Estrogen signaling is not required for prostatic bud patterning or for its disruption by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Abstract

Estrogens play an important role in prostatic development, health, and disease. While estrogen signaling is essential for normal postnatal prostate development, little is known about its prenatal role in control animals. We tested the hypothesis that estrogen signaling is needed for normal male prostatic bud patterning. Budding patterns were examined by scanning electron microscopy of urogenital sinus epithelium from wild-type mice, mice lacking estrogen receptor (ER)alpha, ERbeta, or both, and wild-type mice exposed to the antiestrogen ICI 182,780. Budding phenotypes did not detectably differ among any of these groups, strongly suggesting that estrogen signaling is not needed to establish the prototypical prostatic budding pattern seen in control males. This finding contributes to our understanding of the effects of low-level estrogen exposure on early prostate development. In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can greatly alter the pattern in which prostatic buds form and reduce their number. For several reasons, including a prior observation that inhibitory effects of TCDD on prostatic budding in rats depend heavily on the sex of adjacent fetuses, we tested the hypothesis that estrogen signaling is needed for TCDD to disrupt prostatic budding. However, budding did not detectably differ among wild-type mice, or mice lacking ERalpha, ERbeta, or both, that were exposed prenatally to TCDD (5 microg/kg on embryonic day 13.5). Nor did ICI 182,780 detectably affect the response to TCDD. These results strongly suggest that estrogen signaling is not needed for TCDD to inhibit prostatic epithelial budding.

Fig. 1

Prostatic budding in vehicle- or TCDD-exposed fetal mice lacking one form of estrogen receptor (ER). Wild-type, ERα knockout (kERαKO and mERαKO), and ERβ knockout (ERβKO) fetuses were exposed via maternal dosing on E13.5 to vehicle (5 ml corn oil/kg) or TCDD (5 μg/kg, po). UGSs were collected on E18.5, mesenchyme was removed, and underlying epithelium was visualized by SEM. At least 3 UGSs per genotype and treatment were examined. Ventral prostatic buds are pseudocolored blue, dorsal buds green, lateral buds yellow, and anterior buds red. Abbreviations used are: bladder neck (BN), ductus deferens (DD), pelvic urethra (PU), seminal vesicle (SV).

Fig. 2

Prostatic budding in vehicle- or TCDD-exposed fetal mice lacking both ERα and ERβ. Wild-type, kERαβKO, and mERαβKO fetuses were exposed via maternal dosing on E13.5 to vehicle (5 ml corn oil/kg) or TCDD (5 μg/kg, po). UGSs were collected on E18.5, mesenchyme was removed, and underlying epithelium was visualized by SEM. At least 3 UGSs per genotype and treatment were examined. Ventral prostatic buds are pseudocolored blue, dorsal buds green, lateral buds yellow, and anterior buds red. Abbreviations used are: bladder neck (BN), ductus deferens (DD), pelvic urethra (PU), seminal vesicle (SV).

Fig. 3

Prostatic budding in vehicle- or TCDD-exposed fetal wild-type mice exposed to the antiestrogen ICI 182,780. Wild-type fetuses were exposed to vehicle (10% DMSO/90% corn oil, 5 ml/kg, sc) or ICI 182,780 (1 mg/kg) via daily maternal dosing from E14.5 through E17.5. Dams were also given vehicle (5 ml corn oil/kg) or TCDD (5 μg/kg, po) on E15.5. UGSs were collected on E18.5, mesenchyme was removed, and underlying epithelium was visualized by SEM. At least 3 UGSs per genotype and treatment were examined. Ventral prostatic buds are pseudocolored blue, dorsal buds green, lateral buds yellow, and anterior buds red. Abbreviations used are: bladder neck (BN), ductus deferens (DD), pelvic urethra (PU), seminal vesicle (SV).