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Toxicological Sciences 57, 302-311 (2000)
Copyright © 2000 by the Society of Toxicology

Reproductive and Developmental Toxicology

Antiestrogenic Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Mouse Uterus: Critical Role of the Aryl Hydrocarbon Receptor in Stromal Tissue

David L. Buchanan*,1, Tomomi Sato*, Richard E. Peterson{dagger} and Paul S. Cooke*,2

* Department of Veterinary Biosciences, University of Illinois, Urbana, Illinois 61802; and {dagger} School of Pharmacy and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53706

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the role of aryl hydrocarbon receptor (AhR) in estradiol (E2)-induced uterine epithelial mitogenic activity and secretory protein mRNA expression were determined. Ovariectomized wild-type (wt) and AhR-knockout (AhRKO) mice received oil, E2, or 5 µg/kg TCDD+E2. E2 stimulated similar large increases in the uterine epithelial labeling index (LI) and mRNA abundance for the E2-dependent epithelial secretory protein, lactoferrin (LF), in both wt and AhRKO mice. However, uterine epithelial LI and LF mRNA were significantly reduced by TCDD+E2 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 tissue compartments. Tissue recombinants were grafted into nude mice, which were later ovariectomized and given oil, E2, or TCDD+E2. 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 lacking stromal AhR, even when epithelial AhR was present. Thus, TCDD inhibits E2-induced uterine epithelial mitogenic and secretory activity, and this requires AhR. Anti-proliferative effects of TCDD on uterine epithelia appear to be mediated indirectly through stromal AhR, suggesting that liganded AhR alters epithelial function by disrupting normal E2-induced stromal activity. This is the first demonstration that TCDD impairs uterine epithelial function by altering normal stromal-epithelial interactions in vivo.

Key Words: mouse; estrogen receptor-{alpha}; mitogenesis; epithelium; stroma; antiestrogen; lactoferrin; TCDD; dioxin; uterus; aryl hydrocarbon receptor.


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