Understanding sperm DNA fragmentation

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. We greatly value the commentary by Dr. Gosalvez on the “Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios” by Agarwal et al. (1). The author initiated his well-written note with an overview of the structural and physiologic significance of sperm DNA on male reproduction addressing its association with varicocele, recurrent spontaneous abortion and unexplained infertility, and its implications on embryonic development and fecundity both naturally and after assisted reproductive techniques (ART). Throughout his discussion, Dr. Gosalvez rightly highlighted the importance of understanding the etiology, root causes and types of sperm DNA fragmentation (SDF) as this would ultimately influence interpretation of SDF test result and our understanding of the novel treatment methods utilized in such circumstances. We want to seize this opportunity to elaborate on this particular issue. Mammalian sperm DNA is unique in such a way that it is highly organized, condensed and compacted. In contrast to the DNA structure of somatic cells which is wrapped around an octamer of histones, packaged into nucleosomes and coiled into a solenoid thereby increasing the chromatin volume (2), sperm DNA is rather hindered by the confined sperm nuclear space and hence undergoes necessary modifications to its packaging process. During spermiogenesis histones are lost and replaced with transition proteins and subsequently with protamines (3). Cystein residues of the much smaller protamines further undergo intraand inter-molecular disulfide cross linking resulting in a highly condensed chromatin arranged in a toroid (4). This complex packaging and compaction affords necessary protection to sperm chromatin during its transport from the male to female reproductive tracts and ensures delivery of paternal genetic material to the developing embryo. Although human sperm DNA undergoes the same structural modifications as described above, it is less compact than the sperm DNA of other mammals. A certain amount of histones is retained in human sperm chromatin making it less compact and subject to injury (5). In fact, a higher histone to protamine ratio has been detected in men complaining of infertility (6,7). Furthermore, two types of protamines, P1 and P2, exist with the latter containing fewer cysteine groups and hence less disulfide crosslinks thereby theoretically making the sperm DNA more susceptible to damage (8). While assessing sperm DNA integrity in infertile men with varicocele, Ni et al. reported a significant reduction in protamine 1/2 mRNA ratio in patients with clinical grade 3 varicocele (9). Different types of SDF such as singleor double-stranded DNA breaks, DNA nicks, nuclear protein defects, and alteration of chromatin configuration can occur secondary to a wide variety of etiologic factors. Disease states such as varicocele, infections and inflammations of the genital tract, cancer, genetic mutations, chromosomal abnormalities and environmental and habitual exposures have all been identified resulting in DNA damage to the sperm either during spermiation or during its transit through the male reproductive tract (10-12). Intra-testicular damage is believed to occur secondary to abortive apoptosis or to alteration in sperm maturation. Under normal physiologic circumstances, almost half of germ cells entering meiosis I of spermatogenesis are exposed to markers of the Fas type and hence undergo abortive apoptosis and are expelled by Sertoli cells (13). However, under pathologic conditions Editorial