Abnormal Morphology of the Penis in Male Rats Exposed Neonatally to Diethylstilbestrol Is Associated with Altered Profile of Estrogen Receptor-α Protein, but Not of Androgen Receptor Protein: A Developmental and Immunocytochemical Study1

Abstract

Objectives of the study were to determine developmental changes in morphology and expression of androgen receptor (AR) and estrogen receptor (ER)alpha in the body of the rat penis exposed neonatally to diethylstilbestrol (DES). Male pups received DES at a dose of 10 microg per rat on alternate days from Postnatal Day 2 to Postnatal Day 12. Controls received olive oil vehicle only. Tissue samples were collected on Days 18 (prepuberty), 41 (puberty), and 120 (adult) of age. DES-induced abnormalities were evident at 18 days of age and included smaller, lighter, and thinner penis, loss of cavernous spaces and associated smooth muscle cells, and increased deposition of fat cells in the corpora cavernosa penis. Fat cells virtually filled the entire area of the corpora cavernosa at puberty and adulthood. Plasma testosterone (T) was reduced to an undetectable level, while LH was unaltered in all treated groups. AR-positive cells were ubiquitous and their profile (incidence and staining intensity) did not differ between control and treated rats of the respective age groups. Conversely, ERalpha-positive cells were limited to the stroma of corpus spongiosus in all age groups of both control and treated rats, but the expression in treated rats at 18 days was up-regulated in stromal cells of corpora cavernosa, coincident with the presence of morphological abnormalities. Hence, this study reports for the first time DES-induced developmental, morphological abnormalities in the body of the penis and suggests that these abnormalities may have resulted from decreased T and/or overexpression of ERalpha.

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

“…One potential mechanism by which neonatal estrogen exposure induces developmental abnormalities may involve an activation of ERa-mediated signaling because we previously found an association between ERa upregulation and penile abnormalities in the developing rat penis treated neonatally with DES (Goyal et al 2004b(Goyal et al , 2005b. Similarly, ERa upregulation is associated with abnormal development of rodent female reproductive tract (Yamashita et al 1990, Markey et al 2005, mammary gland (Tekmal et al 2005), male reproductive tract (Sato et al 1994), prostate gland (Prins & Birch 1997, and seminal vesicles .…”

“…Another mechanism of estrogen-inducible, developmental penile abnormalities may involve alterations in androgen action because androgen receptors are ubiquitously present in the rat penis (Goyal et al 2004b), and their concentration is maximal prior to puberty (Rajfer et al 1980, Takane et al 1990). Additionally, neonatal estrogen exposure downregulates androgen receptor level in male reproductive organs (Prins & Birch 1995, Woodham et al 2003 and lowers plasma testosterone (Sharpe et al 1998, Atanassova et al 2000.…”

“…In addition, epoxy sections (1 mm thick) of glutaraldehyde-fixed tissues were stained with toluidine blue. For evaluating the development of os penis, 1 penis from each group was radiographed with a cabinet radiograph system (Faxitron series, Hewlett-Packard) as described previously (Goyal et al 2004b).…”

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

“…Specifically, bisphenol A has been shown to accelerate terminal differentiation of 3T3L1 fibroblasts into adipocytes through the PI 3 kinse pathway [34]. Interestingly, in developmental studies, Goyal et al [35][36][37][38] have shown that administration of estradiol valerate or the estrogen receptor agonist diethylstilbestrol into 2-day-old rats resulted in infertile mature animals (120 d) and accumulation of fat-containing cells in the penile corpus cavernosum. In contrast, animals treated with vehicle exhibited no fat-containing cells and remained fertile.…”

Molecular genetic cascades for external genitalia formation: An emerging organogenesis program

“…Hypospadias is currently repaired by pediatric surgery (Baskin, 2001). As for estrogen-dependent processes of differentiation, its effect on male urogenital organ formation also still remains poorly described (Hess, 2003;Pu et al, 2004;Huang et al, 2005;Goyal et al, 2004).…”