In vivo examination of the inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on estrogen-mediated gene expression responses

Environmental contaminants that act as estrogenic endocrine disruptors (EEDs) are of concern due to their potential to cause reproductive and developmental abnormalities as well as an increased incidence in hormone dependent cancers. Many of these effects are elicited through changes in gene expression mediated by the estrogen receptor (ER), a ligand activated transcription factor. 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) is an EED which induces a wide array of toxic endpoints including lethality, hepatotoxicity and antiestrogenic effects which are mediated via changes in gene expression through activation of the aryl hydrocarbon receptor (AhR). Although the mechanisms by which the ER and AhR modulate gene expression are well established, how these changes result in the subsequent tissue-specific physiological and toxicological responses remains poorly understood. Furthermore, unlike most antiestrogenic compounds, the effects of TCDD are not mediated through binding to the ER but are thought to involve ER/AhR crosstalk which involves the ability of the activated AhR to modulate ER signaling. A number of different crosstalk mechanisms have been proposed, one of which involves the inhibition of estrogen-mediated gene expression responses. However, only a limited number of inhibited responses have been identified in vitro which are unlikely to wholly account for the in vivo antiestrogenic effects. The objective of this research was to develop a more comprehensive understanding of ethynyl estradiol- (EE) and TCDD-mediated gene expression responses in vivo through cDNA microarray analyses of hepatic and uterine tissues. Subsequently, cotreatment studies were performed to identify estrogen-mediated gene expression responses which are inhibited by TCDD to gain insights into this antiestrogenic mechanism.; Treatment of mice with EE or TCDD resulted in complex temporal- and dose-dependent hepatic gene expression responses which were consistent with known physiological and toxicological responses. These data further established the liver as an estrogen-responsive tissue and comparisons to uterine gene expression responses identified common, differential and tissue-specific effects and implicated the uterus as a more EE-responsive tissue. Hepatic gene expression responses to TCDD were related to physiological, histological and clinical responses and provided new insights into the potential mechanisms of TCDD-mediated hepatotoxicity. (Abstract shortened by UMI.)...