Regional differences in the prostate of the neonatally estrogenized mouse

Abstract

Neonatal estrogenization of the mouse with diethylstilbestrol resulted in time-of-exposure and dose-dependent inhibition of the growth of the prostatic lobes observed at the age of 2 mon. The critical time was the days 1-6 of postnatal life. In neonatally estrogenized (neoDES) mice, responses to 5 alpha-dihydrotestosterone in terms of nuclear 3H-thymidine labelling were altered concomitantly with the inhibition of growth and were in accordance with changes in the relative volumes of epithelium, glandular lumina, and interacinar stroma. Secondary estrogen treatment of neoDES mice with 17 beta-estradiol did not increase 3H-thymidine labelling in the prostate of control or neoDES mice. However, it induced squamous epithelial metaplasia in periurethral collecting ducts and proximal parts of coagulating glands of neoDES animals. In control mice only slight epithelial hyperplasia could be observed after similar treatment. Estrogen receptors, located immunocytochemically in nuclei of stromal cell, corresponded with the sites of increased estrogen sensitivity, observed as metaplastic transformation. When the neoDES animals aged, epithelial hyperplasia and dysplasia could be observed at distinct prostatic sites, ie, the periurethral collecting ducts and the coagulating glands and periurethral glands, and stromal inflammation become more extensive. Almost identical location of the epithelial changes and the altered estrogen response is suggestive of causal relationship.

Morphometric studies of neonatal estrogen imprinting in the mature mouse prostate

“…Estrogens elicited a marked stimulation of fibromuscular stroma both in proportional and absolute terms, confirming it as being the primary site for estrogen action and implicate complex mesenchymalepithelial interactions to induce changes at the epithelial level. Similar effects were reported by Pylkkanen et al (1991) who showed localized hyperplasia and dysplasia at distinct sites of the mouse urethro-prostatic complex and increased the expression of the proto-oncogene, c-myc in the prostate after neonatal estrogenization. This increase is believed to be associated with increased prostatic dysplasia in mice (Pylkkanen et al 1993) which is the most common possible pre-malignant lesion of the prostate and may represent the initial transformation event in the majority of prostate cancers (McNeal & Bostwick 1986, McNeal 1991.…”

“…Although ductal tips with DES were significantly reduced compared with EB treatment, VP weight was unaffected owing partially due to increased epithelial width or fibromuscular stroma with DES treatment. Similar reductions in prostate size and alterations in the prostatic composition have also been reported by perinatal exposure to DES or estradiol in rodents in earlier studies (Chung & MacFadden 1980, Higgins et al 1981, Naslund & Coffey 1986, Pylkkanen et al 1991. These long-term alterations might be due to differentiation defects induced in prostatic cells as a result of neonatal estrogen exposure that results in their abnormal pattern of growth later in life (Weinberg 1991).…”

“…Exposure of experimental animals to estrogens during critical periods of development have been reported to lead to altered structure (Chung & MacFadden 1980, Gaytan et al 1986, Naslund & Coffey 1986, Zhao et al 1992, vom Saal et al 1997 and function (Higgins et al 1981, Prins et al 1993) of the prostate. Neonatal estrogens induce long-term modifications in the accessory sex glands of rodents including epithelial changes (Arai 1970, Pylkkanen et al 1991, changed hormonal sensitivity (Rajfer & Coffey. 1978, alterations in the androgen receptor expression (Prins 1992, Prins & Birch 1995, auto-up-regulation of estrogen receptor expression (Prins & Birch.…”

Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy

“…Previous studies by us and others have shown prostatic epithelial dysplasia and inflammatory cell infiltration in the prostates of mice as they age, after they were transiently treated with estrogen during neonatal life. 10,22,34,35 This estrogen-induced inflammatory response also appears to be specifically mediated by ER␣: ER␣ knockout mice show no prostatic response to neonatal diethylstilbestrol, but ER␤ knockout mice show a response similar to that observed in wild-type animals. 12 The observation that estrogen is linked to the development of prostatic inflammation is particularly significant as estrogens, in addition to androgens, have also been implicated in the development of PCa.…”

Delay of Postnatal Maturation Sensitizes the Mouse Prostate to Testosterone-Induced Pronounced Hyperplasia

“…There is strong experimental evidence that, at least in rodents, excessive or untimely exposure to estrogens can induce prostatic neoplasia. [1][2][3][4][5][6] Moreover, aromatizable but not nonaromatizable androgens can cause prostate cancer. 7,8 On the other hand, impaired estrogen action can also lead to structural and functional abnormalities in prostatic epithelium, as has been demonstrated in estrogen receptor (ER)-␤ 9 or aromatase-deficient mice.…”