Dr Victoria Cabrera-Sharp

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Regulation of male fertility

The earliest part of my research career focused mainly on male reproduction, firstly during my post-doctoral studies (1) and then throughout my first post-doctoral position (2).

1) Stress response and male fertility (PhD thesis, Royal Veterinary College, Jan 2008).

Assisted reproductive technology in the pig is limited by a high number of low motility sperm at ejaculation, a decrease in sperm viability after storage and an increase in cell death following cryopreservation (Pursel et al. 1973; Waberski et al. 1994; Johnson et al. 2000; Paulenz et al. 2000; Holt and Harrison 2002).  Endogenous glucocorticoids (cortisol and corticosterone) have established roles in reproductive physiology, which are modulated in several reproductive tissues by one or more of the cloned 11βHSD enzymes (reviewed by Michael et al. 2003).

In the male, glucocorticoids are known to exert deleterious effects on Leydig cell function (Bambino & Hsueh, 1981, Gao et al., 1997, Monder et al., 1994b) and with specific reference to the boar, have recently been shown to induce apoptosis in spermatogonia (Claus et al. 2005).  Until now, the basic understanding of glucocorticoid metabolism and actions in the boar testis and reproductive tract has been limited.

Therefore, the aim of my PhD thesis was to characterise the expression and activities of the cortisol metabolising enzymes, 11βHSD1 and 11βHSD2, and elucidate if 11βHSD enzymes are hormonally regulated in the porcine testis and male reproductive tract, to enable further understanding of the environment in which porcine spermatozoa mature and reside.

This aim was achieved (and reported, follow links) by addressing 4 different questions:

i)              Are 11βHSD1 and/or 11βHSD2 mRNA and protein expressed in the porcine testis and male reproductive tract, before and after puberty? (Sharp et al. 2007, Sharp et al. 2009)

ii)             What are the enzymatic activities of 11βHSD within the pre- and post-pubertal porcine testis and male reproductive tract? (Sharp et al. 2007, Sharp et al. 2009)

iii)            Do gonadotrophins regulate 11βHSD1- and 11βHSD2- mediated cortisol metabolism? (Cabrera-Sharp, 2013)

iv)           Do androgens regulate 11βHSD1- and 11βHSD2- mediated cortisol metabolism? (in preparation).

 


2. To develop new methods of male contraception (Imperial College, London).

The epididymis plays an important role in the maturation of sperm and their acquisition of fertilising capacity. This organ is therefore a promising target for novel strategies of male contraception. The purpose of this project is to identify novel epididymis-specific genes and study their role in the process of sperm maturation, using genetically modified mice as experimental models.

i) Through exploration of the mouse epididymal transcriptome, we identified a few novel genes expressed specifically in the proximal epididymis. We produced a KO mouse for Rnase10 and report in Journal of the Federation of American Societies for Experimental Biology (Vol 12 October 2012) that the encoded product is the first single epididymal secreted protein found to be essential for sperm maturation and normal male fertility, providing evidence that inactivation of function of a single epididymis-specific gene product may be a feasible strategy to develop a male contraceptive.

ii) It is well established that the normal development andfunctional integrity of the epididymis are dependent on androgen action. However, if testosterone levels are restored after castration, the regressive changes in the distal caput, corpus, and cauda epididymidis are reversed but not in the initial segment (IS), which has cast doubt on androgen dependence of this epididymal zone, whose normal function is crucial for the functional maturation of sperm. As a novel approach to elucidate the role of androgen action in epididymal function and in particular in the IS, we used the targeted gene ablation technique, crossing the ArloxP mice with our novel Cre deletor mouse expressing Cre recombinase under the promoter of Rnase10, a gene with specific expression in the proximal epididymis (ProxE-ARKO mouse). The results obtained, reported in Endocrinology (February 2011), clearly demonstrate a role for direct androgen action in the proximal epididymis.

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