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Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility.

ABSTRACT: To study the major differences in the distribution of spermatozoa proteins in infertile men with varicocele by comparative proteomics and validation of their level of expression. The study-specific estimates for each varicocele outcome were combined to identify the proteins involved in varicocele-associated infertility in men irrespective of stage and laterality of their clinical varicocele. Expression levels of 5 key proteins (PKAR1A, AK7, CCT6B, HSPA2, and ODF2) involved in stress response and sperm function including molecular chaperones were validated by Western blotting. Ninety-nine proteins were differentially expressed in the varicocele group. Over 87% of the DEP involved in major energy metabolism and key sperm functions were underexpressed in the varicocele group. Key protein functions affected in the varicocele group were spermatogenesis, sperm motility, and mitochondrial dysfunction, which were further validated by Western blotting, corroborating the proteomics analysis. Varicocele is essentially a state of energy deprivation, hypoxia, and hyperthermia due to impaired blood supply, which is corroborated by down-regulation of lipid metabolism, mitochondrial electron transport chain, and Krebs cycle enzymes. To corroborate the proteomic analysis, expression of the 5 identified proteins of interest was validated by Western blotting. This study contributes toward establishing a biomarker "fingerprint" to assess sperm quality on the basis of molecular parameters.

SUBMITTER: Agarwal A

PROVIDER: S-EPMC4770500 | biostudies-literature | 2016 Mar-Apr

REPOSITORIES: biostudies-literature

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Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility.

Agarwal Ashok A Sharma Rakesh R Samanta Luna L Durairajanayagam Damayanthi D Sabanegh Edmund E

Asian journal of andrology 20160301 2

To study the major differences in the distribution of spermatozoa proteins in infertile men with varicocele by comparative proteomics and validation of their level of expression. The study-specific estimates for each varicocele outcome were combined to identify the proteins involved in varicocele-associated infertility in men irrespective of stage and laterality of their clinical varicocele. Expression levels of 5 key proteins (PKAR1A, AK7, CCT6B, HSPA2, and ODF2) involved in stress response and ...[more]

PMID: 26732106

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Project description: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.

Project description:BACKGROUND:Reactive oxygen species (ROS) plays a major role in the pathology of male infertility. It is an independent biomarker of sperm function. Seminal plasma is a natural reservoir of antioxidants responsible for the nourishment, protection, capacitation, and motility of sperm within the female reproductive tract resulting in successful fertilization and implantation of the embryo. A comparative proteomic analysis of seminal plasma proteins from fertile men and infertile men with varying levels of ROS was carried out to identify signature proteins involved in ROS-mediated reproductive dysfunction. METHODS:A total of 42 infertile men presenting with infertility and 17 proven fertile donors were enrolled in the study. ROS levels were measured in the seminal ejaculates by chemiluminescence assay. Infertile men were subdivided into Low ROS (0-<93 RLU/s/10(6) sperm; n = 11), Medium ROS (>93-500 RLU/s/10(6) sperm; n = 17) and High ROS (>500 RLU/s/10(6) sperm; n = 14) groups and compared with fertile men (4-50 RLU/s/10(6) sperm). 4 subjects from fertile group and 4 each from the Low, Medium and High ROS were pooled. 1D gel electrophoresis followed by in-gel digestion and LC/MS-MS in a LTQ-Orbitrap Elite hybrid mass spectrometer system was used for proteome analysis. Identification of differentially expressed proteins (DEPs), their cellular localization and involvement in different pathways were examined utilizing bioinformatics tools. RESULTS:The results indicate that proteins involved in biomolecule metabolism, protein folding and protein degradation are differentially modulated in all three infertile patient groups in comparison to fertile controls. Membrane metallo-endopeptidase (MME) was uniformly overexpressed (>2 fold) in all infertile groups. Pathway involving 35 focus proteins in post-translational modification of proteins, protein folding (heat shock proteins, molecular chaperones) and developmental disorder was overexpressed in the High ROS group compared with fertile control group. MME was one of the key proteins in the pathway. FAM3D was uniquely expressed in fertile group. CONCLUSION:We have for the first time demonstrated the presence of 35 DEPs of a single pathway that may lead to impairment of sperm function in men with Low, Medium or High ROS levels by altering protein turn over. MME and FAM3D along with ROS levels in the seminal plasma may serve as good markers for diagnosis of male infertility.

