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.

Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System

“…Hypospadias is a congenital abnormality of the penile urethra and/or prepuce, and in the rodent, generally refers to the proximal displacement of the urethral meatus from the tip of the glans penis (Blaschko et al, ). Recently, hypospadias has been critically assessed and more completely defined in rats exposed to flutamide (Sinclair, ). Rodent hypospadias differs from human hypospadias, because of species differences in penile anatomy and development (Cunha et al, ).…”

“…Rodent hypospadias differs from human hypospadias, because of species differences in penile anatomy and development (Cunha et al, ). The nuances of the definition of hypospadias are beyond the subject matter of this article and the reader is referred elsewhere (Blaschko et al, ; Cunha et al, ; Sinclair, ) Other abnormalities of the external genitalia that commonly accompany hypospadias include epispadias, cleft prepuce, and vaginal pouch (Foster and Harris, ).…”

“…Hypospadias and cryptorchidism are abnormalities in the external genitalia due to endocrine disruption during the MPW. They are common in boys occurring in 1:200 to 1:300 births (Blaschko et al, ), and the incidence of this defect has increased in the United States over the last few decades (Kalfa et al, ; Sinclair, ). In humans, hypospadias is defined by three penile abnormalities: abnormal urethral orifice location, penile curvature (chordee), and abnormal foreskin.…”

Discrete Hedgehog Factor Expression and Action in the Developing Phallus

“…The importance of androgens in phallus development and urethral closure has a long evolutionary history [3] and is well described in literature [14][15][16][17][18][19]. The process of urethral closure is highly sensitive to androgen disruption during a critical window of developmental programming that precedes the initiation of closure [20][21][22]. Therefore factors that can interfere with normal androgen signalling during this critical window, such as oestrogenic chemicals, are associated with hypospadias [14,23,24].…”

Developmental mutant mouse models for external genitalia formation

“…29 Hence, it is suggested as one of the essential regulatory gene for masculinization and the candidate gene for human hypospadias phenotype. [56][57][58] Androgen is one of the essential signals regulating many downstream genes. Putative upstream and "interacting" regulatory genes are necessary to set initial genetic regulatory status conferring "mesenchymal competence" for androgen signal.…”