Professor Richard M Sharpe
Research focus and aims.
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.
Lectures/presentations by Richard Sharpe
Plenary lecture on ‘Key developments in reproductive endocrinology’ as part of the ‘Science, Innovation & Society’ session at the meeting of EFSA (European Food Safety Authority) in Milan, October 2015.
Video links/interviews describing the work of the Richard Sharpe Group
Interviews with Penelope Jagessar Chaffer on the masculinization process, fetal origins of male reproductive disorders and exposures to environmental chemicals
Using human tissue to study fetal origins of male reproductive disorders
British Nutrition Foundation: Perinatal effects of sex hormones in programming susceptibility to disease
View the video
CBS News 60 minutes: “Are phthalates safe?”
Stand-up comedy routine at Bright Club Edinburgh as part of the MRC Centenary celebrations in 2013
News from the Richard Sharpe Group
- Congratulations to Afshan (former Group member) and Sander and to numerous others for the final publication of our research on the potential adverse reproductive effects of painkiller use in pregnancy. It has been a long haul and a monumental group effort, but gratifying to see that it has had quite an impact.
- Congratulations to Sander and Chris, as well as to the Rod Mitchell group, for the recent collaborative publication in Science Translational Medicine of Studies showing adverse effects of paracetamol on testosterone production by the fetal human testis. This has made headlines around the world.
- At the Spring meeting of the Academy of Medical Sciences in London, Dr Tom Chambers was selected to present his poster to HRH Princess Anne (see photo). Tom’s poster, which reports on some of the work of his PhD, was entitled ‘Does grandparent’s diet affect weight and risk of hypogonadism in subsequent generations?’
- Congratulations to Dr Tom Chambers for winning best poster prize and to Dr Karen Kilcoyne for being runner- up for the best oral presentation (see picture, right) at the Basic Endocrinology Course in Reproductive Endocrinology meeting in Edinburgh organised by the European (ESE) and UK Societies for Endocrinology in February.
- Congratulations to Kerrie Stevenson who won a £1000 prize for the best student oral presentation at the annual Blair Bell Research Society competition in conjunction with the annual academic meeting of the Royal College of Obstetricians & Gynaecologists in London. Kerrie was presenting the results of her Reproductive Honours project that she undertook in the Sharpe group in 2014, entitled “Investigating the effects of maternal exposure to analgesics on the epigenetic machinery of the rat fetal gonad”.
- Richard Sharpe presented a Science Policy Breakfast for Euro-MPs (MEPs) and associated workers and interest groups on 22nd January in the parliament building in Brussels. The aim of these is to inform MEPs about the science that underlies issues on which they have to vote/make decisions that affect policy and requirements through the EU. His talk was entitled “Endocrine disruptors – who is regulating our hormones?”
- Dr Sander van den Driesche, Postdoctoral Fellow
- Dr Thomas Chambers, Clinical Research Fellow/PhD
- Dr Karen Kilcoyne, MRC Centenary Fellow
- Mr Chris McKinnell, Research
- Mrs Sheila Macpherson
- Lee Smith, Rod Mitchell (CRH, Edinburgh)
- Mandy Drake, (CVS, Edinburgh)
- Hamish Wallace, Chris Kelnar (Sick Children’s Hospital, Edinburgh)
- Paul Fowler, (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 (Copenhagen, Denmark)
- Jorma Toppari, (Turku, Finland)
- Manuel Tena-Sempere( Cordoba, Spain)
- Bernard Jégou (Rennes, France)
- Shanna Swan (Rochester, USA)
Current positions of responsibility
- Convenor, Postgraduate Studies Committee, CRH
- Member of expert panel for Sense about Science UK
- Member, British Nutrition Foundation task force on developmental programming of later disease
- Deputy Editor of Human Reproduction
- Member, ‘Clinical & Environmental health research’ panel, Academy of Finland