Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses - PubMed (original) (raw)

Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

F S vom Saal et al. Proc Natl Acad Sci U S A. 1997.

Abstract

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship.

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Figures

Figure 1

Figure 1

Two stereo pair images (convergent, or cross-eyed viewing) of computer-assisted, serial-section reconstructions showing the dorsal portion of the prostate from two mouse fetuses. The prostate from a control male with 0.21 pg/ml free serum estradiol (blue urethra) is shown below. The top prostate is reconstructed from a male fetus exposed to 0.32 pg/ml free serum estradiol (red urethra). Glandular buds that form into the dorsal (green), lateral (yellow), and dorsocranial (blue) glands in the adult prostate can be seen as outgrowths of the fetal urogenital sinus (ventral buds are not visible). The utriculus (pink) is the remnant of the regressing embryonic female reproductive tract (Müllerian ducts). Compared with controls, estradiol significantly increased the number of prostatic glandular buds and caused a reduction in the size of the lumen of the urethra, which passes through the prostate.

Figure 2

Figure 2

Mean (+ SEM) prostate weight (mg) in 8-month-old male mice produced by mothers implanted s.c. with Silastic capsules containing 0, 25, 100, 200, or 300 μg of estradiol from day 13 to day 19 of pregnancy. The free serum estradiol concentration (in pg/ml) in male fetuses on gestation day 18 in response to these doses of estradiol (controls = 0.21 pg/ml) is shown in relation to adult prostate weight. Group means that differed significantly are indicated by different letters, while groups with the same letter did not differ significantly.

Figure 3

Figure 3

For males exposed during fetal life to 0.21 pg/ml free estradiol (controls) and 0.32 pg/ml free estradiol (25 μg estradiol dose group), mean (+ SEM) total DNA (in μg), androgen receptors per mg of DNA (per cell), and androgen receptors per mg of protein are shown (these were determined after the prostate was weighed). * Statistically significant.

Figure 4

Figure 4

Mean (+ SEM) prostate weight (mg) in 8-month-old CF-1 male mice produced by females fed different doses of DES from day 11 to day 17 of pregnancy. Group means that differed significantly are indicated by different letters.

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