Project description:PurposeDespite the significant role of varicocele in the pathogenesis of male infertility, the impact of varicocele repair (VR) on conventional semen parameters remains controversial. Only a few systematic reviews and meta-analyses (SRMAs) have evaluated the impact of VR on sperm concentration, total motility, and progressive motility, mostly using a before-after analytic approach. No SRMA to date has evaluated the change in conventional semen parameters after VR compared to untreated controls. This study aimed to evaluate the effect of VR on conventional semen parameters in infertile patients with clinical varicocele compared to untreated controls.Materials and methodsA literature search was performed using Scopus, PubMed, Embase, and Cochrane databases following the Population Intervention Comparison Outcome (PICOS) model (Population: infertile patients with clinical varicocele; Intervention: VR [any technique]; Comparison: infertile patients with clinical varicocele that were untreated; Outcome: sperm concentration, sperm total count, progressive sperm motility, total sperm motility, sperm morphology, and semen volume; Study type: randomized controlled trials and observational studies).ResultsA total of 1,632 abstracts were initially assessed for eligibility. Sixteen studies were finally included with a total of 2,420 infertile men with clinical varicocele (1,424 patients treated with VR vs. 996 untreated controls). The analysis showed significantly improved post-operative semen parameters in patients compared to controls with regards to sperm concentration (standardized mean difference [SMD] 1.739; 95% CI 1.129 to 2.349; p<0.001; I²=97.6%), total sperm count (SMD 1.894; 95% CI 0.566 to 3.222; p<0.05; I²=97.8%), progressive sperm motility (SMD 3.301; 95% CI 2.164 to 4.437; p<0.01; I²=98.5%), total sperm motility (SMD 0.887; 95% CI 0.036 to 1.738; p=0.04; I²=97.3%) and normal sperm morphology (SMD 1.673; 95% CI 0.876 to 2.470; p<0.05; I²=98.5%). All the outcomes showed a high inter-study heterogeneity, but the sensitivity analysis showed that no study was sensitive enough to change these results. Publication bias was present only in the analysis of the sperm concentration and progressive motility. No significant difference was found for the semen volume (SMD 0.313; 95% CI -0.242 to 0.868; I²=89.7%).ConclusionsThis study provides a high level of evidence in favor of a positive effect of VR to improve conventional semen parameters in infertile men with clinical varicocele. To the best of our knowledge, this is the first SRMA to compare changes in conventional semen parameters after VR with changes in parameters of a control group over the same period. This is in contrast to other SRMAs which have compared semen parameters before and after VR, without reference to a control group. Our findings strengthen the available evidence and have a potential to upgrade professional societies' practice recommendations favoring VR to improve conventional semen parameters in infertile men.

Project description:Objectives: To investigate the risk of varicocele, erectile dysfunction (ED), infertility, prostatitis, benign prostate hyperplasia (BPH) and prostate cancer associated with metformin use. Materials and methods: A total of 261,838 males, mean age 52.39 years (SD: 11.39), with a new-onset type 2 diabetes mellitus in 1999–2009 were identified from Taiwan’s National Health Insurance. Among them, 175,171 were metformin initiators [metformin (+)] and 86,667 were non-metformin initiators [metformin (−)] in the initial 12-month prescriptions of antidiabetic drugs. Follow-up started after the initial 12-month prescriptions. Outcomes were followed up until 31 December 2011. Intention-to-treat (ITT) and per-protocol (PP) hazard ratios comparing metformin (+) to metformin (−) were estimated by Cox regression incorporated with the inverse probability of treatment-weighting using propensity scores. Results: The median follow-up time ranged 5.55–6.82 years in metformin (−) and 4.36–5.17 years in metformin (+) for different outcomes in ITT analyses. The respective median follow-up time in PP analyses ranged 2.20–2.61 years in metformin (−) and ranged 3.99–4.65 years in metformin (+). In the ITT analyses, for metformin (−), the incidence rates (per 100,000 person-years) of varicocele, ED, infertility, prostatitis, BPH and prostate cancer were 26.42, 455.89, 22.82, 590.23, 4226.19, and 141.69, respectively; and the respective incidence rates for metformin (+) were 25.65, 488.10, 32.60, 510.30, 3685.66, and 116.57. The hazard ratios (95% confidence intervals) comparing metformin (+) to metformin (−) in the ITT analyses were 0.960 (0.784–1.174) for varicocele, 1.077 (1.026–1.130) for ED, 1.368 (1.116–1.676) for infertility, 0.887 (0.849–0.927) for prostatitis, 0.883 (0.868–0.899) for BPH and 0.878 (0.802–0.961) for prostate cancer. The hazard ratios for the respective outcomes in the PP analyses were 0.845 (0.662–1.078), 1.350 (1.264–1.441), 1.396 (1.078–1.808), 0.800 (0.756–0.846), 0.875 (0.855–0.895), and 0.613 (0.548–0.686). Conclusion: Metformin use in patients with type 2 diabetes mellitus is associated with a neutral effect on varicocele, a higher risk of sexual dysfunction (ED and infertility) and a reduced risk of prostate-related health (prostatitis, BPH and prostate cancer).

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Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility.

Publications

Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility.

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