Male and female germ lines are vulnerable to oxidative stress. In spermatozoa, such stress triggers a lipid peroxidation cascade that culminates in the generation of electrophilic lipid aldehydes ...that bind to DNA and a raft of proteins involved in the delivery of functionally competent cells. One set of targets for these aldehydes are the proteins of the mitochondrial electron transport chain. When this interaction occurs, mitochondrial ROS generation is enhanced leading to the sustained generation of oxidative damage in a self-perpetuating cycle. Such damage affects all aspects of sperm function including motility, sperm-egg recognition, acrosomal exocytosis and sperm-oocyte fusion. Oxidative stress in the male germ line also attacks the integrity of sperm DNA with potential impacts on the developmental capacity of embryos and the health and wellbeing of the offspring. Potential pathways of reactive oxygen species (ROS) generation in male germ cells could involve enhanced lipoxygenase activity, activation of NADPH oxidase and/or electron leakage from mitochondria. Similarly, in the female germ line, both the induction of oocyte senescence following ovulation and the deterioration of oocyte quality with maternal age appear to involve the generation of oxidative damage. In this case, the mitochondria appear to be a particularly important source of ROS compromising the viability and fertilizability of the oocyte and interfering with the normal segregation of chromosomes during meiosis. In light of these considerations, antioxidants should have some role to play in the preservation of reproductive function in both men and women; however, we still await appropriate trials to test this hypothesis.
Abstract
Over the past half-century, the world has witnessed a steep decline in fertility rates in virtually every country on Earth. This universal decline in fertility is being driven by increasing ...prosperity largely through the mediation of social factors, the most powerful of which are the education of women and an accompanying shift in life’s purpose away from procreation. In addition, it is clear that environmental and lifestyle factors are also having a profound impact on our reproductive competence particularly in the male where increasing prosperity is associated with a significant rise in the incidence of testicular cancer and a secular decline in semen quality and testosterone levels. On a different timescale, we should also recognize that the increased prosperity associated with the demographic transition greatly reduces the selection pressure on high fertility genes by lowering the rates of infant and childhood mortality. The retention of poor fertility genes within the human population is also being exacerbated by the increased uptake of ART. It is arguable that all of these elements are colluding to drive our species into an infertility trap. If we are to avoid the latter, it will be important to recognize the factors contributing to this phenomenon and adopt the social, political, environmental and lifestyle changes needed to bring this situation under control.
Oxidative stress in the male germ line is thought to affect male fertility and impact upon normal embryonic development. Accordingly, fertility specialists are actively exploring the diagnosis of ...such stress in spermatozoa and evaluating the possible use of antioxidants to ameliorate this condition. In this review, evidence for the presence of oxidative stress in human spermatozoa, the origins of this phenomenon, its clinical significance in the aetiology of male infertility and recent advances in methods for its diagnosis and treatment are re-examined. Moreover, an extensive review of the results presented in published clinical studies has been conducted to evaluate the overall impact of oral antioxidants on measures of sperm oxidative stress and DNA damage. Administration of antioxidants to infertile men has been assessed in numerous clinical studies with at least 20 reports highlighting its effect on measures of oxidative stress in human spermatozoa. A qualitative but detailed review of the results revealed that 19 of the 20 studies conclusively showed a significant reduction relating to some measure of oxidative stress in these cells. Strong evidence also supports improved motility, particularly in asthenospermic patients. However, of these studies, only 10 reported pregnancy-related outcomes, with 6 reporting positive associations. Adequately powered, placebo-controlled comprehensive clinical trials are now required to establish a clear role for antioxidants in the prevention of oxidative stress in the male germ line, such that the clinical utility of this form of therapy becomes established once and for all.
Abstract
In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the ...intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.
Graphical Abstract
Graphical Abstract
Paternal ageing leads to redox imbalance in reproductive tissues and pathologies that impact both testosterone production and the functional and genetic integrity of the germ line. ROS, reactive oxygen species.
Assessments of sperm DNA damage are controversial because of perceived uncertainties over the relationship with pregnancy and the limited range of therapies available should positive results be ...returned. In this article, we highlight recent data supporting a chain of associations between oxidative stress in the male germ line, DNA damage in spermatozoa, defective DNA repair in the oocyte, the mutational load carried by the resulting embryo and the long-term health trajectory of the offspring. Any condition capable of generating oxidative damage in spermatozoa (age, obesity, smoking, prolonged abstinence, varicocele, chemical exposures, radiation etc.) is capable of influencing offspring health in this manner, creating a range of pathologies in the progeny including neuropsychiatric disorders and cancer. If sperm DNA damage is detected, there are several therapeutic interventions that can be introduced to improve DNA quality prior to the use of these cells in ART. We therefore argue that infertility specialists should be engaged in the diagnosis and remediation of sperm DNA damage as a matter of best practice, in order to minimize the risk of adverse health outcomes in children conceived using ART.
