Relative Impact of Oxidative Stress on the Functional Competence and Genomic Integrity of Human Spermatozoa1

Abstract

Reactive oxygen metabolites are known to disrupt sperm-oocyte fusion, sperm movement, and DNA integrity; however, the relative sensitivities of these elements to oxidative stress are unknown. In this study these factors were assessed in human spermatozoa exposed to increasing levels of oxidative stress achieved through the stimulation of endogenous oxidant generation with NADPH or direct exposure to hydrogen peroxide. At low levels of oxidative stress, DNA fragmentation was significantly reduced while the rates of sperm-oocyte fusion were significantly enhanced. As the level of oxidative stress increased, the spermatozoa exhibited significantly elevated levels of DNA damage (p < 0.001) and yet continued to express an enhanced capacity for sperm-oocyte fusion. At the highest levels of oxidative stress, extremely high rates of DNA fragmentation were observed but the spermatozoa exhibited a parallel loss in their capacities for movement and oocyte fusion. These studies emphasize how redox mechanisms can either enhance or disrupt the functional and genomic integrity of human spermatozoa depending on the intensity of the oxidative stimulus. Because these qualities are affected at different rates, spermatozoa exhibiting significant DNA damage are still capable of fertilizing the oocyte. These results may have long-term implications for the safety of assisted conception procedures in cases associated with oxidative stress.

Comparative study of the effects of three semen preparation media on semen analysis, DNA damage and protamine deficiency, and the correlation between DNA integrity and sperm parameters

“…The mechanisms of DNA damage in human spermatozoa include defective sperm chromatin packing, apoptosis and oxidative stress [3][4][5]. Protamine has a critical role in spermatid differentiation; protamine deficiency can lead to sperm DNA damage and embryonic death in mice [6].…”

Protective effects of exogenous gangliosides on ROS-induced changes in human spermatozoa

“…In vitro experiments in which spermatozoa were exposed to initiators of oxidative stress such as H 2 O 2 revealed a significant increase in DNA damage in the form of either single-and double-strand breaks or DNA modification products. [69][70][71] Our investigations have provided evidence showing that DNA fragmentation in human spermatozoa after in vitro exposure to H 2 O 2 could be prevented by the addition of exogenous gangliosides. Flow cytometric analyses revealed that the pre-treatment of spermatozoa with GT1b micelles almost completely abolished H 2 O 2 passage through the cell membrane ( Figure 4).…”

Evaluating a novel panel of sperm function tests for utility in predicting intracytoplasmic sperm injection (ICSI) outcome

“…Tests of DNA integrity are going to be an important part of the overall evaluation of male infertility as use of sperm with damaged DNA in ART has been linked with adverse clinical outcomes, including an increased risk of miscarriage and morbidity in the offspring, including childhood cancer [6,7]. However, DNA integrity test scores must be critically evaluated for utility in directing infertile couples to the 'best' ART keeping in mind that there is a significant increased risk of birth defects in the offspring from couples who had successful ICSI attempts at pregnancy; a risk not found for the offspring from couples with successful IUI, and/or IVF-ET attempts at pregnancy [19].…”

“…The 9 patients with failed ICSI cycles should be evaluated for exposure to agents known to negatively affect male reproductive health by having these patients review a list of the common agents known to negatively affect fertility including, medications, recreational drugs, alcohol, oxidative stress, cigarette smoking, environmental toxins, and even use of cell phones [1,2,[4][5][6][7]50]. If possible, these patients should be removed from agents that they identify may be causing their infertility for 3 months, and then retested to see if their SDD Test score has improved.…”

“…It is important that the tests chosen for the panel have utility in evaluating the male's overall reproductive health that can be negatively affected by exposure to a wide variety of agents including: drugs, oxidative stress, cigarette smoking, environmental toxins, and even use of cell phones [1,2,4,6,7,50]. Males have a complete turnover of their sperm every 3 months.…”