Role of Estrogen in Induction of Penile Dysmorphogenesis: a Review
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REPRODUCTIONREVIEW Role of estrogen in induction of penile dysmorphogenesis: a review H O Goyal1, T D Braden3, C S Williams1 and J W Williams2 1Department of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health and 2Department of Biology and CBR/RCMI, Tuskegee University, Tuskegee, Alabama 36088, USA and 3Department of Physiology and Pharmacology, Auburn University, Auburn, Alabama, USA Correspondence should be addressed to H O Goyal; Email: [email protected] Abstract 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).TheresistanceofERa 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. Reproduction (2007) 134 199–208 species, including humans (Crescioli et al. 2003, Introduction Schultheiss et al. 2003, Dietrich et al. 2004), rodents (Jesmin et al. 2002, 2004), and rabbits (Srilatha & Adaikan The role of androgens in development of male reproduc- 2004). Epidemiological studies have shown links between tive organs is well documented in all mammals (George & inappropriate estrogen exposure and higher frequency of Wilson 1994). While testosterone is essential in develop- reproductive abnormalities in men and wild animals ment of organs derived from the mesonephric duct, (Toppari et al. 1996, McLachlan et al. 2001, Safe et al. including the epididymis, ductus deferens, and seminal 2001, Mosconi et al. 2002, Fisher 2004, Vidaeff & Sever vesicles; dihydrotestosterone (DHT), a 5-a reduced 2005, Storgaard et al. 2006, reviews). Male offspring of testosterone metabolite, is critical in development of women exposed to diethylstilbestrol (DES) during preg- organs derived from the urogenital sinus, genital tubercle, nancy have higher incidence of epididymal cysts, and genital swelling, including the scrotum, prostate, and cryptorchidism, hypospadias, and smaller penis (Gill penis (Anderson & Clark 1990, George & Wilson 1994, et al. 1979, Swan 2000, Klip et al. 2002). Laboratory Wilson & Davies 2007). Alterations in androgenic activity animals exposed neonatally to estrogen develop hypospa- during differentiation can cause maldevelopment of dias (McLachlan et al. 1975, Kim et al. 2004, Newbold internal and external male genitalia, including hypospa- 2004). Neonatal exposure to estrogen at low doses dias and shorter penis (Gray et al. 2001, Sultan et al. 2001, enlarges the prostate gland, while higher doses have the Kim et al. 2002, Foster & Harris 2005). opposite effect (vom Saal et al. 1997, Gupta 2000, Putz et However, unlike androgens, the role of estrogen in al. 2001, vom Saal & Hughes 2005). Taken together, the development of male reproductive organs, especially in above studies suggest that prenatal and/or neonatal the penis, remains largely unknown; although both exposure to estrogens can have permanent deleterious estrogen receptors (ERs) and/or aromatase enzyme have effects on the development of male reproductive organs; been identified in the developing penis of a number of however, the mechanism underlying estrogen-inducible q 2007 Society for Reproduction and Fertility DOI: 10.1530/REP-07-0207 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/29/2021 06:11:50AM via free access 200 H O Goyal and others abnormal phenotypes in the male reproductive tract, as well as in the penis, remains unknown. Recently, we reported permanent dysmorphogenesis of the penis and loss of fertility in adult rats treated neonatally with DES or EV (Goyal et al. 2004a, 2004b, 2005a, 2005b). Importantly, these studies showed replacement of smooth muscle cells and cavernous spaces by fat cells in the corpora cavernosa penis. Additionally, these effects were dose dependent, required a critical window of exposure, and were associated with decreased plasma testosterone and up-regulation of ERa expression in the body of the penis. The objective of this review is to present the above data in a comprehensive manner and discuss the mechanism by which neonatal exposure to estrogen stimulates adipogen- esis and inhibits smooth muscle cell differentiation during a critical period of penile development. Hence, in this review, we will first present a brief description of the rat penis morphology at the gross and histological levels for the purpose of orientation. This will be followed by data that neonatal estrogen exposure results in permanent penile dysmorphogenesis charac- terized 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 Figure 1 (A–J) Micrographs of the penis in adult rats treated neonatally discuss possible mechanisms by which neonatal estro- with oil (control, A–E) or DES (F–J). (A and F) Radiographs of the penis gen exposure results in penile dysmorphogenesis. showing a cylindrical body and a bulbous glans penis containing an os penis consisting of proximal (PO) and distal (DO) parts. Note a reduction in the angle between the body and glans of the penis and Morphology of the rat penis maldevelopment of the os penis, as a result of DES treatment. (B and G) Although different parts of the body of the penis, paired corpora Grossly, the adult penis in control rats consists of a cavernosa penis (cc), corpus spongiosus (cs), and septum containing cylindrical body, a bulbous glans penis, a right angle vein (v) artery (a) and nerve bundles (n) are similarly organized between between the body and the glans, and an os penis that the control and treated rats; the corpora cavernosa in the treated rats are markedly reduced in thickness and contain wider spaces and fewer extends from distal end of the body to tip of the glans and fibers. (C and H) Note a thick, cellular tunica albuginea (arrows), and consists of proximal and distal parts (Fig. 1A). Microscopi- cavernous spaces (csp) in the corpus cavernosum of the control rat, in cally, the body consists of a pair of corpora cavernosa, contrast to empty appearing fat cells (asterisks) and a thinner and much which are located dorsolateral to the urethra and are less cellular tunica albuginea (arrows) in the treated rat. (D and I) Note partially separated by a septum bringing blood vessels and aggregation of black staining fat cells in the corpora cavernosa of the nerves to the penis, and a corpus spongiosus that surrounds treated rat, in contrast to isolated, small fat droplets in the control rat the urethra (Fig. 1B). The corpora cavernosa are surrounded (arrows). (E and J) Note similarities in the histological structure of the corpus spongiosum in the control and treated rats; csp, cavernous by a thick connective tissue capsule called tunica spaces; u, urethra. (B, C, E, G, H and J), Hematoxylin and eosin; (D and albuginea, which consists of an inner cellular layer and I), fat stain. A and F, reproduced with permission, Goyal et al. 2005 an outer fibrous layer, and contain endothelial-lined Biology of Reproduction 70 1504–1512. B–E and G–J, reproduced with cavernous spaces (also called sinusoids or lacunae), smooth permission, Goyal et al. 2004 Reproductive Toxicology 18 265–274. Reproduction (2007) 134 199–208 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/29/2021 06:11:50AM via free access Estrogen-induced penile dysmorphogenesis 201 muscle cells, and collagen fibers (Fig. 1C). Additionally, similar to those observed in the higher dose groups. they also contain a few fat cells that are more clearly In conclusion, neonatal exposure to DES or EV at