With extended periods of time following ovulation, the metaphase II stage oocyte experiences deterioration in quality referred to as post-ovulatory oocyte ageing. Post-ovulatory ageing occurs both in ...vivo and in vitro and has been associated with reduced fertilization rates, poor embryo quality, post-implantation errors and abnormalities in the offspring. Although the physiological consequences of post-ovulatory oocyte ageing have largely been established, the molecular mechanisms controlling this process are not well defined. This review analyses the relationships between biochemical changes exhibited by the ageing oocyte and the symptoms associated with the ageing phenotype. We also discuss molecular events that are potentially involved in orchestrating post-ovulatory ageing with a particular focus on the role of oxidative stress. We propose that oxidative stress may act as the initiator for a cascade of events that create the aged oocyte phenotype. Specifically, oxidative stress has the capacity to cause a decline in levels of critical cell cycle factors such as maturation-promoting factor, impair calcium homoeostasis, induce mitochondrial dysfunction and directly damage multiple intracellular components of the oocyte such as lipids, proteins and DNA. Finally, this review addresses current strategies for delaying post-ovulatory oocyte ageing with a particular focus on the potential use of compounds such as caffeine or selected antioxidants in the development of more refined media for the preservation of oocyte integrity during IVF procedures.
Capacitation is a remarkable process whereby spermatozoa prepare themselves for engagement with the oocyte. Although the existence of this process has been appreciated as a biological phenomenon for ...more than half a century, its molecular underpinnings still await clarification. We know that some of the major changes involve sterol oxidation and efflux from the plasma membrane, the anterior movement of lipid rafts, changes in the surface expression of a variety of proteins including hyaluronidase and receptors for the zona pellucida, an increase in intracellular cyclic adenosine monophosphate (cAMP), the induction of tyrosine phosphorylation and the expression of hyperactivated motility. These changes are dependent on the presence of bicarbonate, to facilitate cAMP generation, maintain an alkaline intracellular pH and support an optimal level of reactive oxygen species generation and are enhanced by the presence of albumin to provide antioxidant protection to the plasma membrane and promote cholesterol efflux. In vivo, the rate at which sperm cells capacitate is carefully controlled in order to ensure that the release of capacitated spermatozoa from a post-insemination reservoir in the isthmic region of the oviduct is synchronized with ovulation. The factors that control these critical events are now being resolved, aided by proteomic studies that are providing critical definitive information on the range of receptors that exist in the sperm plasma membrane and define the manner in which these exquisitely complex cells interact with their environment. Progress in this area has been enhanced by IVF technology pioneered by Bob Edwards and will ultimately facilitate the design of safe, effective culture conditions for optimization of this revolutionary therapy.
In recent times there has been some controversy over the impact of electromagnetic radiation on human health. The significance of mobile phone radiation on male reproduction is a key element of this ...debate since several studies have suggested a relationship between mobile phone use and semen quality. The potential mechanisms involved have not been established, however, human spermatozoa are known to be particularly vulnerable to oxidative stress by virtue of the abundant availability of substrates for free radical attack and the lack of cytoplasmic space to accommodate antioxidant enzymes. Moreover, the induction of oxidative stress in these cells not only perturbs their capacity for fertilization but also contributes to sperm DNA damage. The latter has, in turn, been linked with poor fertility, an increased incidence of miscarriage and morbidity in the offspring, including childhood cancer. In light of these associations, we have analyzed the influence of RF-EMR on the cell biology of human spermatozoa in vitro.
Purified human spermatozoa were exposed to radio-frequency electromagnetic radiation (RF-EMR) tuned to 1.8 GHz and covering a range of specific absorption rates (SAR) from 0.4 W/kg to 27.5 W/kg. In step with increasing SAR, motility and vitality were significantly reduced after RF-EMR exposure, while the mitochondrial generation of reactive oxygen species and DNA fragmentation were significantly elevated (P<0.001). Furthermore, we also observed highly significant relationships between SAR, the oxidative DNA damage bio-marker, 8-OH-dG, and DNA fragmentation after RF-EMR exposure.
