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New Insights on the Mechanisms Affecting Fertility in Men with Non-Seminoma Testicular Cancer before Cancer Therapy
Tania R Dias1,2,3, Ashok Agarwal4, Peter N Pushparaj5
1American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA.
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.
Insights
Sperm mitochondrial dysfunction and altered proteins like NDUFS1, UQCRC2, and ATP1A4 may cause infertility in non-seminoma testicular cancer (NSTC) patients. These proteins could be biomarkers for NSTC-related subfertility.
Area of Science:
- Reproductive biology
- Oncology
- Proteomics
Background:
- Non-seminoma testicular cancer (NSTC) patients often experience subfertility or infertility.
- The molecular mechanisms underlying NSTC-associated male infertility are not fully understood.
Purpose of the Study:
- To compare the sperm proteome of NSTC patients who cryopreserved sperm before treatment with that of healthy fertile men.
- To identify differentially expressed proteins (DEPs) in NSTC patients' sperm.
Main Methods:
- Semen parameters (volume, motility, concentration) were assessed.
- Sperm proteomic analysis was conducted using liquid chromatography-tandem mass spectrometry.
- Bioinformatic tools were used to identify DEPs, with key proteins validated by Western blot.
Main Results:
- 189 DEPs were identified between NSTC patients and controls.
- Validation confirmed underexpression of mitochondrial proteins (NDUFS1, UQCRC2) and ATP1A4 in NSTC patients.
- These proteins are crucial for sperm function and fertilization.
Conclusions:
- Sperm mitochondrial dysfunction is a potential cause of reduced sperm quality in NSTC patients.
- Identified DEPs may serve as biomarkers for NSTC-related subfertility/infertility.
- Dysregulation of sperm molecular mechanisms contributes to reduced fertilizing ability in NSTC patients.
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