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Declining BRCA-Mediated DNA Repair in Sperm Aging and its Prevention by Sphingosine-1-Phosphate
Robert Stobezki1, Shiny Titus1, Dorota Halicka2
1Department of Obstetrics and Gynecology, Laboratory of Molecular Reproduction and Fertility Preservation, Yale University School of Medicine, 310 Cedar Street, FMB Room # 224, New Haven, CT, 06510, USA.
Reproductive Sciences (Thousand Oaks, Calif.)
|January 10, 2020
Summary
Male aging increases sperm DNA damage and impairs reproductive outcomes. Sphingosine-1-phosphate (S1P) treatment enhances DNA repair and may prevent sperm aging, offering a potential pharmaceutical approach to improve male fertility.
Area of Science:
- Reproductive Biology
- Molecular Biology
- Aging Research
Background:
- Paternal age is linked to reduced reproductive success and increased sperm chromosomal abnormalities.
- Sperm quality declines with age, but underlying mechanisms and interventions remain unclear.
- DNA damage and repair are critical for maintaining sperm integrity.
Purpose of the Study:
- To investigate the impact of male aging on sperm DNA damage and repair mechanisms.
- To assess the potential of sphingosine-1-phosphate (S1P) in preventing sperm aging by enhancing DNA double-strand break (DSB) repair.
- To explore the role of BRCA1 and the ATM pathway in age-related sperm quality decline.
Main Methods:
- Comparative analysis of DNA damage and repair gene expression in aged vs. young mouse sperm.
- Assessment of sperm parameters, reproductive outcomes, and embryonic development in wild-type (WT) and BRCA1-haploinsufficient mice.
- Evaluation of S1P effects on DNA damage, repair gene expression, and the involvement of the ATM pathway in sperm.
Main Results:
- Sperm DNA damage significantly increases with age, correlated with decreased expression of key DNA DSB repair genes.
- BRCA1-haploinsufficient male mice exhibited higher DNA damage, apoptosis, reduced sperm count, and lower litter sizes.
- S1P treatment reduced DNA damage, enhanced DNA repair gene expression (e.g., BRCA1) via the ATM pathway, and improved sperm quality.
- Embryos from BRCA1-haploinsufficient males showed increased growth arrest and reduced implantation rates.
Conclusions:
- DNA damage repair is crucial for maintaining sperm integrity and function during male aging.
- Sphingosine-1-phosphate (S1P) demonstrates potential in mitigating age-related sperm DNA damage and enhancing repair.
- S1P may offer a novel pharmaceutical strategy to delay male reproductive aging and improve fertility outcomes.
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