World J Mens Health.  2020 Apr;38(2):198-207. 10.5534/wjmh.180099.

New Insights on the Mechanisms Affecting Fertility in Men with Non-Seminoma Testicular Cancer before Cancer Therapy

• Dias TR
• Agarwal A
• Pushparaj
• Ahmad G
• Sharma R

• KMID: 2471826
• DOI: http://doi.org/10.5534/wjmh.180099

Abstract

PURPOSE
Patients with non-seminoma testicular cancer (NSTC) cancer can be subfertile or infertile, and present reduced sperm quality, but the underlying mechanisms are unknown. The aim of this study was to compare the sperm proteome of patients with NSTC, who cryopreserved their sperm before starting cancer treatment, with that from healthy fertile men.
MATERIALS AND METHODS
Semen volume, sperm motility and sperm concentration were evaluated before the cryopreservation of samples from patients with NSTC (n=15) and the control group (n=15). Sperm proteomic analysis was performed by liquid chromatography-tandem mass spectrometry and the differentially expressed proteins (DEPs) between the two groups were identified using bioinformatic tools.
RESULTS
A total of 189 DEPs was identified in the dataset, from which five DEPs related to sperm function and fertilization were selected for validation by Western blot. We were able to validate the underexpression of the mitochondrial complex subunits NADH:Ubiquinone Oxidoreductase Core Subunit S1 (NDUFS1) and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2), as well as the underexpression of the testis-specific sodium/potassium-transporting ATPase subunit alpha-4 (ATP1A4) in the NSTC group.
CONCLUSIONS
Our results indicate that sperm mitochondrial dysfunction may explain the observed decrease in sperm concentration, total sperm count and total motile count in NSTC patients. The identified DEPs may serve as potential biomarkers for the pathophysiology of subfertility/infertility in patients with NSTC. Our study also associates the reduced fertilizing ability of NSTC patients with the dysregulation of important sperm molecular mechanisms.

Keyword

Cancer therapy; Male fertility; Non-seminoma; Sperm quality; Testicular cancer

MeSH Terms

Adenosine Triphosphatases
Biomarkers
Blotting, Western
Computational Biology
Cryopreservation
Dataset
Electron Transport Complex III
Fertility*
Fertilization
Humans
Male
Mass Spectrometry
Proteome
Semen
Sperm Count
Sperm Motility
Spermatozoa
Testicular Neoplasms*
Adenosine Triphosphatases
Biomarkers
Electron Transport Complex III
Proteome

Figure

• 

  Fig. 1 Number of proteins identified by proteomic analysis of spermatozoa samples obtained from fertile men (control) and men with non-seminoma testicular cancer (NSTC), and expression profile of the differentially expressed proteins (DEPs) identified after comparative analysis between the experimental groups. UE: underexpressed, OE: overexpressed.

• 

  Fig. 2 Graphical representation of the expression levels of proteins involved in sperm function (NDUFS1, UQCRC2, ATP1A4, ANXA2, and ACR) in spermatozoa samples obtained from fertile men (control) and men with non-seminoma testicular cancer (NSTC). Results are presented as fold change to control and expressed as mean±standard error of mean (n=6 for each condition). Significantly different results relative to control are indicated as: * for p<0.05; ** for p<0.01; *** for p<0.001. Representative blots for each protein are also presented. NDUFS1: NADH-ubiquinone oxidoreductase 75 kDa subunit, UQCRC2: cytochrome b-c1 complex subunit 2, ATP1A4: sodium/potassium-transporting ATPase subunit alpha-4, ANXA2: Annexin A2, ACR: acrosin precursor.

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