Effect of TCDD on corpus cavernosum histology and smooth muscle physiology

Dg, Moon; Lee, Keon-Cheol; Kim, Yong Wook; Park, H S; Cho, H Y; Kim, J J

doi:10.1038/sj.ijir.3901060

Cited by 19 publications

(13 citation statements)

References 25 publications

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“…Similar novel effects have not been reported in the rat or any other species except the rabbit, where bisphenol A (Moon et al 2001) or tetrachlorodibenzodioxin (Moon et al 2004) treatment at puberty resulted in deposition of fat, a reduction in cavernous spaces, and an increase in smooth muscle cells in the corpora cavernosa. Some differences between our studies and those of the latter authors may be attributed to differences in the species (rat versus rabbit), estrogenic compound (DES versus bisphenol A), and/or the time of treatment (neonatal versus pubertal).…”

Section: Mechanism Of Estrogen-induced Penile Dysmorphogenesismentioning

confidence: 56%

Role of estrogen in induction of penile dysmorphogenesis: a review

Goyal¹,

Braden²,

Williams³

et al. 2007

Reproduction

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In this review, we report permanent dysmorphogenesis of the penis and loss of fertility in adult rats treated neonatally with estrogen. Specifically, we report replacement of smooth muscle cells and cavernous spaces by fat cells in the corpus cavernosum penis, but not in the adjoining corpus spongiosum. Induction of these novel, region-specific phenotypes is dose-dependent, requires a critical window of exposure and associated with decreased testosterone and up-regulation of estrogen receptor a (ERa). The resistance of ERa knockout mice to develop these abnormalities implies an unequivocal role for ERa in mediating maldevelopment of the penis. Additionally, the prevention of estrogen-inducible penile abnormalities by ER antagonist ICI 182 780 implies that a functional ER-mediated pathway is essential for inducing penile abnormalities. Likewise, the ability of testosterone or dihydrotestosterone to negate these abnormalities suggests a role for an androgen receptor (AR)-mediated pathway. Taken together, these observations led us to hypothesize that neonatal estrogen exposure, via an ER-mediated pathway (direct action) or an AR-mediated pathway (indirect action through decreased testosterone) or both pathways, up-regulates ERa expression in stromal cells of the penis, which are then reprogrammed such that their differentiation into smooth muscle cells is inhibited and their differentiation into adipocytes is stimulated.

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Section: Mechanism Of Estrogen-induced Penile Dysmorphogenesismentioning

confidence: 56%

Role of estrogen in induction of penile dysmorphogenesis: a review

Goyal¹,

Braden²,

Williams³

et al. 2007

Reproduction

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“…Similarities in penile abnormalities presently observed in DES-treated wild-type mice with those previously reported from our laboratory in DES-treated rats (Goyal et al 2005a,b), including malformations of the os penis; reductions in weight, length, and diameter of the penis; reductions in thickness of the tunica albuginea capsule and connective tissue trabeculae in the corpora cavernosa penis; and abnormal accumulation of fat cells in the corpora cavernosa penis; clearly identify the penis as a target organ for harmful effects of neonatal estrogen exposure. Similarly, other studies also reported a smaller penis in laboratory animals exposed neonatally to estrogen (McLachlan et al 1975, Zadina et al 1979, Newbold 2004; and the rabbit penis treated with bisphenol A (Moon et al 2001) or tetrachlorodibenzodioxin (Moon et al 2004) had subtunical deposition of fat in the corpora cavernosa. Additionally, alligators from Lake Apopka, FL, contaminated with environmental pollutants had smaller phalluses (Guillette et al 1994, Milnes et al 2005; and male offspring of women exposed to DES during pregnancy had smaller penises (Gill et al 1979, Swan 2000.…”

Section: Discussionmentioning

confidence: 94%

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

Goyal

Braden²,

Cooke³

et al. 2007

Reproduction

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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.

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“…The role of the ESR pathway in mediating penile maldevelopment should not be surprising, as both ESR1 and ESR2 are present in the neonatal rat penis [16,20] and Esr1-knockout (Esr1 À/À ) mice are resistant to estrogen-inducible abnormalities observed in the wild-type mice [17]. Estrogeninduced histopathological effects have been reported in a rabbit model in which bisphenol A [23] or tetrachlorodibenzodioxin [24] treatment at puberty has resulted in deposition of fat and reduction in cavernous spaces in the body of the penis. An alteration in estrogen/ESR1 signaling during development results in dramatic changes in adipocyte number [25].…”

Section: Discussionmentioning

confidence: 94%

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

Goyal

Braden

Williams

et al. 2009

Biology of Reproduction

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This study tested the hypothesis that the estrogen receptor (ESR) pathway, androgen receptor (AR) pathway, or both mediate estrogen-induced developmental penile disorders. Rat pups received diethylstilbestrol (DES), with or without the ESR antagonist ICI 182,780 (ICI) or the AR agonist dihydrotestosterone (DHT) or testosterone (T), from Postnatal Days 1 to 6. Testicular T concentration, penile morphology and morphometry, and/or fertility was determined at age 7, 28, or 150 days. DES treatment alone caused 90% reduction in the neonatal intratesticular T surge; this reduction was prevented by ICI coadministration, but not by DHT or T coadministration. Unlike the T surge, coadministration of ICI and coadministration of DHT or T mitigated penile deformities and loss of fertility. Generally, ICI, DHT, or T treatment alone did not alter penile morphology; however, fertility was 20% that of controls in ICI-treated rats vs. 70%-90% in DHT- or T-treated rats. The lower fertility in the rats treated with ICI alone could be due to altered sexual behavior, as these males did not deposit vaginal plugs. In conclusion, observations that both an ESR antagonist and AR agonists prevent penile deformities and infertility suggest that both pathways are involved in estrogen-induced penile disorders. Observations that coadministration of ICI, but not DHT or T, prevents the DES-induced reduction in the neonatal T surge suggest that, although ICI exerts its mitigating effect both at the level of Leydig cells and penile stromal cells, DHT and T do so only at the level of stromal cells.

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Effect of TCDD on corpus cavernosum histology and smooth muscle physiology

Cited by 19 publications

References 25 publications

Role of estrogen in induction of penile dysmorphogenesis: a review

Role of estrogen in induction of penile dysmorphogenesis: a review

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

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

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