Policy Tools for U.S. Agriculture.

130 p

Policy Tools for U.S. Agriculture.

84 p

Current understanding of hypospadias: relevance of animal models

Hypospadias is a congenital abnormality of the penile urethra with an incidence of approximately 1:200-1:300 male births, which has doubled over the past three decades. The aetiology of the overwhelming majority of hypospadias remains unknown but appears to be a combination of genetic susceptibility and prenatal exposure to endocrine disruptors. Reliable animal models of hypospadias are required for better understanding of the mechanisms of normal penile urethral formation and hence hypospadias. Mice and/or rats are generally used for experimental modelling of hypospadias, however these do not fully reflect the human condition. To use these models successfully, researchers must understand the similarities and differences between mouse, rat and human penile anatomy as well as the normal morphogenetic mechanisms of penile development in these species. Despite some important differences, numerous features of animal and human hypospadias are shared: the prevalence of distal penile malformations; disruption of the urethral meatus; disruption of urethra-associated erectile bodies; and a common mechanism of impaired epithelial fusion events. Rat and mouse models of hypospadias are crucial to our understanding of hypospadias to ultimately reduce its incidence through better preventive strategies

Phthalate-induced pathology in the foetal testis involves more than decreased testosterone production

Foetal exposure to phthalates is known to adversely impact male reproductive development and function. Developmental anomalies of reproductive tract have been attributed to impaired testosterone synthesis. However, species differences in the ability to produce testosterone have been noted; e.g., following foetal exposure, abnormal clustering of Leydig cells or decreased production of testosterone that is manifested in rats does not occur in mice or humans. Nonetheless, other facets of testicular dysgenesis occur in both rats and mice as well as in some other species tested. We recently published a comprehensive evaluation of the foetal rat testis proteome, following in utero exposure to diethylhexyl phthalate (DEHP), which revealed changes in individual proteins that are known to be factors in cellular differentiation and migration or related to the capacity of the foetal Leydig cell to produce testosterone and fit a pathway network in which each is regulated directly or indirectly by oestradiol. Plasma oestradiol indeed was found to be elevated approximately twofold in 19-day-old DEHP-exposed foetal male rats. In this brief review, we discuss our new findings vis-à-vis ‘oestrogen hypothesis’ as a cause for testicular dysgenesis syndrome.</jats:p

Postweaning exposure to gossypol results in epididymis-specific effects throughout puberty and adulthood in rats

Gossypol, a yellow pigment found in cottonseeds, well known for its antifertility properties in animals, has been used as a contraceptive by men. The aims of this work were to evaluate the effects of gossypol throughout sexual development of male rats and to provide additional data to clarify the target site or sites of this compound in the male reproductive system, Gossypol (15 mg/kg per day) was given to animals from weaning through prepuberty (41 days), early puberty (51 days), puberty (61 days), and sexual maturity (91 days). Ventral prostate weight and fructose levels were similar in control and treated rats, suggesting that androgen levels were normal. No histological effects on the testis were detected, but there was a significant decrease in the sperm concentration in the cauda epididymidis of gossypol-treated animals killed at 61 and 91 days, as well as a significant increase in abnormal sperm in the vas deferens of treated animals. Moreover, the histology of the cauda epididymidis of the rats treated throughout puberty (ie, until days 51 and 61) showed a great number of round bodies in the lumen of the epididymis. These structures stained for the epididymis-specific protein E. Collectively, the data demonstrate that the epididymis is a target of gossypol when postweaning exposure extends throughout pubertal development, and that whereas more subtle histological effects commence around puberty, indicators reproductive competence are compromised in adulthood