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Retinoic Acid Receptors and Retinoids Are Up-Regulated in the Developing and Adult Rat Prostate by Neonatal Estrogen Exposure

Department of Urology, College of Medicine (G.S.P., W.Y.C.), and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (Y.W., R.B.v.B.), University of Illinois, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Gail S. Prins, Ph.D., Department of Urology, University of Illinois, M/C 955, Chicago, Illinois 60612. E-mail: gprins{at}uic.edu.

Exposure to estrogens during the neonatal period interrupts rat prostatic development by reducing branching morphogenesis and by blocking epithelial cells from entering a normal differentiation pathway. Upon aging, ventral prostates exhibit extensive hyperplasia, dysplasia, and massive lymphocytic infiltrate, suggesting that neonatal estrogens may predispose the prostate gland to precancerous lesions. Vitamin A (retinol) and their derivatives (retinoic acids) are known key developmental regulators that bind and activate retinoic acid receptors (RARs). To evaluate whether neonatal estrogenization alters the sensitivity of the developing rat prostate to retinoids, RAR, -ß, and - cellular localization and protein levels were analyzed over the course of development and into adulthood by immunocytochemistry and Western analysis, whereas mRNA levels were measured using RT-PCR. In addition, intraprostatic retinol and retinoic acid levels were quantitated on d 10 and 90 using HPLC-mass spectroscopy. Male rats were given 25 µg estradiol benzoate or oil on d 1, 3, and 5 of life, and prostatic complexes were removed on d 6, 10, 15, 30, and 90. The RARs localized to distinct cell populations: RARß was expressed within basal epithelial cells, RAR was localized to differentiated luminal epithelial cells and smooth muscle cells, and RAR was expressed within periductal stromal cells. Over the normal course of development, total protein and mRNA levels for the RARs declined, so that the adult prostate possessed the lowest amounts of RAR. Exposure to estrogens during the neonatal period resulted in an immediate and sustained increase in RAR levels and in the number of cells that expressed RARß, whereas RAR levels were unaffected. Western analysis confirmed that total prostatic RAR protein levels were significantly increased, whereas RT-PCR demonstrated that RAR and RARß mRNA levels were markedly elevated in response to estrogenic exposure. The total prostatic retinol content was tripled by estrogenic exposure on d 10 and 90, indicating that the ability to retain retinoids within the prostate was permanently increased. Intraprostatic levels of 9-cis- and all-trans-retinoic acid levels were reduced on d 10, whereas 13-cis-retinoic acid levels were increased in response to estrogens. In the adult prostates of rats exposed neonatally to estrogen, total retinoic acid levels were doubled due to significant increases in both 9-cis- and 13-cis-retinoic acids compared with those in control prostates. In summary, levels of specific RARs and their activating ligands are increased in the prostate gland after neonatal estrogenic exposure, and this effect is permanent throughout the life of the animal. Thus, we hypothesize that alterations in morphogenesis as well as dysplasia in the adult prostate may be mediated in part through augmentation of transcriptional signals in the retinoid pathway.

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