Abstract:
Brief exposure of rodents to estrogens during early development altersprostate branching morphogenesis and cellular differentiation in adose-dependant manner. If estrogenic exposures are high, these disturbanceslead to permanent imprints of the prostate, which include reduced growth,differentiation defects of the epithelial cells, altered secretory functionand reduced responsiveness to androgens in adulthood. This process, referredto as neonatal imprinting or developmental estrogenization, is associated withan increased incidence of prostatic lesions with aging, which includehyperplasia, inflammation and dysplasia. To better understand how earlyestrogenic exposures can permanently alter prostate growth and function andpredispose the gland to neoplasia, the effects of estrogens on prostaticsteroid receptors, cell-cell communication molecules and keydevelopmental genes were examined. Transient and permanent alterations in theexpression of prostatic androgen receptors, estrogen receptors α(ERα) and β, and retinoic acid receptors are observed. Itis proposed that the estrogen-induced alterations in these criticaltranscription factors play a fundamental role in initiating prostatic growthand differentiation defects. Down-stream effects of the altered steroidreceptor expression include disruption of TGFβ paracrinecommunication, altered expression of gap junction connexin molecules and lossof epithelial cadherin on epithelial cells. Additionally, specific disruptionsin the expression of prostatic developmental genes are observed in response toneonatal estrogen. An extended developmental period ofhoxa-13 expression, a lack ofhoxd-13 increase with maturation, and an immediate andsustained suppression of hoxb-13 was noted withinprostatic tissue. A transient decrease inNkx3.1expression in the developing prostate was also observed. Thus subtle and overtalterations in Hox-13 and Nkx3.1genes may be involved in the altered prostate phenotype in response toneonatal estrogen exposure. In summary, estrogen imprinting of the prostategland is mediated through up-regulated levels of stromal ERα, whichinitiates alterations in steroid receptor expression within the developinggland. Rather than being an androgen-dominated process, as occurs normally,prostatic development is regulated by alternate steroids, including estrogensand retinoids, in the estrogenized animal. This, in turn, leads to disruptionsin the coordinated expression of critical developmental genes includingTGFβ, Hox-13 genes andNkx3.1. Since a precise temporal expression pattern ofthese and other molecules is normally required for appropriate differentiationof the prostatic epithelium and stroma, the estrogen-initiated disruption inthis pattern would lead to permanent differentiation defects of the prostategland. It is hypothesized that these molecular and cellular changes initiatedearly in life predispose the prostate to the neoplastic state upon aging.Extra keywords: connexins, development, TGFβsteroid receptors.