Seminal biomarkers for the evaluation of male infertility

Bieniek, J; Drabovich, Andrei P.; Lo, Kirk

doi:10.4103/1008-682x.175781

Cited by 131 publications

(89 citation statements)

References 113 publications

(121 reference statements)

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“…Previously, we reported on human TEX101 as a SP biomarker for the differential diagnosis of azoospermia (27,(60)(61)(62). We developed a first-of-a-kind TEX101 ELISA (35) and demonstrated its clinical utility in large cohorts of fertile, sub-fertile and infertile individuals (28).…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Schiza

Korbakis

Panteleli

et al. 2018

Molecular & Cellular Proteomics

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TEX101 is a testis-specific protein expressed exclusively in male germ cells and is a validated biomarker of male infertility. Studies in mice suggest that TEX101 is a cell-surface chaperone which regulates, through protein-protein interactions, the maturation of proteins involved in spermatozoa transit and oocyte binding. Male TEX101-null mice are sterile. Here, we identified by co-immunoprecipitation-mass spectrometry the interactome of human TEX101 in testicular tissues and spermatozoa. The testis-specific cell-surface dipeptidase 3 (DPEP3) emerged as the top hit. We further validated the TEX101-DPEP3 complex by using hybrid immunoassays.Combinations of antibodies recognizing different epitopes of TEX101 and DPEP3 facilitated development of a simple immunoassay to screen for disruptors of TEX101-DPEP3 complex. As a proof-of-a-concept, we demonstrated that anti-TEX101 antibody T4 disrupted the native TEX101-DPEP3 complex. Disrupting antibodies may be used to study the human TEX101-DPEP3 complex, and to develop modulators for male fertility.

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Section: Discussionmentioning

confidence: 99%

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Schiza

Korbakis

Panteleli

et al. 2018

Molecular & Cellular Proteomics

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“…[4][5][6][7][8] Due to complexities of the causes, a comprehensive inspection of the concerned male should be performed. 9 Routine evaluations for MI include physical examination, karyotype analysis, semen analysis, endocrine detection, medical history questionnaire, Ychromosome microdeletion analysis, and additional tests such as sperm DNA fragmentation and genetic screening. molecular mechanisms underlying MI remain obscure.…”

mentioning

confidence: 99%

Metabolic profiling putatively identifies plasma biomarkers of male infertility using UPLC-ESI-IT-TOFMS

Zeng

Zhang

et al. 2018

RSC Adv.

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Male infertility has become a global health problem. Currently, the diagnosis of male infertility depends on the results of semen quality or requires invasive surgical intervention. The process is complex and timeconsuming. Metabolomics is an emerging platform with unique advantages in disease diagnosis and pathological mechanism research. In this study, ultra-performance liquid chromatography-electrospray ionization-ion trap-time of flight mass spectrometry (UPLC-ESI-IT-TOFMS) combined with chemometrics methods was used to discover potential biomarkers of male infertility based on nontargeted plasma metabolomics. Plasma samples from healthy controls (HC, n ¼ 43) and various types of infertile patients, i.e., patients having oligozoospermia (OS, n ¼ 36), asthenospermia (AS, n ¼ 56) and erectile dysfunction (ED, n ¼ 45) were analyzed by UPLC-ESI-IT-TOFMS. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were performed. The results of OPLS-DA showed that HCs could be discriminated from infertile patients including OS (R 2 ¼ 0.903,Some potential biomarkers were successfully discovered by variable selection methods and variable important in the projection (VIP) in combination with the T-test. Statistical significance was set at p < 0.05; the Benjamini-Hochberg false discovery rate was used to reduce type 1 errors resulting from multiple comparisons. The identified biomarkers were associated with energy consumption, hormone regulation and antioxidant defenses in spermatogenesis. To elucidate the pathophysiology of male infertility, relative metabolic pathways were studied. It was found that male infertility is closely related to disturbed phospholipid metabolism, amino acid metabolism, steroid hormone biosynthesis metabolism, metabolism of fatty acids and products of carnitine acylation, and purine and pyrimidine metabolisms. Plasma metabolomics provides a novel strategy for the diagnosis of male infertility and offers a new insight to study pathogenesis mechanism.

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“…Semen and SP are highly relevant biological fluids to search for biomarkers since prostatesecreted proteins are found at much higher concentrations in SP than in either serum or urine 19,57 . An excellent example of this is PSA: PSA concentration in the SP is 6 orders of magnitude higher than levels found in serum or urine.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

Drabovich

Saraon

Drabovich³

et al. 2017

Preprint

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Prostate-specific antigen, a widely used biomarker of prostate cancer, lacks specificity and prognostic significance, which often results in over-diagnosis and over-treatment of prostate cancer. In this study, we investigated if seminal plasma proteins could increase specificity of detecting primary prostate cancer and discriminate between low-and high-grade cancers. To select 148 most promising biomarker candidates, we combined transcripts or proteins identified through five independent data mining or experimental approaches: tissue transcriptomics, seminal plasma proteomics, cell secretomics, tissue specificity and androgen regulation. To follow up these candidates, we designed a rigorous biomarker verification and validation pipeline based on multiplex quantitative selected reaction monitoring assays. We verified 77 and validated 19 most promising proteins in seminal plasma of 67 negative biopsy and 152 prostate cancer patients. Validation revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which could predict prostate cancer on biopsy and outperformed age and serum PSA. In the independent validation set re-measured by an in-house ELISA, TGM4 was significantly up-regulated (3.7-fold, P=0.005) and revealed AUC 0.66 for differentiating between negative biopsy and prostate cancer in patients with age ≥50 and blood serum PSA ≥4 ng/mL. Interestingly, none of validated biomarkers could differentiate between low-and high-grade cancers. Very low levels of TGM4 (120 pg/mL) were detected by ELISA in blood serum, but could not differentiate between negative biopsy, prostate cancer or prostate inflammation. Significantly higher levels of TGM4 in blood serum (3.5-fold, P = 0.0004) were found for younger men (<40 y.o.) relative to older men (≥70 y.o.). Our work may represent one of the most comprehensive studies on prostate cancer biomarkers in seminal plasma. Even though moderate performance of TGM4 as a single biomarker will unlikely result in its immediate use in the clinic, TGM4 may be further investigated in the distinct subtypes of prostate cancer and included into emerging multibiomarker panels.

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Seminal biomarkers for the evaluation of male infertility

Cited by 131 publications

References 113 publications

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies

Metabolic profiling putatively identifies plasma biomarkers of male infertility using UPLC-ESI-IT-TOFMS

Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

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