these effects were enhanced by feeding animals a HF diet. Metabolism studies showed that TCDD administration for 8 or 16 weeks increased the liver microsomal activity for the 2-and 4-hydroxylation of 17β-estradiol in animals fed a control diet, but surprisingly not in animals fed a HF diet. Treatment with TCDD dose-dependently increased the hepatic activity for the O-methylation of catechol estrogens in both control and HF diet-fed animals, and it also decreased the levels of liver microsomal sulfatase activity for hydrolysis of estrone-3-sulfate. TCDD did not significantly affect the hepatic enzyme activity for the glucuronidation or esterification of endogenous estrogens. It is suggested that enhanced metabolic inactivation of 1 This study was supported, in part, by a grant from the American Cancer Society (RSG-02-143-01-CNE to BTZ) and also by grants from the NIH (CA92391, CA97109 and ES05022). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. endogenous estrogens by hepatic estrogen-metabolizing enzymes in TCDD-treated, control diet-fed animals contributes importantly to the reduced incidence of estrogen-associated tumors in animals treated with TCDD. NIH Public Access

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Section: Chemicalsmentioning

confidence: 99%

Section: Assay Of the Nadph-dependent 2-and 4-hydroxylation Of E 2 Bymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Zhu

Gallo

Burger

et al. 2008

Toxicology and Applied Pharmacology

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“…AhR-dependent upregulation of these enzymes results in increased metabolism of some AhR ligands such as PAH and the production of carcinogenic intermediates (Buters et al, 1999;Dertinger et al, 2001). In other cases, activation of the AhR results in transcriptional inhibition of genes such as those encoding the immunoglobulin heavy-chain (Sulentic et al, 2000) and estrogen-inducible p27, cathepsin D, and pS2 (Safe et al, 1998;Porter et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

et al. 2005

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“…TCDD acts as an endocrine disruptor in cell cultures, inhibiting several estrogen-induced responses such as growth of human mammary and endometrial cancer cells (20). TCDD induces the proliferation (21) and terminal differentiation (22,23) of human keratinocytes and both enhances (24) and inhibits (25,26) rat hepatocyte proliferation rates.…”

mentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression

Marlowe

Knudsen

Schwemberger³

et al. 2004

Journal of Biological Chemistry

142

121

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The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic, teratogenic, and carcinogenic effects. TCDD is a ligand for the aromatic hydrocarbon receptor (AHR), a ligand-activated transcription factor believed to be the primary mediator of these effects. Activation of the AHR by TCDD also elicits a variety of effects on cell cycle progression, ranging from proliferation to arrest. In this report, we have characterized further the role of the activated AHR in cell cycle regulation. In human mammary carcinoma MCF-7 and mouse hepatoma Hepa-1 cells, TCDD treatment decreased the number of cells in S phase and caused the accumulation of cells in G 1 . In Hepa-1 cells, this effect correlated with the transcriptional repression of several E2F-regulated genes required for S phase progression. AHR-mediated gene repression was dependent on its interaction with retinoblastoma protein but was independent of its transactivation function because AHR mutants lacking DNA binding or transactivation domains repressed E2F-dependent expression as effectively as wild type AHR. Overexpression of p300 suppressed retinoblastoma protein-dependent gene repression, and this effect was reversed by TCDD. Chromatin immunoprecipitation assays showed that TCDD treatment caused the recruitment of AHR to E2F-dependent promoters and the concurrent displacement of p300. These results delineate a novel mechanism whereby the AHR, a known transcriptional activator, also mediates gene repression by pathways involving combinatorial interactions at E2F-responsive promoters, leading to the repression of E2F-dependent, S phase-specific genes. The AHR seems to act as an environmental checkpoint that senses exposure to environmental toxicants and responds by signaling cell cycle inhibition.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) 1 is the prototypical compound of a class of environmental contaminants that includes many halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons and is a model for the outcome of exposure to these compounds as well as coplanar polychlorinated biphenyls. Exposure to TCDD results in a plethora of toxic and carcinogenic responses in animals, including liver toxicity (1), immunosuppression (2, 3), reproductive and developmental dysfunction (4 -6), endometriosis (7,8), and tumor promotion (9). The most immediate exposure outcome in humans is chloracne (10). Long term effects in humans range from immunological and reproductive perturbations (11) to cardiovascular disease (12, 13) and cancer (14 -18). TCDD itself is poorly metabolized, which leads to biological accumulation and production of sustained effects (19).Although the in vivo effects of TCDD are wide ranging, the in vitro effects are just as varied and often contradictory, affecting cell proliferation, apoptosis, and differentiation, depending on the cell type examined. TCDD acts as an endocrine disruptor in cell cultures, inhibiting several estrogen-induced responses such as growth of human mammary and endometrial canc...

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Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms

Cited by 221 publications

References 11 publications

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression

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