A wide variety of genetic and environmental factors have been proposed to affect male gonadal development and function during fetal life with impacts on subsequent reproductive health. This includes genetic mutations that may result in disorders of sex development (DSD), and environmental exposures to agents such as plasticizers, synthetic oestrogens and analgesics. Much of the data on the specific effects of these genetic mutations and exposures on gonadal development and function are based on studies conducted in rodent models; however, confirmation of such findings in human-relevant model systems are lacking.
We have developed model systems to determine the effects of genetic manipulation and environmental exposures on human fetal testis development and function. Using a xenograft system designed to reproduce normal fetal testis development and in-utero hormonal environment, our results demonstrate important species differences in the effects of exposure to chemicals such as di-n-butyl phthalate (DBP) and diethylstilboestrol (DES) in terms of testosterone production, a key determinant of male reproductive development during fetal life. We have also demonstrated that exposure to analgesics, such as paracetamol, result in a significant reduction in testosterone production and also impact on germ cell development in the human fetal testis. Importantly, these effects are apparent at therapeutic levels of exposure using a standard therapeutic regimen. In addition, we have developed this system to model the effects of known and novel genetic mutations associated with DSD on gonad development during fetal and early postnatal life.
Our work, demonstrates the importance of choosing appropriate model species, experimental systems and exposure regimens to determine the potential impact of genetic mutations and environmental exposures on gonadal development during fetal life which will ultimately determine male reproductive function during adulthood.
11 Jul 2016 - 11 Jul 2016