On the possible origins of DNA damage in human spermatozoa.
DNA damage in the male germ line has been linked with a variety of adverse clinical outcomes including impaired fertility, an increased incidence of miscarriage and an enhanced risk of disease in the offspring. The origins of this DNA damage could, in principle, involve: (i) abortive apoptosis initiated post meiotically when the ability to drive this process to completion is in decline (ii) unresolved strand breaks created during spermiogenesis to relieve the torsional stresses associated with chromatin remodelling and (iii) oxidative stress. In this article, we present a two-step hypothesis for the origins of DNA damage in human spermatozoa that highlights the significance of oxidative stress acting on vulnerable, poorly protaminated cells generated as a result of defective spermiogenesis. We further propose that these defective cells are characterized by several hallmarks of 'dysmaturity' including the retention of excess residual cytoplasm, persistent nuclear histones, poor zona binding and disrupted chaperone content. The oxidative stress experienced by these cells may originate from infiltrating leukocytes or, possibly, the entry of spermatozoa into an apoptosis-like cascade characterized by the mitochondrial generation of reactive oxygen species. This oxidative stress may be exacerbated by a decline in local antioxidant protection, particularly during epididymal maturation. Finally, if oxidative stress is a major cause of sperm DNA damage then antioxidants should have an important therapeutic role to play in the clinical management of male infertility. Carefully controlled studies are now needed to critically examine this possibility.
Aitken
R J
RJ
ARC Centre of Excellence in Biotechnology and Development and Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW, Australia. john.aitken@newcastle.edu.au
De Iuliis
G N
GN
D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism; D013094:Spermatozoa / Q000378:metabolism*
D002843:Chromatin; D017382:Reactive Oxygen Species