title: Mouse hypospadias: A critical examination and definition.
abstract: Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation. The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12-P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12-P10, DES P0-P10 and DES P5-P15 groups, and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12-P10, DES P0-P10 and DES P5-P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0-P10 period. In "estrogen mutant mice" (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process.
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Adriane Watkins
authors.initials: AW
authors.lastname: Sinclair
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Physiological Sciences, University of Florida, Gainsville, FL 32610, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Cooke
authors.affiliation: Monash Institute of Reproduction and Development, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Gail
authors.initials: G
authors.lastname: Risbridger
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Laurence
authors.initials: L
authors.lastname: Baskin
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States. Electronic address: gerald.cunha@ucsf.edu.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
mesh_terms: D000818:Animals; D004054:Diethylstilbestrol / Q000633:toxicity; D047108:Embryonic Development; D006801:Humans; D007021:Hypospadias / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009024:Morphogenesis; D010413:Penis / Q000196:embryology / Q000503:physiopathology*; D014521:Urethra / Q000187:drug effects / Q000503:physiopathology
chemical_list: D004054:Diethylstilbestrol
keywords: Estrogen; Hypospadias; Mouse; Penile urethra; Penis