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Endocrinology |
ERKO and ßERKO Mice1
Department of Urology, University of Illinois at Chicago, Chicago, Illinois 60612 [G. S. P., L. B.]; Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [J. F. C., K. S. K.]; Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 61801 [J. F. C.]; and Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 [I. C., B. K.]
Neonatal exposure of rodents to high doses of estrogen permanently imprints the growth and function of the prostate and predisposes this gland to hyperplasia and severe dysplasia analogous to prostatic intraepithelial neoplasia with aging. Because the rodent prostate gland expresses estrogen receptor (ER)-
within a subpopulation of stromal cells and ERß within epithelial cells, the present study was undertaken to determine the specific ER(s) involved in mediating prostatic developmental estrogenization. Wild-type (WT) mice, homozygous mutant ER (ERKO) -/- mice, and ßERKO -/- mice were injected with 2 µg of diethylstilbestrol (DES) or oil (controls) on days 1, 3, and 5 of life. Reproductive tracts were excised on days 5 or 10 (prepubertal), day 30 (pubertal), day 90 (young adult), or with aging at 6, 12, and 18 months of age. Prostate complexes were microdissected and examined histologically for prostatic lesions and markers of estrogenization. Immunocytochemistry was used to examine expression of androgen receptor, ER, ERß, cytokeratin 14 (basal cells), cytokeratin 18 (luminal cells), and dorsolateral protein over time in the treated mice. In WT-DES mice, developmental estrogenization of the prostate was observed at all of the time points as compared with WT-oil mice. These prostatic imprints included transient up-regulation of ER, down-regulation of androgen receptor, decreased ERß levels in adult prostate epithelium, lack of DLP secretory protein, and a continuous layer of basal cells lining the ducts. With aging, epithelial dysplasia and inflammatory cell infiltrate were observed in the ventral and dorsolateral prostate lobes. In contrast, the prostates of ERKO mice exhibited no response to neonatal DES either immediately after exposure or throughout life up to 18 months of age. Furthermore, neonatal DES treatment of ßERKO mice resulted in a prostatic response similar to that observed in WT animals. The present findings indicate that ER is the dominant ER form mediating the developmental estrogenization of the prostate gland. If epithelial ERß is involved in some component of estrogen imprinting, its role would be considered minor and would require the presence of ER expression in the prostatic stromal cells.
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M.-M. Liu, C. Albanese, C. M. Anderson, K. Hilty, P. Webb, R. M. Uht, R. H. Price Jr., R. G. Pestell, and P. J. Kushner Opposing Action of Estrogen Receptors alpha and beta on Cyclin D1 Gene Expression J. Biol. Chem., June 28, 2002; 277(27): 24353 - 24360. [Abstract] [Full Text] [PDF]
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