Induction of a DNA adduct detectable by 32P-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 dysplasia and, subsequently, adenocarcinoma in the dorsolateral prostate 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 estrogen carcinogenicity, induction of DNA adducts detectable by 32P-postlabeling was investigated in the prostate target tissue. NBL rats were treated with separate Silastic tubing implants containing testosterone and 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 dorsolateral and ventral prostate and the coagulating gland (= anterior prostate) was isolated and analyzed by nuclease P1-enhancement of the 32P-post-labeling assay. DNA adducts were quantitated by Cerenkov counting. An adduct occurred selectively in DNA of the dorsolateral prostate of rats treated with estradiol plus testosterone for 16 or 24 weeks with relative adduct level values of approximately 10 x 10(9), but not in DNA 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 control tissues. This adduct was unique with respect to chromatographic location and has not been observed before in any tissue of control or hormone-treated animals. Neither the structure of the treatment-induced adduct nor the mechanism of its formation is known. However, the selective 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 adduct formation and prostate cancer development in testosterone plus estradiol-17 beta-treated rats.
Han
X
X
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
Liehr
J G
JG
Bosland
M C
MC
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D006224:Cricetinae; D004247:DNA / Q000032:analysis; D018736:DNA Adducts / Q000032:analysis / Q000096:biosynthesis*; D004958:Estradiol / Q000633:toxicity*; D008297:Male; D010761:Phosphorus Radioisotopes; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000633:toxicity*
D018736:DNA Adducts; D010761:Phosphorus Radioisotopes; D013739:Testosterone; D004958:Estradiol; D004247:DNA