Hypospadias Differentiation and Endocrine Disruptors

University Of California San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Hypospadias or incomplete formation of the urethra is the most common congenital abnormality effecting penile development. Hypospadias has received very little basic research attention. The etiology remains undefined in the overwhelming majority of cases. Recent worldwide reports document an increase in the incidence of hypospadias. The main goal of this proposal is to investigate the mechanism of normal and abnormal urethral development in the mouse and in a mouse model of hypospadias secondary to endocrine disruptors. During normal development tubularization of the urethra requires urethral fold formation from the urethral plate, fusion of the urethral folds, formation of an epithelial seam and subsequent seam removal. In this grant we plan two related hypotheses. (#1) We hypothesize a novel mechanism that the urethral plate acts as the organizer of normal urethral development, directing urethral seam formation and remodeling via epithelial-mesenchymal interactions, and (#2) We hypothesize that maternal exposure to xogenous estrogens and/or antiandrogens disrupts these processes resulting in urethral disruption or hypospadias. To test these hypotheses, we plan four specific aims: (1) Define sexual dimorphism of the genital tubercle (GT) in the normal male and female mouse; (2) Define abnormal GT development in genetically engineered mice that spontaneous develop hypospadias or have GT abnormalities (Shh, Fgf-8, Fgf-10, Hoxa-13 and Igf- RI); (3) Induce abnormal genital development with maternal exposure to endocrine disruptors (synthetic estrogens and antiandrogens); and (4) Define the role of epithelial-mesenchymal interactions in penile growth, differentiation and urethra formation. The relevance of this proposal is that: (1) The mouse urethra develops in a similar fashion to the human urethra; (2) Defining the cellular and molecular mechanisms of hypospadias in the mouse is germane to understanding the human condition of hypospadias; and (3) If the endocrine disrupter theory can be definitely proven in the mouse, further efforts to document an endocrine disruptor hypothesis in humans is warranted. Ultimately preventative steps to decrease prenatal toxic exposure may be the must useful intervention with the mouse model providing a means to test suspected agents.