These abnormalities occurred in animals that were treated with DES before 12 days of age but not after. Previously, we reported that adult rats treated neonatally with the antiandrogen GnRH-antagonist or estrogens developed similar penile abnormalities, including loss of cavernous spaces and accumulation of fat cells. However, none of these studies reported effects on differentiation of cavernous spaces or cavernous smooth muscle cells. Collectively, the above-mentioned studies suggest that exposure to antiandrogens or estrogens is detrimental for development of the male reproductive tract, including the penis. Alligators from Lake Apopka (FL), contaminated with industrial estrogenic chemicals, had smaller phalluses. Bisphenol A treatment in rodents increased prostate size and predisposed the gland to a precancerous growth. Laboratory animals treated prenatally with estrogens developed hypospadias. A high prevalence of micropenis was reported in newborns from Brazil and in infants and prepubescent boys from Denmark whose mothers were exposed to pesticides during pregnancy. Similarly, estrogen exposure has been linked with higher frequency of reproductive abnormalities. Infant boys whose mothers had higher level of phthalates had smaller penises. Perinatal exposure to antiandrogens, such as phthalates and vinclozolin, induce male reproductive tract abnormalities, including smaller phalluses. Testosterone or its metabolite dihydrotestosterone (DHT) is required for development and growth of the male reproductive tract, including the penis. These findings imply an important role for androgens in maintaining normal function of cavernous smooth muscle cells. The cells were reduced in castrated rabbits and mice and a low testosterone level was correlated with their impaired relaxation in patients with erectile dysfunction. Cavernous smooth muscle cells were reduced in impotent men and diabetic rats compared to those in controls. Vascular diseases impairing engorgement of cavernous spaces are considered a major cause for erectile dysfunction. It is estimated that 152 million males world wide experienced some degree of erectile dysfunction in 1995, and this number is expected to increase to 322 million in 2025. Cavernous smooth muscle cells have been targets of pharmaceutical drugs that enhance erection by prolonging their relaxation.
Unlike other body smooth muscle cells, cavernous smooth muscle cells remain contracted most of the time they relax under sexual stimulation, which engorges cavernous spaces with blood and, consequently, produces erection. The rat penis, similar to the human penis, contains cavernous spaces and smooth muscle cells (cavernous smooth muscle cells), two structures essential for erection in a vascular penis. Both the ESR and the AR pathways probably mediate this effect. Collectively, results provided evidence that DES treatment in neonatal rats inhibited cavernous smooth muscle cell differentiation, as shown by down-regulation of MYH11 expression at the mRNA and protein levels and by reduced immunohistochemical staining of smooth muscle alpha actin.
Additionally, DES treatment significantly up-regulated Esr1 mRNA expression and suppressed the neonatal testosterone surge by 90%, which was mitigated by ICI coadministration but not by DHT coadministration. Immunohistochemical localization of smooth muscle alpha actin, another biomarker for smooth muscle cell differentiation, showed fewer cavernous smooth muscle cells in DES-treated animals than in controls. Temporally, from 7 to 21 days of age, Myh11 expression was onefold increased ( P ≥ 0.05) in DES-treated rats versus threefold increased ( P ≤ 0.001) in controls, implying the long-lasting inhibitory effect of DES on smooth muscle cell differentiation. Quantitative real time-PCR and Western blot analyses showed 50%–80% reduction ( P ≤ 0.05) in Myh11 expression in DES-treated rats compared to that in controls and ICI and DHT coadministration mitigated the decrease. The smooth muscle cell biomarker MYH11 was studied in depth because microarray data showed it was significantly down-regulated, along with other biomarkers, in DES treatment. Tissues were collected at 7, 10, or 21 days of age. Neonatal rats received diethylstilbestrol (DES), with or without the estrogen receptor (ESR) antagonist ICI 182,780 (ICI) or the androgen receptor (AR) agonist dihydrotestosterone (DHT), from Postnatal Days 1 to 6. In this study, we investigated effects of estrogen exposure on biomarkers for smooth muscle cell differentiation in the penis. Cavernous smooth muscle cells are essential components in penile erection.
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