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Declining BRCA-Mediated DNA Repair in Sperm Aging and its Prevention by Sphingosine-1-Phosphate

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Abstract

Recent data suggest that paternal age can have major impact on reproductive outcomes, and with increased age, there is increased likelihood of chromosomal abnormalities in the sperm. Here, we studied DNA damage and repair as a function of male aging and assessed whether sphingosine-1-phosphate (S1P), a ceramide-induced death inhibitor, can prevent sperm aging by enhancing DNA double-strand breaks (DSB) repair. We observed a significant increase in DNA damage with age and this increase was associated with a decline in the expression of key DNA DSB repair genes in mouse sperm. The haploinsufficiency of BRCA1 male mice sperm showed significantly increased DNA damage and apoptosis, along with decreased chromatin integrity when compared to similar age wild type (WT) mice. Furthermore, haploinsufficiency of BRCA1 male mice had lower sperm count and smaller litter size when crossed with WT females. The resulting embryos had a higher probability of growth arrest and reduced implantation. S1P treatment decreased genotoxic-stress-induced DNA damage in sperm and enhanced the expressions of key DNA repair genes such as BRCA1. Co-treatment with an ATM inhibitor reversed the effects of S1P, implying that the impact of S1P on DNA repair is via the ATM-mediated pathway. Our findings indicate a key role for DNA damage repair mechanism in the maintenance of sperm integrity and suggest that S1P can improve DNA repair in sperm. Further translational studies are warranted to determine the clinical significance of these findings and whether S1P can delay male reproductive aging.

Summary

There is mounting evidence that sperm quality declines with age, similar to that of the oocyte. However, the reasons behind this decline are poorly understood and there is no medical intervention to improve sperm quality. Our study suggests a strong role for DNA damage repair in maintenance of sperm quality, and for the first time, a potential pharmaceutical approach to prevent sperm aging

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Funding

NIH Grant R01 HD053112 to K.O. partially supported this work.

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Authors and Affiliations

  1. Department 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

    Robert Stobezki, Shiny Titus & Kutluk Oktay

  2. Department of Pathology and Brander Cancer Research Institute, New York Medical College, Valhalla, NY, 10595, USA

    Dorota Halicka & Zbigniew Darzynkiewicz

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  1. Robert Stobezki
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  2. Shiny Titus
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  4. Zbigniew Darzynkiewicz
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  5. Kutluk Oktay
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Contributions

K.O. conceived the idea and designed and directed the study; R.S. and S.T. performed the laboratory experiments and statistical analysis; D.H. and Z.D. measured and analyzed samples for flow cytometry and laser scanning cytometry; R.S. wrote the initial draft of the manuscript; and K.O., S.T., Z.D., D.H. reviewed and edited the manuscript.

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Correspondence to Kutluk Oktay.

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The authors declare that they have no competing interests.

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Stobezki, R., Titus, S., Halicka, D. et al. Declining BRCA-Mediated DNA Repair in Sperm Aging and its Prevention by Sphingosine-1-Phosphate. Reprod. Sci. 27, 940–953 (2020). https://doi.org/10.1007/s43032-019-00098-1

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  • DOI: https://doi.org/10.1007/s43032-019-00098-1

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