Battle of Sex Hormones in Genitalia Anomalies
Total Page：16
File Type：pdf, Size：1020Kb
COMMENTARY COMMENTARY Battle of sex hormones in genitalia anomalies Liang Maa,b,1 exposures to antiandrogen or estrogenic com- aDivision of Dermatology, Department of Medicine, Washington University School of pounds can lead to a range of penile anoma- Medicine, St. Louis, MO 63110; and bDepartment of Developmental Biology, Washington lies similar to human CPAs (2). However, University School of Medicine, St. Louis, MO 63110 how and when EDCs may influence normal external genitalia development is not very clear. In PNAS, Zheng et al. (3) use a state- To cope with their transition to a terrestrial anomalies (CPAs), including ambiguous gen- of-the-art conditional androgen receptor lifestyle, vertebrates had to extensively modify italia, hypospadias, chordee, and micropenis, (AR) knockout mouse model to show that their reproductive organs to facilitate repro- represent one of the most common birth de- disruption of androgen signaling at different duction on land (1). The mammalian penis fects, second only to congenital cardiac de- developmental stages can produce the full represents such a pinnacle in mammalian fects. Hypospadias is an arrest in urethra spectrum of CPAs. The authors go on to evolution, which enabled internal fertilization development, such that the urethra opening show that androgen and estrogen signaling and successful land invasion. There are two is located anywhere along the ventral side of antagonize each other during neonatal mouse phases of external genitalia development in the penile shaft instead of at the glans penis. i genital development and identify a signaling mammals: ( ) an ambisexual stage, in which Chordee is the abnormal bending of the penis, molecule, Indian hedgehog (Ihh), as a novel male and female embryos undergo the same resulting from tethering of urethral epithelium AR target required for penile masculinization. ii genital outgrowth program; and ( )asexu- to the skin. Over the past few decades, the Mammalian external genitalia develop- ally dimorphic stage, in which further growth reported CPA incidents have increased signif- ment begins with the outgrowth of a genital and differentiation of the male penis depend icantly, raising the speculation that in utero tubercle (GT), which is the anlage of penis on androgen. Consequently, it is the second exposure to endocrine disrupting chemicals in males and clitoris in females. In mice, the phase of genitalia development that is sensi- (EDCs)mayberesponsibleforthisincrease. GT develops as a pair of genital swellings tive to perturbations of the hormonal milieu Published studies using either the mouse around the cloaca and slightly caudal to during development. Congenital penile or rat model showed that developmental the hindlimbs on embryonic day (E) 10.5 (Fig. 1A). By E11.5, the two swellings have merged and formed a single GT (4, 5). The GT and limb bud use a common ge- netic cassette to promote their outgrowth, which involves a signaling center containing Wnt and Fgf activities (6). However, the sig- naling center in the GT is the endodermally derived distal urethral epithelium, in con- trast to the ectodermally derived apical ec- todermal ridge in limbs (4). By E13.5, a pair of preputial swellings emerge on either side of the GT, which eventually will engulf the GT, while inside the GT tubulogenesis com- mence in a proximal-distal direction involv- ing canalization of urethral epithelium from its bilaminar plate precursor (Fig. 1A). Work from the Yamada laboratory dem- onstrated that before E15, male and female mouse GTs are morphologically indistin- guishable (7). However, after E15.5, GT devel- opment enters the sexually dimorphic stage, where they are sensitive to androgen and anti- androgen treatments. Consistent with this finding, Zheng et al. (3) examine the sexual dimorphic expression of AR and estrogen re- ceptor (ERα) in both male and female geni- talia throughout development and show that Author contributions: L.M. wrote the paper. Fig. 1. (A) A schematic diagram of mouse external genitalia development from the sexual indifferent stage (E10.5–E15) The author declares no conflict of interest. to adult sexual dimorphic stage. Reprinted from ref. 6. (B) A developmental time window when penile development is sensitive to endocrine disruption. (C) Signaling pathways implicated in genital masculinization. b, baculum (os penis); EB, See companion article on page E7194. estradiol benzoate; Flut, flutamide; gp, glans penis; p, prepuce; u, urethra. