Wellcome Trust Intermediate Clinical Fellow
Consultant Paediatric Endocrinologist
Development of the immature human testis in relation to disorders of sexual development (DSD) and testicular cancer
Current Research Projects
1. The germ stem cell niche in the human fetal testis and the origins of testicular cancer
2. The effect of exposure to endocrine disruptors on development of the human fetal testis using a xenograft approach
3. Xenografting of isolated human fetal testis tissue/cells as a model of seminiferous cord formation and disorders of sex development
My research focus is on fetal development of the testis and particularly that of germ cells in relation to the origins of testicular cancer. Testicular cancer is thought to result from disrupted development of germ cells during fetal life which results in pre-malignant carcinoma in-situ cells. The precise mechanisms of how this occurs are unknown.
Fetal testis development may potentially be disrupted by environmental and genetic factors and may increase the risk of developing testicular cancer. These factors are being investigated using a variety of animal and human models of testis development. This includes the use of testicular xenografting using human fetal testis tissue into host mice and subsequent exposure of these host animals to environmental factors or genetic manipulation of various cells prior to xenografting.
Isolation of testis cells and in-vitro techniques may also be used prior to transplantation in order to alter the local environment of the germ cells. The use of the xenografting model system has already been validated by our group as comparable to normal fetal testis development in-vivo.My other area of interest is of fertility preservation in the pre-pubertal testis and this focuses on developing strategies for removing and storing testis tissue from patients prior to potentially sterilizing treatments in order that germ cell development can be achieved using in-vitro or in-vivo techniques. Understanding the origins of testicular cancer and developing fertility preservation strategies require further understanding of the germ cell niche and we hope that by using the models described above that we will learn more about the interactions between germ cells and their surrounding cells during testis development.
External Grant Awards (Role: Principal Investigator)
1. Wellcome Trust Intermediate Clinical Fellowship
2. The Academy of Medical Sciences
3. The Society for Endocrinology
4. British Society for Paediatric Endocrinology & Diabetes £25,000 (2011-2013)
- Mitchell R, Sharpe RM, Anderson RA, McKinnell C, Macpherson S, Smith LB, Wallace WHB, Kelner C, and van den Driesche SS. Diethylstilboestrol exposure does not reduce testosterone production in human fetal testis xenografts. PLoS ONE 8(4): e61726. 2013.
- Sharpe RM and Mitchell RT. The downside of ‘inappropriate messaging’: new insight into the development of testicular germ cell tumours in young men?. Journal of Pathology. 229(4):497-501. 2013
- McKinnell C, Mitchell RT, Morris K, Anderson RA, Kelnar CJH, Wallace WHB, Sharpe RM. Perinatal germ cell development and differentiation in the male marmoset (Callithrix jacchus): similarities with the human and differences from the rat. Human Reproduction. 28(4):886-96. 2013
- Mitchell RT, Childs AJ, Anderson RA, van den Driesche S, Saunders PTK, McKinnell C, Wallace WHB, Kelnar CJH, Sharpe RM. 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(3): E341-8. 2012 (Faculty 1000 Cited – Must read)
- Van den Driesche S, Walker M, McKinnell C, Scott HM, Eddie SL, Mitchell RT, Seckl JR, Drake AJ, Smith LB, Anderson RA and Sharpe RM. Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of which leads to Masculinization Disorders in Rodents. PLoS ONE . 7(5): e37064. 2012
- Mitchell RT, Saunders PTK, Childs AJ, Cassidy-Kojima C, Anderson RA, Wallace WH, Kelnar CJ, Sharpe RM. Xenografting of human fetal testis tissue: a new approach to study fetal testis development and germ cell differentiation. Human Reproduction. 25(10): 2405-2414. 2010
- Mitchell RT, Saunders, PTK, Sharpe, RM, Kelnar CJK, Wallace, WHB. Male Fertility and Strategies for Fertility Preservation Following Childhood Cancer Treatment. Endocrine Development. 15: 101-34. 2009
- McKinnell C, Mitchell RT, Walker M, Morris K, Kelnar CJ, Wallace WH, Sharpe RM. Effect of fetal or neonatal exposure to monobutyl phthalate (MBP) on testicular development and function in the marmoset. Human Reproduction. 24(9): 2244-54. 2009
- Mitchell RT, Cowan G, Morris KD, Anderson RA, Fraser HM, Mckenzie KJ, Wallace WHB, Kelnar CJH, Saunders PTK and Sharpe RM. Germ cell differentiation in the marmoset (Callithrix jacchus) during fetal and neonatal life closely parallels that in the human. Human Reproduction. 23(12): 2755-65. 2008
- Mitchell RT, McDougall CM, Crum JE. Decreasing Prevalence of Obesity in Primary Schoolchildren. Archives of Disease in Childhood. 92: 153-154. 2007
- Murray GI, McFadyen MCE, Mitchell RT, Cheung YL, Kerr AC. Cytochrome P-450 CYP3A in Human Renal Cell Cancer. British Journal of Cancer. 79(11/12): 1836-1842. 1999