Richard Sharpe leads a Research Team on ‘Male reproductive health’.
His expertise covers masculinisation and its disorders, endocrinology, environmental ‘endocrine disruptors’ and their effects on reproductive development and function, effects of lifestyle (smoking, obesity, diet,
use of personal care products), and the inter-relationships between reproductive health and wider aspects of health (aging, obesity, cardiometabolic diseases).
Job title: PI, Group Leader
Research focus and aims
The overall aim is to identify how (common) male reproductive disorders originate, what causes them and how could we prevent them? The disorders manifest at birth -hypospadias, cryptorchidism- or in young adulthood -low sperm counts, testicular germ cell cancer (TGCC), reduced testosterone levels; they are remarkably common and/or increasing in incidence. Lifestyle/environmental factors must be responsible for this increase, implying there is potential for prevention, once causes are identified.
The ‘testicular dysgenesis syndrome’ (TDS) hypothesis proposes that these disorders can have a common fetal origin. We have identified that androgens from the fetal testis act within a critical time window – the ‘masculinisation programming window’ (MPW) – to program normal development and ultimate adult size of all male reproductive organs and anogenital distance (AGD). AGD provides a life-long ‘read out’ of androgen exposure in the MPW and enables us to ‘look back in time’. The occurrence and severity of TDS disorders is related to AGD, pointing to their origin in the MPW because of deficient androgen action.
The primary goal of our research is to establish the pathways that govern normal testis development and function in fetal life that are vulnerable to disruption, resulting in TDS disorders. Once these pathways are identified, we study what sorts of factors relevant to human males (eg diet, lifestyle, chemical exposures) can impact them; this can form the basis for preventative strategies. A growing interest is to establish how fetal events determine adult testosterone levels, and if this then alters predisposition to develop obesity and related cardiometabolic disorders as an adult.
We are also interested in germ cell development during fetal life, and how exogenous factors (diet, lifestyle, exposures of the parents) may affect the epigenome of germ cells during the critical fetal period when epigenetic marks are erased and then reinstated. Can epigenetic changes to germ cells be induced as a result of eating a ‘Western’ style diet, and if so, can these be transmitted to the next generation and alter reproductive function or disease susceptibilities in offspring.
Our main research approach is to develop and use appropriate animal models. For example, we have developed and validated a rodent model of TDS based on fetal exposure to the environmental chemical, dibutyl phthalate. Other approaches use dietary modifications or the use of transgenic mice (collaboration with Prof Lee Smith). To ensure these animal studies are relevant to human males, we use human fetal testis tissue grafted into immune-compromised mice, as the grafted tissue develops normally (collaboration with Dr Rod Mitchell). These xenografts provide the main approach for studies into the origins of TGCC and its precursor (CIS cells) and provide a direct means of translating new findings from our animal studies to man.
By identifying when and how the fetal testis is sensitive to disruption, these studies will improve our ability to protect the human fetus during its critical phases and thus minimize risk of later-onset TDS and related disorders. This programme of work fits with theme 2 of the MRC strategic plan.
News from the Richard Sharpe Group
Congratulations are due to several team members (and our collaborative colleagues):
- To Sander van den Driesche on the award of an Early Career Development grant from the Society for Endocrinology.
- To Karen Kilcoyne for winning a poster prize at the British Endocrine Societies meeting in Harrogate in March.
- To Rod Mitchell and Sander van den Driesche for winning a poster prize at the British Endocrine Societies meeting in Harrogate in March.
- To Laura Kennedy (medical student) for being the overall winner of her category at the National Student Association of Medical Research for her poster that described the results from her 4th year research project in our group.
- To all team members, but especially to Afshan Dean for recent acceptance of new manuscripts for publication.
H index = 63
- Scott HM, Hutchison GR, Mahood IK, Hallmark N, Welsh M, de Gendt K, Verhoeven G, O’Shaughnessy PJ, Sharpe RM (2007) Role of androgens in fetal testis development and dysgenesis. Endocrinology 148: 2027-2036 [IF=5.1]
- 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 [IF=15.4]
- 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 [IF=5.1]
- 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 [IF=19.8]
- Mitchell RT, Saunders PTK, Childs AJ, Cassidy-Kojima C, Anderson RA, Wallace HB, Kelnar CJH, Sharpe RM (2010) Xenografting of human fetal testis tissue: a new approach for studying the fetal origins of male reproductive disorders. Human Reproduction 25: 2405-2414 [IF=4.5]
- van den Driesche S, Walker M, McKinnell C, Scott HM, Eddie SL, Seckl JR, Drake AJ, Smith LB, Anderson RA, Sharpe RM (2012) Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which results in masculinization disorders in rodents. PlosOne 7: e37064 [IF=4.4]
- Mitchell RT, Childs AC, Anderson RA, van den Driesche S, Saunders PTK, McKinnell C, Wallace WHB, Kelnar CJH, Sharpe RM (2012) Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di(n-butyl) phthalate. Journal of Clinical Endocrinology and Metabolism 97: E341-E348 [IF=6.0]
- Dr Sander van den Driesche, Postdoctoral Fellow
- Dr Afshan Dean, Postdoctoral Fellow
- Dr Thomas Chambers, Clinical Research Fellow/PhD
- Dr Xiajun Zhu, China Fellow (PhD)
- Miss Karen Kilcoyne, PhD student
- Mr Chris McKinnell, Research
- Mrs Sheila Macpherson
- Lee Smith, Rod Mitchell (CRH, Edinburgh)
- Mandy Drake, Jonathan Seckl (CVS, Edinburgh)
- Hamish Wallace, Chris Kelnar (Sick Children’s Hospital, Edinburgh)
- Paul Fowler, Stewart Rhind (Aberdeen)
- Michelle Bellingham, Peter O’Shaughnessy (Glasgow)
- Luzi Renata de Franca (Belo Horizonte, Brazil)
- Serge Nef (Switzerland)
- Nina Atanassova (Bulgaria)
- Niels Skakkebaek, Anna-Maria Andersson, Katharina Main, Niels Jorgensen
- Jorma Toppari (Turku, Finland)
- Bernard Jégou (Rennes, France)
- Shanna Swan (Rochester, USA)
Current positions of responsibility
- Convenor, Postgraduate Studies Committee, CRH
- Co-Chairman, Special Interest Group (SIG) on Endocrine Disruptors, UK Society for Endocrinology
- Member of expert panel for Sense about Science UK
- Member, British Nutrition Foundation task force on developmental programming of later disease
- Ex-officio member, UK Society of Endocrinology Public Engagement Committee
- Member of Council, UK Society for Endocrinology
- Deputy Editor of Human Reproduction
- Member, ‘Clinical & Environmental health research’ panel, Academy of Finland
Page last updated 23 January 2013