Declining BRCA-Mediated DNA Repair in Sperm Aging and its Prevention by Sphingosine-1-Phosphate.
Aging
DNA fragmentation
Gene expression
Sperm
Journal
Reproductive sciences (Thousand Oaks, Calif.)
ISSN: 1933-7205
Titre abrégé: Reprod Sci
Pays: United States
ID NLM: 101291249
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
14
05
2019
accepted:
17
07
2019
pubmed:
10
1
2020
medline:
15
12
2020
entrez:
10
1
2020
Statut:
ppublish
Résumé
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. 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.
Identifiants
pubmed: 31916095
doi: 10.1007/s43032-019-00098-1
pii: 10.1007/s43032-019-00098-1
pmc: PMC7065969
mid: NIHMS1548628
doi:
Substances chimiques
BRCA1 Protein
0
Lysophospholipids
0
sphingosine 1-phosphate
26993-30-6
Sphingosine
NGZ37HRE42
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
940-953Subventions
Organisme : NICHD NIH HHS
ID : R01 HD053112
Pays : United States
Organisme : NICHD NIH HHS
ID : R21 HD061259
Pays : United States
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