Influence of neonatal estrogens on rat prostate development.

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.