Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin

Abstract

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...

Exposure to endocrine disruptors during adulthood: consequences for female fertility

“…Acute and chronic TCDD exposure (100 ng/kg/day) induced uterine tissue inflammation and increased the incidence of uterine lesions in rats (Yoshizawa et al 2009). TCDD (30 μg/kg) also caused anti-uterotrophic effects in ovariectomized mice by inhibiting estrogen-mediated gene expression (Boverhof et al 2008). Moreover, TCDD (30 μg/kg/day) inhibited estradiol-mediated uterine epithelial function via the aryl hydrocarbon receptor (Buchanan et al 2000).…”

Cross-talk of dioxin and estrogen receptor signals through the ubiquitin system

“…AhR appears to modulate estrogen/androgen signaling both positively and negatively depending on the cellular context. Anti-estrogenic effects of dioxins, such as the inhibition of estrogen-induced uterine enlargement, MCF-7 cell growth, and target-gene induction are well described [18,19]. Dioxins have also been shown to have estrogenic effects including the stimulation of uterine enlargement [20], and the induction of estrogen-responsive genes [21].…”

Evolution of the Human Brain: the key roles of DHA (omega-3 fatty acid) and Δ6-desaturase gene

“…Lastly, the GLUT-1 protein is attached to the submembranous actin cytoskeleton by an anchoring protein known as GIPC1 (Reed et al, 2005). Estradiol increases the expression of GIPC1 mRNA (Boverhof et al, 2008).…”