Analysis of the Antiestrogenic Activity of 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-dioxin in Human Ovarian Carcinoma BG-1 Cells

Rogers, Jane M.; Denison, Michael S.

doi:10.1124/mol.61.6.1393

Cited by 50 publications

(29 citation statements)

References 39 publications

(52 reference statements)

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“…This included the well characterized induction of Cyp1a1 as well as the induction of inhibitor of growth 1 (Ing1), karyopherin alpha 6 (Kpna6), and replication protein A2 (Rpa2). The induction of these genes cannot be dismissed as a contributing factor to the antiestrogenic effects of TCDD because the induction of inhibitory factors is a previously proposed mechanism (Rogers and Denison, 2002).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin

Boverhof

Burgoon

Williams³

et al. 2007

Mol Pharmacol

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exhibits antiestrogenic properties, including the inhibition of estrogen-induced uterine growth and proliferation. The inhibition of estrogenmediated gene expression through ER/AhR cross-talk has been proposed as a plausible mechanism; however, only a limited number of inhibited responses have been investigated that are unlikely to fully account for the antiuterotrophic effects of TCDD. Therefore, the effects of TCDD on ethynyl estradiol (EE)-mediated uterine gene expression were investigated using cDNA microarrays with complementary physiological and histological phenotypic anchoring. Mice were gavaged with vehicle, 3 daily doses of 10 g/kg EE, a single dose of 30 g/kg TCDD, or a combination of EE plus TCDD and sacrificed after 4, 12, 24, and 72 h. TCDD cotreatment inhibited EE-induced uterine wet weight by 37, 23, and 45% at 12, 24, and 72 h, respectively. TCDD cotreatment also reduced EE-mediated stromal edema, hypertrophy, and hyperplasia and induced marked luminal epithelial cell apoptosis. A 2 ϫ 2 factorial microarray design was used to identify EE-and TCDD-specific differential gene expression responses as well as their interactive effects. Only 133 of the 2753 EE-mediated differentially expressed genes were significantly modulated by TCDD cotreatment, indicating a gene-specific inhibitory response. The EE-mediated induction of many genes, including trefoil factor 1 and keratin 14, were inhibited by greater than 90% by TCDD. Functional annotation of inhibited responses was associated with cell proliferation, water and ion transport, and maintenance of cellular structure and integrity. These inhibited responses correlate with the observed histological alterations and may contribute to the antiuterotrophic effects of TCDD.Estrogens regulate growth, development, and reproductive function in men and women and have been implicated in the etiology of breast and endometrial cancers (Hewitt et al., 2005). Many estrogen effects are mediated through the estrogen receptor (ER), a ligand-activated transcription factor and member of the nuclear receptor superfamily (Nilsson et al., 2001). In the traditional mechanism, ligand binding to the ER results in dissociation from heat shock and chaperone proteins, homodimerization, and interaction with regulatory elements near estrogen-responsive genes known as estrogen response elements (EREs) (Klinge, 2001). However, the activated ER can also mediate effects via interactions with Fos/ Jun at AP-1 sites, via Sp1 at GC-rich promoter regions (Hall et al., 2001;Nilsson et al., 2001), and through ligand-independent, DNA binding-independent, and cell-surface (nongenomic) signaling mechanisms (Hall et al., 2001). These ER-mediated alterations in gene expression and signaling pathways are responsible for the subsequent molecular and physiological responses to estrogens.Like the ER, the aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor but is a member of the basic helix-loop-helix-PER/ARNT/SIM (periodicity/a...

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Section: Resultsmentioning

confidence: 99%

Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin

Boverhof

Burgoon

Williams³

et al. 2007

Mol Pharmacol

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“…Female rats chronically treated with TCDD are also less likely to develop mammary and uterine tumors (22). The molecular basis for this cross talk is unclear and may be a combination of several different mechanisms, such as rapid metabolism of estrogen, increased ER degradation (58), inhibitory XREs located in estrogen-responsive genes (7), squelching of common cofactors (4), and the induction of inhibitory factors (37).…”

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confidence: 99%

Aryl Hydrocarbon Receptor-Mediated Transcription: Ligand-Dependent Recruitment of Estrogen Receptor α to 2,3,7,8-Tetrachlorodibenzo- p-Dioxin-Responsive Promoters

