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Human masculinisation disorders: investigation of mechanistic origins using an animal model

Formation of a testis and its subsequent production of androgens in early fetal life are prerequisites for masculinisation. It is now clear that disruption of these early events can have adverse consequences later in life, a phenomenon known as the testicular dysgenesis syndrome (TDS).

TDS can lead to (common) reproductive disorders which may manifest at birth (cryptorchidism and hypospadias) or in adulthood (reduced sperm count, testis germ cell cancer and primary hypogonadism). We have developed and validated a rat model of TDS involving exposure in utero to the environmental chemical dibutyl phthalate (Van den Driesche et al., 2012, 2015, 2017). This model has shown that exposure of the testis to dibutyl phthalate during the so-called masculinisation programming window (embryonic day (e)15.5-e18.5), results in impaired androgen production, late-onset focal dysgenesis, reduced Sertoli cell number and downstream male reproductive disorders. Reduced androgen production/action is central to all of these changes, but the mechanisms for these effects are unknown.

Recent evidence suggests a potential role for microRNAs in linking reduced androgen production/action during the masculinisation programming window and masculinisation disorders. Androgens regulate microRNA expression in prostate, muscle, liver and mouse Sertoli cells and intriguingly, several microRNAs have been identified in association with testis germ cell tumours (a TDS disorder) in human samples.

The aim of this PhD project will be to investigate the hypothesis that temporal differences in the expression of microRNAs underlie the androgen effects on the developing testis during the masculinisation programming window, and that altered microRNA expression accounts for dibutyl phthalate-induced testicular dysgenesis. In this project the temporal expression of microRNA in the developing testis and the effect of exposure to dibutyl phthalate on the microRNA profile will be explored. Raw data are available from a previously performed next generation miRNA sequencing, which will provide the starting point for the project. Techniques will include: bioinformatics, quantitative RT-PCR, immunohistochemistry/fluorescence, microdissection, tissue culture.

Primary supervisor

Dr Sander van den Driesche

Dr Sander van den Driesche lab

 +44 (0)131 650 3112

S.vandenDriesche@ed.ac.uk

Second supervisor

Prof Norah Spears

Co-supervisor

Dr Rod Mitchell

Further information

Centre for Integrative Physiology website