MRC Human Reproductive Sciences Unit

Research focus
1. To identify how lifestyle, nutritional and environmental factors (eg exposure to common environmental chemicals) can interfere with normal development and function of the fetal testis so as to result in reproductive disorders that manifest either at birth (failure of testis descent into the scrotum (cryptorchidism); abnormality of penis development (hypospadias) or in young adulthood (low sperm counts/subfertility, testicular cancer).

These disorders may comprise a 'testicular dysgenesis syndrome'. Our objective is to identify the causes and mechanisms leading to these disorders. This may allow modifications to lifestyle etc. that will avoid or protect the fetus from such effects.

2. To identify the mechanisms via which hormones, in particular androgens such as testosterone, regulate sperm production by the adult testis. These mechanisms hold the key to understanding what underpins male fertility. Identification of these mechanisms would improve our ability to treat male infertility or to induce infertility for contraceptive purposes.

Background to the research
Disorders of male reproductive development and function can affect as many as 1 in 6 males, with low sperm counts in young men being the commonest such abnormality.

There is growing evidence that such disorders are becoming ever more common, an increase that is thought to result from the impact of environmental and lifestyle factors on the developing testis in fetal life (eg maternal smoking, cosmetic use) or shortly after birth (eg choice of feeding for infants).

Recent Progress

Development of an animal model for 'testicular dysgenesis syndrome (TDS)' disorders which has enabled identification of pathways to these disorders and potential environmental causes.

Via collaboration with European colleagues, development of a transgenic mouse via which to identify how androgens regulate sperm production.

Figure 1.

Figure1: Induction of testicular dysgenesis by fetal exposure to dibutyl phthalate in the rat, as seen at puberty.

Leydig cells (brown) should only be present in the spaces between the seminiferous tubules (*) but are also found misplaced within the tubules (Arrows); wherever the latter occur, no germ cells (stained pink for Dazl protein) survive in the immediate vicinity. Blue staining shows cell nuclei.

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Professor Richard Sharpe Principal Investigator		Contact
Research focus 1. To identify how lifestyle, nutritional and environmental factors (eg exposure to common environmental chemicals) can interfere with normal development and function of the fetal testis so as to result in reproductive disorders that manifest either at birth (failure of testis descent into the scrotum (cryptorchidism); abnormality of penis development (hypospadias) or in young adulthood (low sperm counts/subfertility, testicular cancer). These disorders may comprise a 'testicular dysgenesis syndrome'. Our objective is to identify the causes and mechanisms leading to these disorders. This may allow modifications to lifestyle etc. that will avoid or protect the fetus from such effects. 2. To identify the mechanisms via which hormones, in particular androgens such as testosterone, regulate sperm production by the adult testis. These mechanisms hold the key to understanding what underpins male fertility. Identification of these mechanisms would improve our ability to treat male infertility or to induce infertility for contraceptive purposes. Background to the research Disorders of male reproductive development and function can affect as many as 1 in 6 males, with low sperm counts in young men being the commonest such abnormality. There is growing evidence that such disorders are becoming ever more common, an increase that is thought to result from the impact of environmental and lifestyle factors on the developing testis in fetal life (eg maternal smoking, cosmetic use) or shortly after birth (eg choice of feeding for infants). Recent Progress Development of an animal model for 'testicular dysgenesis syndrome (TDS)' disorders which has enabled identification of pathways to these disorders and potential environmental causes. Via collaboration with European colleagues, development of a transgenic mouse via which to identify how androgens regulate sperm production. Figure 1. Figure1: Induction of testicular dysgenesis by fetal exposure to dibutyl phthalate in the rat, as seen at puberty. Leydig cells (brown) should only be present in the spaces between the seminiferous tubules (*) but are also found misplaced within the tubules (Arrows); wherever the latter occur, no germ cells (stained pink for Dazl protein) survive in the immediate vicinity. Blue staining shows cell nuclei.		r.sharpe@hrsu.mrc.ac.uk Tel: +44 (0)131 242 9100 Fax: +44 (0)131 242 6197

		Publications
		Publications - full listing
		Publications - Selected; recent
		Research Programmes
		Androgens and male fertility
		Perinatal origins of male reproductive health disorders

		Research Staff
		Professor Sharpe's research group currently comprises 1 Senior Investigator Scientist (Dr Lee Smith), 1 Career Development Fellow, 1 Clinical Research Training Fellow, 2 research support staff and 4 PhD students.

		Editorships/Affiliations/Collaborations
		Has served as Editor/associate Editor on several reproduction/endocrine journals.
		Has served on UK Government advisory/working groups asked to assess reproductive health impacts of hormones/chemicals in food and consumer products.
		Chairman of the Expert Group on Endocrine Disruptors, representing the UK Society for Endocrinology
		Longstanding collaborations with several European groups directed at improving understanding about the deterioration of male reproductive health across Europe (funded by the EC).

		Biographical Profile
		Professor Richard Sharpe biographical profile

		Selected recent publications
		Sharpe RM Bisphenol A exposure and sexual dysfunction in men Human Reproduction, Vol.25, No.2 pp. 292–294, 2010 Welsh M, MacLeod D, Walker M, Saunders PTK, Sharpe RM (2010) Critical androgen-sensitive periods of development and growth of the rat penis and clitoris: implications for humans. International Journal of Andrology 33: e144-e152 Scott HM, Mason JI, Sharpe RM (2009) Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocrine Reviews 30: 883-925 Drake AJ, Van den Driesche S, Scott HM, Hutchison G, Seckl JR, Sharpe RM (2009) Glucocorticoids amplify dibutyl phthalate-induced disruption of fetal testosterone production and male reproductive development. Endocrinology 150: 5055-5064 Welsh M, Saunders PTK, Atanassova N, Sharpe RM, Smith LB (2009) Androgen action via testicular peritubular myoid cells is essential for male fertility. FASEB Journal 23: 4218-4230 Welsh M, Saunders PTK, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism Journal of Clinical Investigation 118: 1479-1490 Scott HM, Hutchison GR, Jobling MS, McKinnell C, Drake AJ, Sharpe RM (2008) Relationship between androgen action in the ‘male programming window’, fetal Sertoli cell number and adult testis size in the rat. Endocrinology 149: 5280-5287 Mitchell R, Cowan G, Morris KD, Anderson RA, Fraser HM, Mckenzie KJ, Wallace WHB, Kelnar CJH, Saunders PTK, Sharpe RM (2008) Germ cell differentiation in the marmoset (Callithrix jacchus) during fetal and neonatal life closely parallels that in the human. Human Reproduction 23: 2755-2765 Sharpe RM, Skakkebaek NE (2008) Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. Fertility & Sterility 89 Suppl 1: e33-e38


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