Ontogeny of Estrogen Receptor (ER) .ALPHA. and .BETA. in the Female Reproductive Tissues of Mice Neonatally Exposed to Diethylstilbestrol.

Abstract

Ontogenical expression of estrogen receptor (ER) isoforms, ERa and ERb, was examined in order to study the roles of the isoforms in the morphogenesis of neonatal diethylstilbestrol (DES) treatment in the female reproductive tissues using an immunohistochemical method. The intensity of ERa immunostaining gradually increased with aging in the epithelial cells of oviducts, uteri, cervices and vaginae in the vehicle-treated control animals. Neonatal DES-treatment up-regulated the expression of ERa in the epithelial cells in these tissues and down-regulated it in the stromal cells at least until 10 days of age including the period of DES-treatment. On day 21, both control and DES-mice showed almost similar ERa distribution in these tissues. There were no differences in the ERa distribution in the ovaries of two experimental groups. ERa was localized in the theca cells and some stromal cells located interfollicularly. Neonatal DES exposure did not influence the distribution pattern of ERb protein during the period of treatment and postnatal development. The nuclear ERb-immunoreaction was seen in the granulosa cells of ovaries but not in the cells of reproductive tracts. These results demonstrated that ERa is the critical ER isoform for the estrogen-dependent responses in the normal female genital tract, and that the presence of ERa in the epithelial cells during the period of DES exposure should play important roles in the the induction of abnormal characteristics in the genital tract of DES-mice.

Expression of Estrogen-Regulated Genes During Development in the Mouse Uterus Exposed to Diethylstilbestrol Neonatally

“…Several investigators have reported similar results in the uterus of mice exposed to DES perinatally [29][30][31][32]. By contrast, no ERβ protein was detected in the uterus of either controls or DES mice during maturation, and only the granulosa cells of the ovaries showed a positive reaction in both the control and DES-mice [15].…”

“…Until at least 15 days of age, DES-treatment strongly up-regulated expression of ERα in the epithelial cells in the genital tract including uteri, and down-regulated the expression in the stromal cells ( Fig. 1B) [15]. In the DES-mice even on day 4, almost all uterine epithelial cells exhibited strong ERα-immuoreaction ( Fig.…”

“…In the DES-mice on days 4, 10, and 15, the epithelium was hyperplastic and composed of pseudostratified columnar or simple high columnar cells (Figs. 3b and 3d) [15]. The endometrium was thinner from day 4 to day 20 in the uteri of DES-mice than in those of control groups, and accumulation of collagen fibers was observed in the extracellular matrix (Figs.…”

“…These effects of estrogens in the female genital tract are mainly mediated by their nuclear receptor, estrogen receptor α (ERα), because ERβ is barely detectable in the genital tract and ERα knockout mice exposed to DES neonatally do not exhibit any DES-induced phenotypes [12][13][14][15]. ERα has been demonstrated to regulate transcriptional activities through the following pathways.…”

Localization of estrogen and androgen receptors in male reproductive tissues of mice and rats

“…Frozen sections (7 m thick) were fixed with 4% paraformaldehyde dissolved in 0.15 M phosphate buffer (pH 7.4) for 20 min at room temperature (Yamashita, 2002). The fixed sections were washed with phosphate-buffered saline (PBS), 10 mM phosphate buffer, and pH 7.4 containing 0.85% NaCl, and were then treated with 0.2% glycine in PBS for 30 min.…”