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* To whom correspondence should be addressed. E-mail: B.Gadella{at}vet.uu.nl.
The main goal of this study was to investigate whether and at what level damage of paternal DNA influences fertilization of oocytes and early embryonic development. We hypothesized that post-testicular sperm DNA damage will only marginally affect sperm physiology due to the lack of gene expression, but that it will effect embryo development at the stage that embryo genome (including the paternal damaged DNA) expression is initiated. To test this we artificially induced sperm DNA damage by irradiation with X or gamma rays (doses of 0-300 Gy). Remarkably sperm cells survived the irradiation quite well and when compared to non-irradiated cells, sperm motility and integrity of plasma membrane, acrosome and mitochondria were not altered by this irradiation treatment. In contrast, a highly significant logarithmic relation between irradiation dose and induced DNA damage to sperm cells was found by both terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick end labeling (TUNEL) and the acridin orange assay. Despite the DNA damage, irradiated sperm cells did not show any sign of apoptosis (nuclear fragmentation, depolarization of inner mitochondrial membranes or phospholipid scrambling) and were normally capable to fertilize oocytes, as there was no reduction in cleavage rates when compared to non-irradiated sperm samples up to irradiation doses of <10 Gy. Further embryonic development was completely blocked as the blastocyst rates at day 7 and 9 dropped from 28 % (non-irradiated sperm) to <3% by >2.5 Gy irradiated sperm.. This block in embryonic development was accompanied with the initiation of apoptosis after the second or third cleavage. Specific signs of apoptosis such as nuclear fragmentation and aberrations in spindle formation were observed in all embryos resulting from IVF with irradiated sperm (irradiation doses >1.25 Gy). The results show that sperm DNA damage does not impair fertilization of the oocyte or completion of the first 2-3 cleavages, but blocks blastocyst formation by inducing apoptosis. Embryos produced by assisted reproductive techniques (ART) could have incorporated aberrant paternal DNA (frequently detected in sperm of sub/infertile males). Analogously, in the present work, we discuss the possibility of following embryo development of oocytes fertilized by ART through the blastocyst stage before embryo transfer into the uterus in order to reduce risks of reproductive failure.
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