Influence of neonatal estrogens on rat prostate development

Abstract

Brief exposure of rodents to estrogens during early development alters prostate branching morphogenesis and cellular differentiation in a dose-dependant manner. If estrogenic exposures are high, these disturbances lead to permanent imprints of the prostate, which include reduced growth, differentiation defects of the epithelial cells, altered secretory function and reduced responsiveness to androgens in adulthood. This process, referred to as neonatal imprinting or developmental estrogenization, is associated with an increased incidence of prostatic lesions with aging, which include hyperplasia, inflammation and dysplasia. To better understand how early estrogenic exposures can permanently alter prostate growth and function and predispose the gland to neoplasia, the effects of estrogens on prostatic steroid receptors, cell-cell communication molecules and key developmental genes were examined. Transient and permanent alterations in the expression of prostatic androgen receptors, estrogen receptors alpha (ERalpha) and beta, and retinoic acid receptors are observed. It is proposed that the estrogen-induced alterations in these critical transcription factors play a fundamental role in initiating prostatic growth and differentiation defects. Down-stream effects of the altered steroid receptor expression include disruption of TGFbeta paracrine communication, altered expression of gap junction connexin molecules and loss of epithelial cadherin on epithelial cells. Additionally, specific disruptions in the expression of prostatic developmental genes are observed in response to neonatal estrogen. An extended developmental period of hoxa-13 expression, a lack of hoxd-13 increase with maturation, and an immediate and sustained suppression of hoxb-13 was noted within prostatic tissue. A transient decrease in Nkx3.1 expression in the developing prostate was also observed. Thus subtle and overt alterations in Hox-13 and Nkx3.1 genes may be involved in the altered prostate phenotype in response to neonatal estrogen exposure. In summary, estrogen imprinting of the prostate gland is mediated through up-regulated levels of stromal ERalpha, which initiates alterations in steroid receptor expression within the developing gland. Rather than being an androgen-dominated process, as occurs normally, prostatic development is regulated by alternate steroids, including estrogens and retinoids, in the estrogenized animal. This, in turn, leads to disruptions in the coordinated expression of critical developmental genes including TGFbeta, Hox-13 genes and Nkx3.1. Since a precise temporal expression pattern of these and other molecules is normally required for appropriate differentiation of the prostatic epithelium and stroma, the estrogen-initiated disruption in this pattern would lead to permanent differentiation defects of the prostate gland. It is hypothesized that these molecular and cellular changes initiated early in life predispose the prostate to the neoplastic state upon aging.

Estrogen receptor α and imprinting of the neonatal mouse ventral prostate by estrogen

“…In the adult mouse VP, ER␣ is not detectable in the epithelium. Because adult VP epithelium is devoid of ER␣, the current view is that imprinting is mediated by stromal ER␣ (1,5).…”

“…branching morphology ͉ immunohistochemistry ͉ androgen receptor ͉ proliferation ͉ 5␣-androstane-3␤,17␤-diol E xposure of neonatal mice to the nonsteroidal estrogen diethylstilbestrol disturbs prostatic development, alters epithelial cell differentiation, and predisposes mice as they age to prostatic hyperplasia and dysplasia analogous to human prostatic intraepithelial neoplasia (1)(2)(3). This delayed effect of a brief neonatal exposure to estrogens is called imprinting.…”

“…In the adult rodent ventral prostate (VP), ER␤ is the only ER expressed in the epithelium, whereas ER␣ is expressed in the stroma (6). To explain the role of ER␣ in imprinting of the prostate, it was hypothesized that estrogen acts on stromal ER␣ to stimulate growth factor release, and these growth factors cause epithelial proliferation (1,5).…”

Neonatal treatment of rats with diethylstilboestrol (DES) induces stromal-epithelial abnormalities of the vas deferens and cauda epididymis in adulthood following delayed basal cell development

“…Second, studies of animals in which one or both oestrogen receptors (ERa, ERb) have been inactivated using transgenesis in mice (Couse & Korach 1999). The precise physiological role(s) played by oestrogens in development of the male reproductive system is still unclear, but the prevailing impression gained from the aforementioned studies is that excessive exposure to oestrogens, and consequent disruption of the androgenoestrogen balance, can cause permanent malformations (Arai et al 1983, Toppari et al 1996, Prins et al 2001b, Rivas et al 2002 and predispose to further aberrant changes in later life (Cunha 2001, Prins et al 2001b.…”

“…Studies in rats treated neonatally with diethylstilboestrol (DES), have shown impaired development of the epithelium and relative overgrowth of stromal tissue in the epididymis , vas deferens , seminal vesicles , and prostate (Prins et al 2001b, during or soon after the cessation of treatment. These gross structural changes are associated with reduced expression of the androgen receptor (AR; Prins 1992, Prins & Birch 1995, 2001, and with induction of abnormal expression of ERa , Prins et al 2001b.…”