Matthews

Wihlén

Thomsen

et al. 2005

Molecular and Cellular Biology

184

158

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Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several coregulators to the CYP1A1 promoter. AhR displayed a time-dependent recruitment, reaching a peak at 75 min and maintaining promoter occupancy for the remainder of the time course. Recruitment of AhR was followed by TIF2/SRC2, which preceded CBP, histone H3 acetylation, and RNA polymerase II (RNAPII). Simultaneous recruitment to the enhancer and the TATA box region suggests the formation of a large multiprotein complex bridging the two promoter regions. Interestingly, estrogen receptor ␣ (ER␣) displayed a TCDD-and time-dependent recruitment to the CYP1A1 promoter, which was increased by cotreatment with estradiol. Transfection in HuH7 human liver cells confirmed previously reported ER␣ enhancement of AhR activity. In contrast, TCDD did not induce the recruitment of ER␣ to the estrogen-responsive pS2 promoter, and after 120 min of cotreatment with estradiol, ER␣ is still present on the CYP1A1 promoter but no longer at pS2. RNA interference studies with T47D cells support a role for ER␣ in TCDD-dependent CYP1A1 expression. Our data suggest that ER␣ acts as a coregulator of AhR-mediated transcriptional activation and that the recruitment of ER␣ by AhR represents a novel mechanism AhR-ER␣ cross talk.

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“…Nuclear extracts were prepared as described previously (Rogers and Denison, 2002). A complementary pair of synthetic oligonucleotides containing the XRE3 binding site for the transformed AHR/ ARNT complex (5Ј-GATCTGGCTCTTCTCACGCAACTCCG-3Ј and 5Ј-GATCCGGAGTTGCGTGAGAAGAGCCA-3Ј) were synthesized, purified, annealed, and radiolabeled with [␥-32 P]ATP as described previously (Denison et al, 1988).…”

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confidence: 99%

tert-BUTYLHYDROQUINONE IS A NOVEL ARYL HYDROCARBON RECEPTOR LIGAND

Gharavi¹,

El‐Kadi²

2004

Drug Metab Dispos

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ABSTRACT:In contrast to the beneficial effects of tert-butylhydroquinone (tBHQ) as a food antioxidant, a number of studies have shown that chronic exposure to tBHQ may induce carcinogenicity. Therefore, we examined the ability of tBHQ to induce the cytochrome P450 1a1 (Cyp1a1), an enzyme known to play an important role in the chemical activation of xenobiotics to carcinogenic derivatives. A significant concentration-dependent increase in Cyp1a1 mRNA, protein, and activity occurred after treatment of murine hepatoma Hepa 1c1c7 cells with tBHQ. The increase in mRNA was apparent 3 h after treatment. The RNA polymerase inhibitor, actinomycin D, completely blocked the Cyp1a1 induction by tBHQ, indicating a requirement of de novo RNA synthesis through transcriptional activation. The protein synthesis inhibitor cycloheximide superinduced the tBHQ-mediated induction of Cyp1a1 mRNA and completely prevented the increase in Cyp1a1 activity, indicating that the induction of enzyme activity by tBHQ is dependent on de novo protein synthesis. In addition, the aryl hydrocarbon receptor (AHR) antagonist, resveratrol, inhibited the increase in Cyp1a1 activity by tBHQ. Gel electrophoretic mobility shift assays showed that tBHQ causes activation or transformation of the AHR in nuclear extracts, indicating that AHR-dependent mechanisms contributed to the Cyp1a1 induction. Similar to murine Hepa 1c1c7 cells, tBHQ caused a concentration-dependent increase in CYP1A1 at the mRNA and activity levels in human HepG2 cells. This is the first demonstration that the phenolic antioxidant, tBHQ, can directly induce Cyp1a1 gene expression in an AHR-dependent manner and may represent a novel mechanism by which tBHQ promotes carcinogenicity.

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Analysis of the Antiestrogenic Activity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Human Ovarian Carcinoma BG-1 Cells

Cited by 50 publications

References 39 publications

Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin

Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin

Aryl Hydrocarbon Receptor-Mediated Transcription: Ligand-Dependent Recruitment of Estrogen Receptor α to 2,3,7,8-Tetrachlorodibenzo- p-Dioxin-Responsive Promoters

tert-BUTYLHYDROQUINONE IS A NOVEL ARYL HYDROCARBON RECEPTOR LIGAND

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