ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P263

Endocrine disruptors and their association with male reproductive disorders and testicular dysgenesis syndrome: establishing a xenografting model of human fetal testis development

Rod Mitchell1,3, Philippa Saunders1, Andrew Childs2, Claire Cassidy-Kojima3, Richard Anderson3, Hamish Wallace2, Chris Kelnar2 & Richard Sharpe1

1MRC Human Reproductive Sciences Unit, Edinburgh, UK; 2Edinburgh Royal Hospital for Sick Children, Edinburgh, UK; 3Edinburgh University, Edinburgh, UK.

Testicular dysgenesis syndrome (TDS) is a group of associated conditions (testicular germ cell tumours (TGCT), cryptorchidism, hypospadias and low sperm counts) that are thought to have a common origin in fetal life. Exposure of fetal rats to environmental chemicals such as the endocrine disrupting chemical di(n-butyl) phthalate (DBP) results in a TDS-like syndrome. However, exposed rats do not develop TGCT and the rodent is a poor model in this context. The effects of phthalates on human fetal testis development and function are difficult to study in the short-term in vitro. Development of a model system in which to investigate normal human fetal testis development and the mechanisms underpinning the fetal origin of TDS/TGCT cells would represent a major advance.

We have, therefore, xenografted human fetal testis tissue from first and second trimester fetuses into nude mice hosts for 6 weeks and demonstrated normal development of tissue (including normal seminiferous cord formation) in comparison to age-matched controls. Xenografts continue to grow, and the component cells proliferate and functionally differentiate normally. Xenografts are able to produce basal levels of testosterone that can be increased by injection of host mice with hCG. Exposure of xenografts to DBP for 24–96 h by daily oral gavage results in germ cell aggregation and formation of multinucleated gonocytes, whereas GC aggregation was not demonstrated in vehicle treated controls and MNG were found infrequently.

These results have validated an exciting and novel way in which to investigate the mechanisms of human fetal testis development in health and disease. Importantly, this model may also be applied to study the effects of other environmental factors on human testis development. Results of such studies will help to determine the risk posed to human health by exposure to these chemicals during a critical time in gonadal development.