Neonatal estrogen exposure induces lobe-specific alterations in adult rat prostate androgen receptor expression.

Abstract

Brief administration of estrogen to newborn rats results in permanent suppression of prostate growth and reduced prostatic responsiveness to testosterone in adulthood. To determine whether this imprinting may be a result of alterations in androgen receptor (AR) expression, the separate adult prostate lobes of neonatally estrogenized rats were examined for AR concentration and distribution. Sprague-Dawley rat pups were given 25 micrograms estradiol benzoate or oil alone on days 1, 3, and 5 and were killed on day 90. Half of the animals received 2-cm testosterone implants 10 days before death to assess the activational response to androgen. In a separate series, neonatally estrogenized rats were given prepubertal dihydrotestosterone pellets for 3 weeks as well as testosterone implants in adulthood to determine if the observed effects of neonatal estrogen on the adult prostate were an indirect result of androgen deprivation during developmentally critical periods. The ventral, dorsal, and lateral prostate lobes were processed for nuclear AR quantitation by [3H]dihydrotestosterone exchange binding assay and for indirect immunocytochemical localization of AR. Weights and DNA contents of the three prostate lobes were significantly reduced in neonatally estrogenized rats, and this decrease was only partially reversed by prepubertal and/or adult androgen replacement. Histologically, the hypoplastic ventral and dorsal lobes exhibited a relative increase in interacinar stromal tissue, disorganized acini with epithelial hyperplasia, luminal sloughing, and an apparent lack of differentiation. The hypoplastic lateral lobe also showed a relative increase in the stromal fraction; however, the acinar epithelium appeared differentiated, with normal basal/apical orientation and luminal secretions. The AR concentration was significantly reduced in the ventral and dorsal prostates of estrogenized rats, but was unaltered in the lateral lobe. Immunocytochemistry revealed a marked reduction or absence of epithelial AR in ventral and dorsal lobes from estrogenized rats, whereas the lateral lobe epithelial cells expressed AR similarly to controls. The incidence of AR-positive fibroblastic stromal cells increased in lateral prostates from 5% in controls to approximately 25% in estrogenized rats. Neonatally estrogenized rats given testosterone for 10 days in adulthood showed increased levels of AR in the ventral and dorsal lobes compared to nonstimulated rats; however, these levels remained well below control values. Lateral lobe epithelial histology and AR expression appeared relatively unchanged in estrogenized rats given testosterone during adulthood, whereas an increased proportion of stromal cells (approximately 35%) were AR positive. In summary, neonatal estrogen administration permanently altered prostatic growth and produced lobe-specific changes in AR expression in the adult gland.(ABSTRACT TRUNCATED AT 400 WORDS)