Influence of neonatal estrogens on rat prostate development
Authors: Prins Gail S. , Birch Lynn , Habermann Helga , Chang William Y. , Tebeau Christopher , Putz Oliver , Bieberich Charles 
Published: September 2002

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 α
(ERα) and β, 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 TGFβ 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 inNkx3.1
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 ERα, 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
TGFβ, 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.