: This project will study aspects of initiation of dorsolateral prostate (DLP) carcinogenesis in the Noble rat by combined estrogen-androgen treatment. It seeks to test the hypothesis that: (i) DLP dysplasia induced by androgen + estrogen treatment is a true preneoplastic lesion, and (ii) estrogen, but not non-aromatizable androgen, is an initiator of DLP carcinogenesis by causing DNA adduction. The appearance of DLP dysplasia, a putative preneoplastic lesion, and of DLP carcinoma will be used as end-points to investigate the following questions: (1) Is the DLP dysplasia induced by administration of estradiol-17beta(E2) in combination with 5alpha-dihydrotestosterone (DHT) a preneoplastic lesion, and what is the most effective dose of E2 for studying the long term effects of the hormonal treatment? The histogenesis of the dysplasia and its progression to carcinoma will be studied in a serial sacrifice experiment, and a dose-response study will be conducted to examine the effect of two lower doses of E2 than previously investigated. (2) Does estrogen act as initiating agent in the rat DLP? It will be determined whether short-term treatment with E2 in combination with continuous administration of DHT or of a combination of DHT and 2-fluoroestradiol, a non-carcinogenic estrogen, is sufficient to induce DLP (pre)neoplasia. (3) Are estrogen-generated DNA-adducts formed in the DLP upon exposure to E2 and DHT, using 32P-postlabeling techniques. (4) Does estrogen formation by aromatization of androgens play a role in DLP carcinogenesis? The potential to induce DLP (pre)neoplasia of long-term treatment with non-aromatizable DHT and aromatizable testosterone will be compared, and it will be determined whether long-term exposure to aromatizable androgen produces estrogen-generated DNA adducts.