ESPE Abstracts (2018) 89 S2.2

Disruption of Testicular Development and Function

Rod Mitchell

University of Edinburgh, Edinburgh, UK

Male reproductive disorders are common and there is evidence for increasing incidence over recent decades. These disorders may present at birth (hypospadias and cryptorchidism) or in adulthood (infertility, testicular cancer) and can arise as a result of underlying genetic abnormalities or following environmental (e.g. phthalates) and pharmaceutical (e.g. analgesics, chemotherapy) exposures that impact fetal, neonatal of prepubertal testicular development. Understanding the relevance of these perturbations on the testis and subsequent reproductive function in humans is often based on the findings of animal studies, however there are important differences between rodent and human in terms of fetal and postnatal testis development, in particular germ cell development. Therefore, reliable human experimental models that can demonstrate human and clinical relevance are required. We have validated in-vitro and ex-vivo experimental models of human testis development. This includes a ‘hanging drop’ culture system and a human testis xenograft approach that can be utilised to investigate the development and function of the human testis during fetal, neonatal and prepubertal life. These model systems can recapitulate seminiferous cord formation, germ and somatic cell development and hormone production. Furthermore these model systems can be combined to investigate the long-term effects of genetic disruption to model the gonadal effects of Disorders of Sex Development and environmental exposures (e.g. industrial chemicals, pharmaceuticals and chemotherapeutics) on the testis. We have utilised these models to mimic in-utero exposure to analgesics on human fetal testis development and function and the effects of therapeutic analgesic exposures on human fetal germ cell development and testosterone production will be described. The effect of knockdown, in the human fetal testis, of known and novel genes implicated in Testicular Dysgenesis Syndrome and Disorders of Sex Development will also be presented. The model systems have also been adapted for the investigation of human prepubertal testis development as part of a fertility preservation programme for boys treated for cancer. Studies investigating the effects of chemotherapy exposure on the prepubertal testis will be described, in addition to experimental approaches to preserving fertility in childhood cancer.

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