Novel epididymal proteins as targets for the development of post-testicular male contraception

Abstract

Apart from condoms and vasectomy, modern contraceptive methods for men are still not available. Besides hormonal approaches to stop testicular sperm production, the post-meiotic blockage of epididymal sperm maturation carries lots of promise. Microarray and proteomics techniques and libraries of expressed sequence tags, in combination with digital differential display tools and publicly available gene expression databases, are being currently used to identify and characterize novel epididymal proteins as putative targets for male contraception. The data reported indicate that these technologies provide complementary information for the identification of novel highly expressed genes in the epididymis. Deleting the gene of interest by targeted ablation technology in mice or using immunization against the cognate protein are the two preferred methods to functionally validate the function of novel genes in vivo. In this review, we summarize the current knowledge of several epididymal proteins shown either in vivo or in vitro to be involved in the epididymal sperm maturation. These proteins include CRISP1, SPAG11e, DEFB126, carbonyl reductase P34H, CD52, and GPR64. In addition, we introduce novel proteinases and protease inhibitor gene families with potentially important roles in regulating the sperm maturation process. Furthermore, potential contraceptive strategies as well as delivery methods will be discussed. Despite the progress made in recent years, further studies are needed to reveal further details in the epididymal sperm maturation process and the factors involved, in order to facilitate the development of new epididymal contraceptives.

The Blood-Testis Barrier and Its Implications for Male Contraception

“…Introduction. Unlike hormonal contraception (e.g., testosterone), which exerts its effects to disrupt the hypothalamic-pituitary-testicular axis (Page et al, 2008;Huhtaniemi, 2010;Wang and Swerdloff, 2010), or approaches that target the epididymis (O'Rand et al, 2007;Blithe, 2008;Kopf, 2008;Mruk, 2008;Sipilä et al, 2009), the development of nonhormonal male contraceptives, such as adjudin Cheng and Mruk, 2010b), bisdichloroacetyldiamines (Hogarth and Griswold, 2010;Amory et al, 2011;Hogarth et al, 2011), gamendazole (Tash et al, 2008a,b), indenopyridine 5SR,3,4,4a,5,-1H-indeno-[1,2-c]-pyridine-hydrochloride, also known as RTI-4587-073) (Hild et al, 2004(Hild et al, , 2007aKoduri et al, 2008), and immunological approaches that target sperm-specific postmeiotic germ cell antigens (Suri, 2005;Mruk, 2008;McLaughlin and Aitken, 2011), requires a better understanding of the BTB because these compounds exert their effects, at least in part, behind the BTB in the apical compartment of the seminiferous epithelium Cheng and Mruk, 2010b;Mok et al, 2011b). As described above, the BTB largely dictates how much drug can enter the apical compartment of the seminiferous epithelium to exert its effects behind the immunological barrier.…”

Loss of Bmyc results in increased apoptosis associated with upregulation of Myc expression in juvenile murine testis

“…Recent advances in high-throughput genome approaches have led to an intensive search of genes coding for proteins involved in epididymal sperm maturation processes (Sipilä et al 2009). As many of these genes are expressed exclusively in the epididymis, the identification of transcription factors regulating their expression is also of interest, although still only superficially known.…”

Spink13, an Epididymis-specific Gene of the Kazal-type Serine Protease Inhibitor (SPINK) Family, Is Essential for the Acrosomal Integrity and Male Fertility

“…The mammalian spermatozoa produced in the testis do not have the ability to fertilize oocytes; they become fertilizationcompetent during passage through the epididymis, where they undergo sequential membrane modifications collectively known as sperm maturation (1)(2)(3)(4)(5). During this process, the male gamete will undergo a sequence of well orchestrated biochemical modifications that are modulated by the epididymal intraluminal composition, in particular secreted epididymal proteins (6,7).…”

“…This suggests that the sperm surface architecture depends on correct localization of its components and highlights the importance of the sequential proteolytic processing of the sperm surface proteins in the epididymal duct. Proteolysis in the epididymal lumen thus needs to be well controlled, and several protease inhibitors expressed in the certain epididymal regions are expected to be responsible for this control (3,8).…”