INDUCTION OF A DNA ADDUCT DETECTABLE BY P-32 POSTLABELING IN THE DORSOLATERAL PROSTATE OF NBL CR RATS TREATED WITH ESTRADIOL-17-BETA AND TESTOSTERONE/

Treatment with estradiol-17 beta and testosterone induces epithelial d ysplasia and, subsequently, adenocarcinoma in the dorsolateral prostat e of NBL rats. The purpose of this study was to determine whether this carcinogenic effect is mediated by genotoxicity. Analogous to adducts produced by estrogens in the male hamster kidney, a target of estroge n carcinogenicity, induction of DNA adducts detectable by P-32-postlab eling was investigated in the prostate target tissue. NBL rats were tr eated with separate Silastic tubing implants containing testosterone a nd estradiol-17 beta. Control animals received empty implants, Animals were killed at 8, 16 and 24 weeks after initiation of treatment, and accessory sex glands were sampled for adduct analysis, DNA of the dors olateral and ventral prostate and the coagulating gland (= anterior pr ostate) was isolated and analyzed by nuclease P1-enhancement of the P- 32-post-labeling assay. DNA adducts were quantitated by Cerenkov count ing, An adduct occurred selectively in DNA of the dorsolateral prostat e of rats treated with estradiol plus testosterone for 16 or 24 weeks with relative adduct level values of similar to 10x10(9), but not in D NA of the ventral or anterior prostate. The adduct was not present in DNA of prostate tissue of rats treated for 8 weeks or in DNA of contro l tissues. This adduct was unique with respect to chromatographic loca tion and has not been observed before in any tissue of control or horm one-treated animals. Neither the structure of the treatment-induced ad duct nor the mechanism of its formation is known. However, the selecti ve occurrence of this adduct in the tissue of origin of the carcinomas and its appearance coinciding with putative preneoplastic lesions and preceding carcinoma development suggests a causal relation between ad duct formation and prostate cancer development in testosterone plus es tradiol-17 beta-treated rats.