Stimulation of prostatic epithelial cell proliferation by androgens during exposure to chemical carcinogens increases the susceptibility of the rat prostate to cancer induction as a co-carcinogen. Testosterone is a weak complete carcino gen, but is a very strong tumor promotor for the rat prostate at near-physiological plasma concentrations [199]. The very strong tumor-promoting activity of androgens is perhaps responsible for their weak complete carcinogenic activity on the rat prostate. A slight elevation of circulating testosterone can lead to a marked increase in prostate cancer in rat models. This observation is very important in view of the aforementioned weak association between human prostate cancer risk and slightly elevated circulating androgen levels found in some epidemiological studies [173]. Thus, the experimental animal data provide strong support for the concept that minimal increases in circulating an-drogens may have substantial enhancing effects on prostate cancer risk. The addition of 17^-estradiol to chronic androgen treatment strongly enhances the carcinogenic activity of testosterone for the rat dorsolateral prostate, particularly the proximal periurethral ducts of the dorsolateral and anterior prostate. The 17^-estradiol plus testosterone treatment also induces acinar lesions that are similar to human PIN. These observations strongly suggest a critical role for estrogens in prostate carcinogenesis. Perinatal estrogen exposure can also be carcinogenic for the male rodent accessory sex glands. The proximal peri-urethral ducts of the dorsolateral and anterior prostate and seminal vesicle and the intraprostatic urethral epithelium appear to be the male rodent genital tract tissues most sensitive to the carcinogenic effects of perinatal estrogen exposure. Interesting in this regard is the report by Driscoll and Taylor [233] of hypertrophy and squamous metaplasia of the prostatic utricle and prostatic ducts in 55 -71% of 31 male infants that had been exposed to DES in utero and had died perinatally from unrelated causes. Such squamous metaplastic changes have also been reported to occur in human fetal prostatic tissue transplanted into nude mice that were subsequently treated with DES [234]. These human observations suggest that the DES findings in rodents may have human relevance. There are no other data on carcinogenic effects of environmental hormonal agents for the prostate in animal models.

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