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1518491112 PNAS | December 29, 2015 | vol. 112 | no. 52 | 15779–15780 Downloaded by guest on September 27, 2021 sexually dimorphic AR and ER staining pat- to increase their predicative power as to of Ihh in genital masculinization (Fig. 1C). terns were first observed at E15.5 (3). More whether in utero exposure to certain chemi- Given the well-documented role for Ihh in importantly, exposure to exogenous estrogen cals is associated with genital defects later cartilage and bone development (14), it is or androgen can up-regulate its own receptor in the adult. tempting to speculate that Ihh expression is expression, while simultaneously repressing Although it has been known for quite elevated in male mouse genitalia to promote expression of the other receptor. These find- some time that sex hormones play important penian bone (os penis) and cartilaginous ings lend support to the idea that sexual dif- roles in genital differentiation, the down- MUMP development because there is no car- ferentiation of the genitalia is a balance stream targets—especially those paracrine tilage tissue in the female clitoris and the between the two sex hormones, because for factors mediating local tissue interactions— bone segment (os clitoris) is very small (8). alongtimeitwasthoughtthatfemalegeni- remain mostly illusive. The Cohn (10) and If this hypothesis is correct, it would then be talia represent the default state until it was Yamada (7) groups have previously identified interesting to examine genital Ihh expression found that ERα knockout females showed Fgf and Wnt pathways as targets of andro- in other mammalian species whose genitalia masculinized external genitalia (8). During gen signaling, respectively. The Hedgehog do not contain bone or cartilage, such as normal male development, androgen pro- pathway may represent another androgen- those in marsupials and hyenas, as well as duced by the Leydig cells promotes further regulated pathway as deletion of Shh during in human beings. Such studies may provide genital growth, as well as mesenchymal con- sexual differentiation led to hypospadias additional insight into the function of Ihh in C – densation within the glans penis, to give rise (Fig. 1 )(1113). In the current study, genital masculinization. to various corporal tissues and penile bones Zheng et al. (3) use a candidate approach Epidemiological studies, as well as studies that are either missing or rudimentary in fe- and examine the expression of 88 genes in using experimental animals, have shown that A males (Fig. 1 ). Consequently it is the mes- the Hedgehog, Bmp, Wnt, and Fgf pathways, a cadre of EDCs can lead to development of enchymal AR but not ectodermal or and compare their expression to either anti- hypospadias. These include chemicals that endodermal AR that is required in genital androgen (flutamide) -treated or estrogen interfere with androgen-signaling, such as masculinization (3, 7). In the Zheng et al. (estradiol benzoate) -treated GT. Another li- phthalates and fungicides, compounds with study (3), the authors varied the timing of gand of the Hedgehog pathway, IHH, is one estrogenic activities, such as diethylstilbestrol, AR disruption either pharmacologically or ge- of only two molecules whose expression is and finally progestins. Despite some notice- netically. Surprisingly, early (E13.5) deletion down-regulated by both compounds. To test Ihh able anatomical and morphogenetic differ- of AR led to feminization of male penis sim- whether is required for masculinization ences between rodent and human penises (2), ilar to that found in tfm mice, whereas late of the male genitalia, Zheng et al. (3) used Hoxa13Cre Ihh most pathways governing penile develop- (E17.5) deletion resulted in micropenis but to conditionally deleted in ment and differentiation should be con- did not affect urethral tube closure (3). On both the urethal epithelium and mesenchyme served. Unfortunately, our knowledge of the other hand, disruption of androgen sig- of the developing GT. The resulting mutant genitalia development and differentiation is naling between E12.5 to E16.5 with an AR penis is underdeveloped and shows much still in its infancy. Because genome-wide as- antagonist, flutamide, caused urethral tube reduced penile structures, including the sociation studies have only yielded a handful closure defects, similar to human genital de- fibrocartilaginous male urogenital mat- of candidate genes for hypospadias (15, 16), fect-hypospadias with chordee (Fig. 1B). ing protuberance (MUMP) and the MUMP perhaps more effort should be devoted to These results show that disruption of a single ridge. During sexual differentiation, Ihh is model organism studies exemplified by the genetic pathway at different times during de- strongly expressed in urethral epithelium current study to better understand the nor- velopment can generate the wide spectrum of and genital mesenchyme of male but not fe- mal biological process of genitalia outgrowth CPA. In addition