The rationale for this project is that the developing prostate is responsive to estrogen and inappropriate developmental estrogenization is hypothesized to contribute to abnormal function and disease of the prostate in adult life. This is a relevant issue for humans. Approximately 4.8 million women in the U.S. took the potent synthetic estrogen, diethylstilbestrol (DES), during pregnancy between 1938-1971. Although this population of """"""""DES sons"""""""" is not yet old enough to assess whether they have increased incidence of prostatic disease, rodent models demonstrate long-term alteration in prostatic function following perinatal exposure to DES. In addition, there has been considerable debate in the past several years about whether developmental exposure to estrogenic environmental chemicals could elicit DES-like effects on the prostate. The overall goal of this proposal is to investigate the cellular and molecular mechanisms underlying estrogen action on the developing prostate with an emphasis on the role of cell-cell interactions and estrogen receptors (ERalpha and ERbeta). The first specific aim in this proposal entails exposing developing mice (wild-type, alphaERKO and betaERKO) to DES and assessing long-term effects on the prostate.
The second aim i s to develop a mouse ventra1 prostate organ culture system for utilization of wild-type, alphaERKO and betaERKO mice. In parallel, short-term in vivo experiments will be conducted to validate the organ culture system. The goal of the third aim is to determine the respective contributions of ERalpha and ERbeta in mediating DES- induced squamous metaplasia of the prostate. For this experiment, tissue recombinants (TRs) will be prepared from wild-type, alphaERKO and betaERKO animals followed by transplantation of the TRs into an athymic host mouse. The host mice will be chronically treated with DES to induce squamous metaplasia of the prostate. Finally, the fourth aim seeks to extend the results of the third aim by preparing TRs between wild-type, alphaERKO, betaERKO mouse tissue and human tissue for confirmation that mechanisms of estrogen response are similar in the rodent and human.
