Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse uterus: Critical role of the aryl hydrocarbon receptor in stromal tissue

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the role of a ryl hydrocarbon receptor (AhR) in estradiol (E-2)-induced uterine epithelia l mitogenic activity and secretory protein mRNA expression were determined. Ovariectomized wild-type (wt):and AhR-knockout (AhRKO) mice received oil, E-2, or 5 mu g/kg TCDD+E-2. E-2 stimulated similar large increases in the u terine epithelial labeling index (LI) and mRNA abundance for the E-2-depend ent epithelial secretory protein, lactoferrin (LF), in both wt and AhRKO mi ce. However, uterine epithelial LI and LF mRNA were significantly reduced b y TCDD+E-2 in wt but not AhRKO mice. To determine the roles of stromal and epithelial AhR in the TCDD effect, uterine stroma and epithelium from AhRKO and wt mice were enzymatically separated and recombined into four types of tissue recombinants that either contained or lacked AhR in one or more tis sue compartments. Tissue recombinants were grafted into nude mice, which we re later ovariectomized and given oil, E-2, or TCDD+E-2. Epithelial LI was significantly reduced by TCDD in grafts containing stromal AhR, regardless of epithelial AhR status. However, LI was unaffected by TCDD in grafts lack ing stromal AhR, even when epithelial AhR was present. Thus, TCDD inhibits E-2-induced uterine epithelial mitogenic and secretory activity, and this r equires AhR. Antiproliferative effects of TCDD on uterine epithelia appear to be mediated indirectly through stromal AhR, suggesting that liganded:AhR alters epithelial function by disrupting normal E-2-induced stromal activi ty. This is the first demonstration that TCDD impairs,uterine epithelial fu nction by altering normal stromal-epithelial interactions in vivo.