Estrogenic regulation of signaling pathways and homeobox genes during rat prostate development.

The developing prostate gland is regulated by its hormonal milieu, most notably androgens, which dictate its growth and differentiation (Price, 1936; Lasnitzki and Mizuno, 1980). In addition, the developing prostate is sensitive to estrogenic exposures (Price, 1963). During prostate morphogenesis, elevated levels of endogenous estrogens (maternal or excess local production) or exogenous estrogens (diethylstilbestrol [DES] or, potentially, environmental estrogens) have been shown to induce permanent disturbances in prostate growth and predispose to precancerous lesions, a process referred to as developmental estrogenization or estrogen imprinting (Santti et al, 1994). The rodent prostate has evolved as a useful model to study early estrogenic exposures since the gland develops postnatally and can be used to model in utero events for human prostate development. The specific model used in our laboratory to study developmental estrogenization of the prostate gland is the Sprague–Dawley rat given injections of 25 mg of estradiol on neonatal days 1, 3, and 5. It is important to mention that although this is considered ‘‘high-dose,’’ the majority of neonatally administered estradiol is bound to a-fetoprotein, which circulates at high levels in neonatal rat serum (Sheehan and Young, 1979). Consequently, neonatal estradiol is 75-fold less potent than an equivalent dose of DES (Sheehan and Branham, 1987) or, put another way, 25 mg of estradiol per pup is equivalent to 0.33 mg of DES per pup. Recent work from our laboratory has examined a dose–response relation for increasing neonatal estradiol exposures and have observed a monotonic effect on the prostate, with growth inhibition and reduced androgen receptor observed at doses of 10 mg per pup (equivalent to 0.13 mg of DES per pup) and no prostatic stimulation at lower