Received for publication August 2, 2007.
Revised October 17, 2007.
Accepted for publication October 17, 2007.

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 estrogen-mediated gene expression through ER/AhR crosstalk has been proposed as a plausible mechanism, however, only a limited number of inhibited responses have been investigated which are unlikely to fully account for the anti-uterotrophic 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 either vehicle, 3 daily doses of 10 µg/kg EE, a single dose of 30 µg/kg TCDD or a combination of EE plus TCDD and sacrificed after 4, 12, 24 and 72 hours. TCDD cotreatment inhibited EE induced uterine wet weight by 37, 23 and 45% at 12, 24 and 72 hrs, respectively. TCDD cotreatment also reduced EE-mediated stromal edema, hypertrophy and hyperplasia and induced marked luminal epithelial cell apoptosis. A 2 x 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 2,753 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 anti-uterotrophic effects of TCDD.

Key words: Sex hormones, Regulation of gene expression, Ah receptor, Toxicant-induced gene express

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