title: Flutamide-induced hypospadias in rats: A critical assessment.
abstract: This paper provides the first detailed description of flutamide-induced hypospadias in the rat based upon wholemount, histologic, three-dimensional reconstruction, scanning electron microscopic, and immunocytochemical analysis. The penile malformations elicited by this potent anti-androgen include a substantial proximal shift in the urethral meatus that clearly conforms to the definition of hypospadias based upon specific morphological criteria for this malformation. Through examination of the normal penile development and flutamide-induced abnormal penile development observed in prenatally oil- and flutamide-treated rats, our analysis provides insights into the morphogenetic mechanism of development of hypospadias. In this regard, a common theme in normal penile development is midline fusion of epithelia followed by removal of the epithelial seam and establishment of midline mesenchymal confluence during development of the penile urethra and prepuce, processes which are impaired as a result of prenatal flutamide treatment. The developmental processes occurring in normal penile development, through comparison with development of female external genitalia and those impaired due to prenatal flutamide treatment, are consistent with critical role of androgen receptors in normal penile development in the rat, and the specific penile abnormalities embodied in flutamide-induced rat hypospadias.
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, USA.
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, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Anatomy and Neuroscience, School of BioSciences, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pask
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, USA.
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, USA. Electronic address: gerald.cunha@ucsf.edu.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
mesh_terms: D000818:Animals; D004848:Epithelium / Q000503:physiopathology* / Q000648:ultrastructure; D005485:Flutamide / Q000633:toxicity; D007021:Hypospadias / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D010413:Penis / Q000254:growth & development / Q000503:physiopathology* / Q000648:ultrastructure; D051381:Rats; D014521:Urethra / Q000503:physiopathology* / Q000648:ultrastructure
chemical_list: D005485:Flutamide
keywords: Androgen receptor; Development; External genitalia; Hypospadias; Penis