Abstract
BackgroundThe etiology of varicocele, a common cause of male factor infertility, remains unclear. Proteomic changes responsible for the underlying pathology of unilateral varicocele have not been evaluated. The objective of this prospective study was to employ proteomic techniques and bioinformatic tools to identify and analyze proteins of interest in infertile men with unilateral varicocele.MethodsSpermatozoa from infertile men with unilateral varicocele (n = 5) and from fertile men (control; n = 5) were pooled in two groups respectively. Proteins were extracted and separated by 1-D SDS-PAGE. Bands were digested and identified on a LTQ-Orbitrap Elite hybrid mass spectrometer system. Bioinformatic analysis identified the pathways and functions of the differentially expressed proteins (DEP).ResultsSperm concentration, motility and morphology were lower, and reactive oxygen species levels were higher in unilateral varicocele patients compared to healthy controls. The total number of proteins identified were 1055, 1010 and 1042 in the fertile group, and 795, 713 and 763 proteins in the unilateral varicocele group. Of the 369 DEP between both groups, 120 proteins were unique to the fertile group and 38 proteins were unique to the unilateral varicocele group. Compared to the control group, 114 proteins were overexpressed while 97 proteins were underexpressed in the unilateral varicocele group. We have identified 29 proteins of interest that are involved in spermatogenesis and other fundamental reproductive events such as sperm maturation, acquisition of sperm motility, hyperactivation, capacitation, acrosome reaction and fertilization. The major functional pathways of the 359 DEP related to the unilateral varicocele group involve metabolism, disease, immune system, gene expression, signal transduction and apoptosis. Functional annotations showed that unilateral varicocele mostly affected small molecule biochemistry and post-translational modification proteins. Proteins expressed uniquely in the unilateral varicocele group were cysteine-rich secretory protein 2 precursor (CRISP2) and arginase-2 (ARG2).ConclusionsThe expression of these proteins of interest are altered and possibly functionally compromised in infertile men with unilateral varicocele. If validated, these proteins may lead to potential biomarker(s) and help better understand the mechanism involved in the pathophysiology of unilateral varicocele in infertile men.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0007-2) contains supplementary material, which is available to authorized users.
Highlights
The etiology of varicocele, a common cause of male factor infertility, remains unclear
Rodova et al showed that ATP1A4 was essential for male germ cell gene expression [67,77]. We found this protein to be underexpressed with very low abundance in unilateral varicocele group; spermatozoa with deficiency of this protein show a characteristic bend in the sperm flagellum which is indicative of abnormal ion regulation, reduced motility and hyperactivation which is essential for capacitation
DLD, glutathione Stransferase Mu 3 (GSTM3), TGM4, NPC23, ODF2GPR64, PSM8, HIST1H2BA and PARK7 were overexpressed in the unilateral varicocele group suggesting that sperm quality and functional capacity was abnormally affected
Summary
The etiology of varicocele, a common cause of male factor infertility, remains unclear. Proteomic changes responsible for the underlying pathology of unilateral varicocele have not been evaluated. The objective of this prospective study was to employ proteomic techniques and bioinformatic tools to identify and analyze proteins of interest in infertile men with unilateral varicocele. The causes of varicocele are multiple and include increased scrotal temperature, stunted testicular growth, semen abnormalities, oxidative stress and Leydig cell dysfunction [2,3,6]. Oxidative-stress induced apoptosis is associated with increased scrotal temperature, but not varicocele grade [8]. Varicoceles are associated with decreased semen quality such as sperm count, motility, and morphology [9], increased oxidative stress and DNA damage [3,6,10,11]. Conventional semen analysis is important in the evaluation of the infertile male, it has its flaws and offers low predictive value [12]
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