Tissue-Specific Mediation of Estrogen-Induced Epithelial Events by the Estrogen Receptor in Female Reproductive Tract Organs

Estrogen receptor-alpha (ERalpha), which mediates the normal uterine and vaginal epithelial proliferative and differentiative effects of 17-beta estradiol (E2), is present in both stroma and epithelium of female reproductive tract organs. Although, the epithelial response to E2 has been assumed to be mediated directly through epithelial ER, indirect mediation by stromal ER may be responsible. The estrogenic response in reproductive tissues may also be influenced by natural and synthetic chemicals. To understand the role of ERalpha in E2-induced uterine and vaginal epithelial responses, uterus and vagina were removed from ERalpha knockout (ERKO) and wild-type mice to enzymatically separate the epithelial and stromal fractions. Isolated tissue fractions were recombined to produce tissue recombinants that contained ERalpha in both epithelium and stroma or lacked ERalpha in one or both tissue compartments. Recombined tissues were grafted to host animals and grown in vivo. By monitoring the extent of epithelial mitogenesis and differentiation in the various tissue recombinants, the role of ERalpha in each tissue compartment was definitively determined. Results show that normal E2-induced epithelial proliferation in female reproductive tract organs is mediated indirectly through stromal ERalpha while epithelial ERalpha are neither necessary nor sufficient to mediate this response. Conversely, E2 induction of epithelial differentiative events require both epithelial and stromal ERalpha. When ovariectomized mice were exposed to the suspected antiestrogenic environmental contaminant and aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), normal E2-induced uterine epithelial function was inhibited. However, uterine epithelial function in mice that lack AhR (AhRKO) was not affected by TCDD exposure. Uterine epithelial and stromal tissue fractions from AhRKO mice were then recombined with that of wild-type mice, to create tissue recombinants that lacked AhR in either stroma, epithelia or both. Results indicate that the TCDD anti-proliferative effect on epithelia is mediated indirectly through stromal AhR. Thus, both AhR and ERalpha mediate epithelial effects indirectly through the stroma. These findings provide exciting new insight into the mechanism of AhR action and suggest liganded AhR may interfere somehow with ERalpha action to prevent mediation of the E2 signal.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Veterinary Clinical Medicine

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Buchanan, David Lee

Contributors dc:contributor

• Cooke, Paul S.

• Biology, Molecular

Language dc:language

eng

Identifier

(MiAaPQ)AAI9955688

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/87144