title: Estrogen receptor-alpha and beta are differentially distributed, expressed and activated in the fetal genital tubercle.
abstract: OBJECTIVE
  We examined the ontogenic and sex specific expression of estrogen receptor-alpha and beta in mouse genital tubercles and assessed the effects of in utero estrogen exposure on these parameters.
  
  
  METHODS
  Expression of the 2 genes was detected in mouse genital tubercles from fetuses collected on gestational days 12, 14, 16 and 18, and from newborns using immunohistochemistry and quantitative polymerase chain reaction. Pregnant dams were exposed to ethinyl estradiol or corn oil as the control.
  
  
  RESULTS
  Estrogen receptor-alpha and beta proteins first appeared on gestational days 12 and 14, respectively. The 2 proteins were expressed in the urethral plate and mesenchyma. Staining intensity was more prominent in the mesenchyma for estrogen receptor-alpha and in the urethral plate for estrogen receptor-beta. Female genital tubercles expressed more estrogen receptor-alpha than male genital tubercles (p <0.01), while estrogen receptor-alpha expression increased gradually in the 2 sexes until birth. Estrogen receptor-beta expression did not differ between males and females, and it showed no notable variation during fetal life. Ethinyl estradiol led to a 2.1 and 3.8-fold increase in estrogen receptor-alpha expression in females and in males with hypospadias (p = 0.002 and 0.04, respectively). Estrogen receptor-beta expression did not change in response to ethinyl estradiol.
  
  
  CONCLUSIONS
  This study provides in vivo evidence that estrogen receptor-alpha expression in the genital tubercles of each sex increases until parturition but estrogen receptor-beta expression does not, implying genital tubercle sensitivity to estrogen increases during fetal life. Exogenous administration of estrogens results in a response of increased expression of estrogen receptor-alpha but not of estrogen receptor-beta. These differential findings for estrogen receptor-alpha and beta imply that the 2 receptors may have different roles in normal or anomalous genital tubercle development.
authors.affiliation: Institute for the Study and Treatment of Hypospadias, Department of Urology, UCSF Children's Medical Center, University of California-San Francisco, San Francisco, CA, USA. kagras@yahoo.co.uk
authors.forename: Koray
authors.initials: K
authors.lastname: Agras
authors.forename: Emily
authors.initials: E
authors.lastname: Willingham
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shiroyanagi
authors.forename: Petros
authors.initials: P
authors.lastname: Minasi
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Baskin
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000502:physiology; D005260:Female; D005836:Genitalia, Female / Q000196:embryology / Q000378:metabolism*; D005837:Genitalia, Male / Q000196:embryology / Q000378:metabolism*; D007021:Hypospadias / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012733:Sex Differentiation
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D012333:RNA, Messenger