Estrogen Receptor- Messenger Ribonucleic Acid Ontogeny in the Prostate of Normal and Neonatally Estrogenized Rats

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Abstract
Neonatal exposure to estrogens permanently alters rat prostate growth and epithelial differentiation leading to prostatic dysplasia on aging. The effects are lobe-specific, with the greatest response ob- served in the ventral lobe. Recently, a novel estrogen receptor (ER) complementary DNA was cloned from the rat prostate and termed ER-b (ERb) due to its high homology with the classical ERa. The protein possesses high affinity for 17b-estradiol, indicating that ERb is an alternate molecule for mediating estrogenic effects. Importantly, ERb messenger RNA (mRNA) was localized to rat prostatic epithelial cells, which contrasts with the stromal localization of ERa in the rat prostate. The present study was undertaken to determine the ontog- eny of ERb mRNA expression in the rat prostate lobes and to examine the effects of early estrogen exposure on prostatic ERb expression. Male rat pups were given 25 mg estradiol or oil on days 1, 3, and 5; were killed on day 1, 3 (oils only), 6, 10, 30, or 90; and prostate lobes were frozen. Longitudinal sections were processed for in situ hybrid- ization using an 35S-labeled antisense mRNA probe corresponding to a 400-bp EcoRI-AccI fragment in the 59untranslated region of rat ERb complementary DNA. Image analysis was used to quantitate silver grains. In addition, total RNA was isolated from the ventral prostate (VP) and used for semiquantitative RT-PCR. Results from in situ hybridization revealed that at birth, ERb was equivalently expressed at low levels in both mesenchymal and epithelial cells in oil-treated rats. From day 1 onwards, expression in all stromal cells slowly and significantly declined, so that in the control adult prostate, stromal ERb mRNA was slightly above background. In the oil-treated control rats, epithelial ERb mRNA increased to moderate levels between days 6 -10 in the VP and days 10 -15 in the dorsal and lateral lobes as cells began differentiation and ducts lumenized. A further significant in- crease in ERb message was observed at day 30, which indicates that full epithelial ERb expression may require the completion of func- tional differentiation. By day 90, expression levels were maximal and similar between the lobes. RT-PCR substantiated this developmental increase in ERb between days 1-90. Neonatal exposure to estrogens did not have an immediate effect on prostatic ERb mRNA levels as determined by in situ hybridization and RT-PCR. However, the marked increase in epithelial cell expression at day 30 observed in the control VP was dampened in the VP of animals exposed neonatally to estrogens. By day 90, the VP of estrogenized rats possessed low ERb message levels compared with the high expression in oil controls. In contrast, the dorsal and lateral lobes of neonatally estrogenized rats possessed high levels of ERb mRNA at day 90, equivalent to controls. The present data demonstrate that ERb mRNA expression in the rat prostate is developmentally regulated, and that neonatal estrogen can affect this expression in the adult VP. Because the effect of neo- natal estrogens was not immediate, the data imply that early estrogen exposure may not directly autoregulate ERb expression, and suggests that the adult effects on ERb mRNA expression may be indirect. The differences in ERb mRNA imprinting in the separate lobes may ac- count for or reflect the lobe-specific neonatal estrogen imprints pre- viously observed in the rat prostate. (Endocrinology 139: 874 - 883, 1998)

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