Estrogen receptor-α mediates estrogen-inducible abnormalities in the developing penis

Abstract

Previously, we reported an association between estrogen receptor-a (ERa) upregulation and detrimental effects of neonatal diethylstilbestrol (DES) exposure in the rat penis. The objective of this study was to employ the ERa knockout (ERaKO) mouse model to test the hypothesis that ERa mediates DES effects in the developing penis. ERaKO and wild-type C57BL/6 mice received oil or DES at a dose of 0.2 mg/pup per day (0.1 mg/kg) on alternate days from postnatal days 2 to 12. Fertility was tested at 80-240 days of age and tissues were examined at 96-255 days of age. DES caused malformation of the os penis, significant reductions in penile length, diameter, and weight, accumulation of fat cells in the corpora cavernosa penis, and significant reductions in weight of the bulbospongiosus and levator ani muscles in wild-type mice. Conversely, ERaKO mice treated with DES developed none of the above abnormalities. While nine out of ten male mice sired pups in the wild-type/control group, none did in the wildtype/DES group. ERaKO mice, despite normal penile development, are inherently infertile. Both plasma and intratesticular testosterone levels were unaltered in the DES-treated wild-type or DES-treated ERaKO mice when compared with controls, although testosterone concentration was much higher in the ERaKO mice. Hence, the resistance of ERaKO mice to developing penile abnormalities provides unequivocal evidence of an obligatory role for ERa in mediating the harmful effects of neonatal DES exposure in the developing penis.

Molecular mechanisms of induction of persistent changes by estrogenic chemicals on female reproductive tracts and external genitalia

“…ERs are endogenously expressed in the embryonic external genitalia [93,106,107]. Further, ER␣ mutant mice are resistant to estrogens-induced penile abnormalities [108] indicating that estrogen-exposure could directly perturb male genitalia development.…”

Estrogen-Induced Developmental Disorders of the Rat Penis Involve Both Estrogen Receptor (ESR)- and Androgen Receptor (AR)-Mediated Pathways1

“…These region-specific effects of neonatal estrogen exposure in the body of the penis are dose dependent [14], require a critical window of exposure [15], and are associated with suppressed neonatal testosterone (T) surge from ages 5 to 8 days [15] and with upregulation of estrogen receptor alpha (ESR1) in penile stromal cells [16]. In addition, observations that Esr1-knockout (Esr1 À/À ) mice are resistant to estrogen-inducible penile abnormalities present in the wild-type littermates imply an unequivocal role for ESR1 in mediating maldevelopment of the penis [17].…”

Role of estrogen in induction of penile dysmorphogenesis: a review

“…This will be followed by data that neonatal estrogen exposure results in permanent penile dysmorphogenesis characterized by replacement of cavernous spaces and smooth muscle cells by fat cells in the body of the penis (Goyal et al 2004a); estrogen-induced penile disorders are dose-dependent (Goyal et al 2005a), as well as are dependent upon estrogen exposure during a critical period of penile development (Goyal et al 2005b); neonatal estrogen exposure results in up-regulation of ERa, but without any alteration in ERb or androgen receptor (AR) expression, in the body of the penis (Goyal et al 2004b); ERa knockout (ERaKO) mice are resistant to estrogen-inducible penile abnormalities (Goyal et al 2007); neonatal estrogen exposure lowers testosterone secretion at puberty or adulthood (Goyal et al 2004b) and suppresses neonatal testosterone surge (Goyal et al 2005b); and the coadministration of ER antagonist or androgen with estrogen mitigates estrogen-inducible developmental penile abnormalities. Finally, we will discuss possible mechanisms by which neonatal estrogen exposure results in penile dysmorphogenesis.…”