The dynamic onset of DNA fragmentation in mammalian sperm populations varies widely in different species when the spermatozoa are incubated in vitro at body temperature for several hours, and recent studies have shown that the dynamic rate of DNA fragmentation within a species has considerable predictive value in terms of fertility. The reasons for such variation are unclear, but here we show that differences in protamine sequence and identity could be partially responsible. Sets of 10 normal semen samples from 11 species (ram, goat, boar, white-tailed deer, rabbit, human, domestic and Spanish fighting bull, horse, donkey, rhinoceros, and koala) were cryopreserved, thawed, diluted in an appropriate extender for each species, and then incubated for 4 hr at 37 °C. Semen samples from human infertility patients were also included for comparison with the donors. DNA fragmentation analysis was undertaken immediately after thawing (t(0)) and after 4 hr (t(4)) using the Halomax/Halosperm procedure, and the differences in DNA fragmentation between t(0) and t(4) were examined in the context of the respective protamine genomes. The expression of protamine 2 in a species significantly enhanced the likelihood of sperm DNA fragmentation; greater numbers of cysteine residues in protamine 1 tended to confer increased sperm DNA stability, and there were logical evolutionary relationships between species in terms of their sperm DNA stability. Human spermatozoa from infertility patients exhibited considerably higher DNA instability than the normal semen donors, a difference that could be indirectly attributed to unbalanced protamine 1-to-protamine 2 ratios.

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Although it has been thirty years since publication of one of the most influential papers on the value of assessing sperm DNA damage, andrologists have yet to reach a general consensus about how to apply this seminal parameter to improve or predict reproductive outcomes. Studies that have attempted to establish a causal relationship between sperm DNA damage and pregnancy success have often resulted in conflicting findings, eroding the practitioner's confidence to incorporate this phenomenon into their appraisal of fertility. In this review we have identified and answered ten important unresolved questions commonly asked by andrologists with respect to the relationship between sperm DNA damage and fertility. We answer questions ranging from a basic comprehension of biological mechanisms and external factors that contribute to increased levels of sperm DNA damage in the ejaculate to what type of DNA lesions we might be expect to occur and what are some of the consequences of DNA damage on early embryonic development. We also address some of the fundamental technical issues associated with the most appropriate measurement of sperm DNA damage and the need to attenuate the confounding impacts of iatrogenic damage. We conclude by asking whether it is possible to reduce elevated levels of sperm DNA damage therapeutically.

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