DNA fragmentation of sperm: a radical examination of the contribution of oxidative stress and age in 16 945 semen samples

Abstract

STUDY QUESTION What is the relationship between sperm DNA fragmentation and oxidative stress (OS) with increasing male age? SUMMARY ANSWER Sperm DNA fragmentation increases with age and is likely related to both defective spermatogenesis and increasing OS levels. WHAT IS KNOWN ALREADY Sperm quality declines with age. The presence of DNA damage in a high fraction of spermatozoa from a raw semen sample is associated with lower male fertility in natural conception and intrauterine insemination. STUDY DESIGN, SIZE, DURATION A retrospective cohort study of 16 945 semen samples analysed at a single reference laboratory between January 2010 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS All males were undergoing an infertility evaluation. The cohort was divided into seven age categories: <30, 30–34, 35–39, 40–44, 45–49, 50 to <54 and ≥55 years. The mean age was 37.6 years (SD 6.8). Sperm DNA fragmentation index (DFI) and high DNA stainability (HDS) were calculated using flow cytometry. OS levels were measured using the oxidative stress adducts (OSA) test, by spectrophotometry. ANOVA with weighted polynomial contrast analysis was used to evaluate trends for DFI, OSA and HDS values across age categories. MAIN RESULTS AND THE ROLE OF CHANCE Mean DFI significantly increased across all age groups (Ptrend < 0.001). OSA was lowest in patients <30 years old (mean 3.6, SD 1.0) and also increased as age increased (Ptrend < 0.001). There was a statistically significant difference between age groups for each of the three parameters (P < 0.001). There was a significant linear trend for DFI, OSA and HDS across the seven age categories (P < 0.001). Among patients with high DFI, there was a decreasing age-dependent trend in the patients observed with high OSA (P < 0.001). LIMITATIONS, REASONS FOR CAUTION This is a retrospective study. All males included in the study were undergoing a work-up for infertility and may not be representative of a fertile population. Additional patient demographics and clinical data were not available. WIDER IMPLICATIONS OF THE FINDINGS DNA and/or oxidative damage in sperm may be just as important to understand as the chromosomal aberrations that are carried in the oocyte. Further studies are needed to evaluate the effect of advancing paternal age on the male genome and, ultimately, on the health of the offspring. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained for this study. V.D. is an employee of Reprosource/Quest Diagnostics. D.S. reports he was a Scientific Advisor to Cooper Surgical. TRIAL REGISTRATION NUMBER N/A

A Global Survey of Reproductive Specialists to Determine the Clinical Utility of Oxidative Stress Testing and Antioxidant Use in Male Infertility

“…This correlation has also been reported in males with subclinical, normozoospermic, asthenozoospermic and oligozoospermic varicocele [ 40 ]. Linear correlations between SDF and seminal OS with increasing paternal age [ 41 ] have also been noted. However, it is suggested that both SDF and another measure of OS should be used in the evaluation of infertile men [ 39 ].…”

Influence of age on sperm characteristics evaluated by light and electron microscopies

“…Regarding sperm apoptosis, this data is in accord with some observations made in testes of old mice that showed low apoptotic frequencies than young adults 48,49 , however the correlation between aging and sperm DNA integrity represents another controversial question. Using different methods of investigations, it was suggested a detrimental effect of advanced paternal age on sperm chromatin integrity or DNA fragmentation 17,18,50,51 . TEM analysis enabled to clearly discriminate the chromatin status (uncondensed, disrupted and with holes) evaluating at same time different sperm characteristics as acrosome, plasma membrane, mitochondria, axoneme, and, after mathematical elaboration, it indicated that the chromatin damage was especially referred to necrosis more than apoptosis and immaturity.…”

“…Studies have also considered the possibility of age-related changes in sperm genetics, such as sperm DNA fragmentation [16][17][18] , sperm aneuploidy 19 , telomere length 20 and epigenetics 21 . Moreover, an increased risk of congenital abnormalities, neuropsychiatric diseases 6 , autism 22 and childhood acute lymphoblastic leukemia 23 in offspring of men with advanced paternal age have been described.…”

Molecular Drivers of Developmental Arrest in the Human Preimplantation Embryo: A Systematic Review and Critical Analysis Leading to Mapping Future Research

“…DNA fragmentation is a well-examined condition related to male infertility [ 251 ]. DNA fragmentation in a semen sample is correlated with diminished fertility and reduces the probabilities of natural conception and intrauterine insemination success [ 252 ], as the presence of high levels of DNA damage lead to embryonic arrest. It has been established that sperm DNA integrity affects fertilization rate, developmental arrest, and live birth rates [ 253 ].…”