Oxidative stress and male reproductive biology

Spermatozoa were the first cell type in which the cellular generation of reactive oxygen was demonstrated. This activity has now been confirmed in spermatozoa from all mammalian species examined including the rat, mouse, rabbit, horse, bull and human being. Under physiological circumstances, cellular redox activity is thought to drive the cAMP-mediated, tyrosine phosphorylation events associated with sperm capacitation. In addition to this biological role, human spermatozoa also appear to suffer from oxidative stress, with impacts on the normality of their function and the integrity of their nuclear and mitochondrial DNA. Recent studies have helped to clarify the molecular basis for the intense redox activity observed in defective human spermatozoa, the nature of the subcellular structures responsible for this activity and possible mechanisms by which oxidative stress impacts on these cells. Given the importance of oxidative damage in the male germ line to the origins of male infertility, early pregnancy loss and childhood disease, this area of sperm biochemistry deserves attention from all those interested in improved methods for the diagnosis, management and prevention of male-mediated reproductive failure.

Download Full-text

002.Human spermatozoa: fruits of creation, seed of doubt

Reproduction Fertility and Development ◽

10.1071/srb04abs002 ◽

2004 ◽

Vol 16 (9) ◽

pp. 2

Author(s):

R. J. Aitken

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Dna Repair ◽

Germ Cells ◽

Oxidative Dna Damage ◽

Germ Line ◽

Early Embryo ◽

Human Spermatozoa ◽

Obstructive Azoospermia ◽

Male Germ Line

Defective sperm function is the largest defined cause of human infertility, affecting one in twenty Australian males. Despite its prevalence, we are only just beginning to understand the underlying mechanisms. The past decade has seen two major advances in this field: (1) the discovery that Y chromosome deletions play a key role in the aetiology of non-obstructive azoospermia/oligozoospermia; and (2) recognition that oxidative stress can impact upon the functional competence of human spermatozoa through peroxidative damage to the sperm plasma membrane. Oxidative stress has also been found to disrupt the integrity of DNA in the male germ line and may represent an important mechanism by which environmental impacts on human health are mediated. Thus, paternal exposure to various toxicants (cigarette smoke, organic solvents, heavy metals) has been linked with oxidative DNA damage in spermatozoa and developmental defects, including cancer, in the F1 generation. The male germ line becomes particularly vulnerable to such factors during the post meiotic stages of differentiation. Pre-meiotic germ cells always have the option of undergoing apoptosis if DNA damage is severe. However, post meiotic germ cells have lost both the ability to mount an apoptotic response and the capacity for DNA repair. As a result, germ cells are particularly vulnerable to genotoxic agents during spermiogenesis and epididymal maturation. If the fertilizing capacity of the spermatozoa is retained following toxicant exposure, then DNA damage will be transferred to the zygote and must be repaired subsequently by the oocyte and/or early embryo. Aberrant DNA repair at this stage has the potential to create mutations that will compromise embryonic development and, ultimately, the normality of the offspring. Elucidating the causes of oxidative damage in spermatozoa should help resolve the aetiology of conditions such as male infertility, early pregnancy loss and childhood disease, including cancer.

Download Full-text

248. Oxidative stress and DNA damage in human spermatozoa

Reproduction Fertility and Development ◽

10.1071/srb08abs248 ◽

2008 ◽

Vol 20 (9) ◽

pp. 48

Author(s):

G. N. De Iuliis ◽

J. M. Finnie ◽

R. J. Aitken

Keyword(s):

Oxidative Stress ◽

Mass Spectrometry ◽

Dna Damage ◽

Metal Ions ◽

Electromagnetic Radiation ◽

Germ Line ◽

Human Spermatozoa ◽

Ros Production ◽

Male Germ Line ◽

Catechol Estrogens

Unusually high levels of DNA damage in the male germ line are, unfortunately, characteristic of our species. A great deal of circumstantial evidence has linked DNA damage in human spermatozoa with adverse reproductive outcomes including reduced fertility and high rates of miscarriage. Although oxidative stress is thought to make a significant contribution to DNA damage in the male germ line, the mechanisms responsible for creating this stress have not yet been elucidated. We have undertaken a detailed analysis of the ability of estrogens, electromagnetic radiation and xenobiotics including metal ions to trigger reactive oxygen species (ROS) production and/or DNA damage in human spermatozoa in vitro. This investigation was completed using a range of techniques validated for use in these highly specialised cells. DNA integrity was assessed using the Comet and TUNEL assays, oxidative DNA adducts were detected by an anti-8-oxo-dG assay and cross-linking adducts were characterised by mass spectrometry. Intracellular redox activity was monitored using dihydroethidium as the probe. Of the factors evaluated, catechol estrogens, certain transition metal ions, radio frequency electromagnetic radiation and heat were all capable of stimulating ROS production in human spermatozoa. The oxidative stress created by exposure to such factors lead to the induction of significant DNA damage. Generally, redox inert compounds including non-catechol estrogens and xenobiotics such as phthalate esters did not lead to ROS production or measurable DNA damage. Mass spectrometry also indicated that catechol estrogens were capable of forming dimers that can cross-link the densely packed DNA strands in sperm chromatin. These findings raise fundamental questions about the importance of xenobiotics, environmental factors as well endogenous compounds in creating oxidative stress and DNA damage in the male germ line.

Download Full-text