Han X, Liehr J G, Bosland M C
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
Carcinogenesis. 1995 Apr;16(4):951-4. doi: 10.1093/carcin/16.4.951.
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.
用17β -雌二醇和睾酮处理可诱导NBL大鼠背外侧前列腺发生上皮发育异常，随后引发腺癌。本研究的目的是确定这种致癌作用是否由基因毒性介导。与雌激素在雄性仓鼠肾脏（雌激素致癌作用的一个靶点）产生的加合物类似，在前列腺靶组织中研究了通过32P后标记法可检测到的DNA加合物的诱导情况。用分别含有睾酮和17β -雌二醇的硅胶管植入物处理NBL大鼠。对照动物接受空植入物。在开始治疗后的8、16和24周处死动物，并采集附属性腺进行加合物分析。分离背外侧前列腺、腹侧前列腺和凝固腺（=前前列腺）的DNA，并通过核酸酶P1增强的32P后标记测定法进行分析。通过切伦科夫计数对DNA加合物进行定量。在用雌二醇加睾酮处理16或24周的大鼠背外侧前列腺DNA中选择性地出现了一种加合物，相对加合物水平值约为10×10⁹，但在腹侧或前前列腺DNA中未出现。在处理8周的大鼠前列腺组织DNA或对照组织DNA中未发现该加合物。就色谱位置而言，这种加合物是独特的，在对照或激素处理动物的任何组织中以前都未观察到。治疗诱导的加合物的结构及其形成机制均未知。然而，这种加合物在癌组织起源部位的选择性出现及其与假定的癌前病变和癌发展之前的出现时间一致，表明在睾酮加17β -雌二醇处理的大鼠中，加合物形成与前列腺癌发展之间存在因果关系。
