Dioxin Induces an Estrogen-Like, Estrogen Receptor-Dependent Gene Expression Response in the Murine Uterus

Boverhof, Darrell R.; Kwekel, Joshua C.; Humes, Daryl; Burgoon, Lyle D.; Zacharewski, Timothy R.

doi:10.1124/mol.105.019638

Cited by 74 publications

(36 citation statements)

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“…5A). In addition, TCDD displayed similarities to EE, consistent with our previous studies describing the estrogenlike gene expression profile of TCDD (Boverhof et al, 2006). Clustering by treatment and time point further revealed the temporal similarity of the EE and EE ϩ TCDD treatment groups as each of their gene expression time points clustered with one another (Fig.…”

Section: Resultssupporting

confidence: 72%

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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: Resultssupporting

confidence: 72%

“…Reports have indicated that TCDD elicits an estrogen-like, ER-dependent gene expression profile in the uterus (Ohtake et al, 2003;Watanabe et al, 2004;Boverhof et al, 2006). The regulation of similar genes by EE and TCDD suggests that these responses may represent targets for inhibition.…”

Section: Estrogen-tcdd Uterine Gene Expression Cross-talk 89mentioning

confidence: 99%

Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin

Boverhof

Burgoon

Williams³

et al. 2007

Mol Pharmacol

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“…Previous studies have suggested that POPs could interfere with the effects of estrogen receptor (Boverhof et al, 2006;Ma and Sassoon, 2006). In order to minimize the effects of estrogen receptor, we chose only males in our experiment.…”

Section: Methodsmentioning

confidence: 99%

Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

Shan

Wang

Huang

et al. 2014

Toxicology and Applied Pharmacology

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Keywords:PCBs TCDD Atherosclerosis PF4 MCP-1 RIG-I 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent organic pollutants found as complex mixtures in the environment throughout the world. Therefore, humans are ubiquitously and simultaneously exposed to TCDD and PCBs. TCDD and PCBs alone have been linked to atherosclerosis. However, the effects of interactions or synergism between TCDD and PCBs on atherogenesis are unknown. We investigated the possible enhanced atherogenesis by co-exposure to TCDD and PCBs and the potential mechanism(s) involved in this enhancement. Male ApoE −/− mice were exposed to TCDD (15 μg/kg) and Aroclor1254 (55 mg/kg, a representative mixture of PCBs) alone or in combination by intraperitoneal injection four times over six weeks of duration. Our results showed that mice exposed to TCDD alone, but not Aroclor1254 alone, developed atherosclerotic lesions. Moreover, we found that atherosclerotic disease was exacerbated to the greatest extent in mice co-exposed to TCDD and Aroclor1254. The enhanced lesions correlated with several proatherogenic changes, including a marked increase in the accumulation of the platelet-derived chemokine PF4, and the expression of the proinflammatory cytokine MCP-1 and the critical immunity gene-RIG-I. Our data demonstrated that co-exposure to TCDD and Aroclor1254 markedly enhanced atherogenesis in ApoE −/− mice. Significantly, our observations suggest that combined exposure to TCDD and PCBs may be a greater cardiovascular health risk than previously anticipated from individual studies.

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“…Studies also reported that 6-methyl-1,3,8-trichlorodibenzofuran can inhibit E2-induced cell proliferation and tumor growth and prevent E2-increased levels of ER and progesterone receptors (PR) [69][70]. But some studies found that dioxins can elicit AhR-mediated estrogenic activity by interacting with ER and promote gene expression and the proliferation of breast cancer cells [71][72]. In contrast to the above two viewpoints, Spink and his collaborators thought TCDD-induced AhR expression had no relationship with the proliferation and estrogen-stimulated tumor formation of MCF-7 cells [73].…”

Section: Dioxinsmentioning

confidence: 99%