RF-EMR in both the power density and frequency range of mobile phones enhances mitochondrial reactive oxygen species generation by human spermatozoa, decreasing the motility and vitality of these cells while stimulating DNA base adduct formation and, ultimately DNA fragmentation. These findings have clear implications for the safety of extensive mobile phone use by males of reproductive age, potentially affecting both their fertility and the health and wellbeing of their offspring.
DNA damage is frequently encountered in spermatozoa of subfertile males and is correlated with a range of adverse clinical outcomes including impaired fertilization, disrupted preimplantation ...embryonic development, increased rates of miscarriage and an enhanced risk of disease in the progeny. The etiology of DNA fragmentation in human spermatozoa is closely correlated with the appearance of oxidative base adducts and evidence of impaired spermiogenesis. We hypothesize that oxidative stress impedes spermiogenesis, resulting in the generation of spermatozoa with poorly remodelled chromatin. These defective cells have a tendency to default to an apeptotic pathway associated with motility loss, caspase activation, phosphatidylserine exteriorization and the activation of free radical generation by the mitochondria. The latter induces lipid peroxidation and oxidative DNA damage, which then leads to DNA fragmentation and cell death. The physical architecture of spermatozoa prevents any nucleases activated as a result of this apoptotic process from gaining access to the nuclear DNA and inducing its fragmentation. It is for this reason that a majority of the DNA damage encountered in human spermatozoa seems to be oxidative. Given the important role that oxidative stress seems to have in the etiology of DNA damage, there should be an important role for antioxidants in the treatment of this condition. If oxidative DNA damage in spermatozoa is providing a sensitive readout of systemic oxidative stress, the implications of these findings could stretch beyond our immediate goal of trying to minimize DNA damage in spermatozoa as a prelude to assisted conception therapy.
Abstract
BACKGROUND
A defining feature of sexual reproduction is the transmission of genomic information from both parents to the offspring. There is now compelling evidence that the inheritance of ...such genetic information is accompanied by additional epigenetic marks, or stable heritable information that is not accounted for by variations in DNA sequence. The reversible nature of epigenetic marks coupled with multiple rounds of epigenetic reprogramming that erase the majority of existing patterns have made the investigation of this phenomenon challenging. However, continual advances in molecular methods are allowing closer examination of the dynamic alterations to histone composition and DNA methylation patterns that accompany development and, in particular, how these modifications can occur in an individual’s germline and be transmitted to the following generation. While the underlying mechanisms that permit this form of transgenerational inheritance remain unclear, it is increasingly apparent that a combination of genetic and epigenetic modifications plays major roles in determining the phenotypes of individuals and their offspring.
OBJECTIVE AND RATIONALE
Information pertaining to transgenerational inheritance was systematically reviewed focusing primarily on mammalian cells to the exclusion of inheritance in plants, due to inherent differences in the means by which information is transmitted between generations. The effects of environmental factors and biological processes on both epigenetic and genetic information were reviewed to determine their contribution to modulating inheritable phenotypes.
SEARCH METHODS
Articles indexed in PubMed were searched using keywords related to transgenerational inheritance, epigenetic modifications, paternal and maternal inheritable traits and environmental and biological factors influencing transgenerational modifications. We sought to clarify the role of epigenetic reprogramming events during the life cycle of mammals and provide a comprehensive review of how the genomic and epigenomic make-up of progenitors may determine the phenotype of its descendants.
OUTCOMES
We found strong evidence supporting the role of DNA methylation patterns, histone modifications and even non-protein-coding RNA in altering the epigenetic composition of individuals and producing stable epigenetic effects that were transmitted from parents to offspring, in both humans and rodent species. Multiple genomic domains and several histone modification sites were found to resist demethylation and endure genome-wide reprogramming events. Epigenetic modifications integrated into the genome of individuals were shown to modulate gene expression and activity at enhancer and promoter domains, while genetic mutations were shown to alter sequence availability for methylation and histone binding. Fundamentally, alterations to the nuclear composition of the germline in response to environmental factors, ageing, diet and toxicant exposure have the potential to become hereditably transmitted.
WIDER IMPLICATIONS
The environment influences the health and well-being of progeny by working through the germline to introduce spontaneous genetic mutations as well as a variety of epigenetic changes, including alterations in DNA methylation status and the post-translational modification of histones. In evolutionary terms, these changes create the phenotypic diversity that fuels the fires of natural selection. However, rather than being adaptive, such variation may also generate a plethora of pathological disease states ranging from dominant genetic disorders to neurological conditions, including spontaneous schizophrenia and autism.
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