Phosphoinositide 3-kinase signalling pathway involvement in a truncated apoptotic cascade associated with motility loss and oxidative DNA damage in human spermatozoa

Koppers, Adam J.; Mitchell, Lana; Wang, Ping; Lin, Mingwei; Aitken, R. John

doi:10.1042/bj20110114

Cited by 212 publications

(197 citation statements)

References 60 publications

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“…Several authors have suggested the involvement of sperm apoptosis in impaired men's fertility with consequences for reducing sperm fertilizing potential [97][98][99]. Mature spermatozoa have been reported to express distinct markers of early and late apoptosis-related cell damage, including the externalization of phosphatidylserine (PS) from the inner to the outer membrane, caspase activation, the loss of mitochondrial membrane potential (∆ym), and DNA fragmentation [96]. According to a novel theory regarding apoptotic process in mature spermatozoa, the increase in the production of ROS by the mitochondria is one of the first signs of intrinsic apoptosis.…”

Section: Apoptosis/necrosismentioning

confidence: 99%

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Mechanisms of the harmful effects of bacterial semen infection on ejaculated human spermatozoa: potential inflammatory markers in semen

Frączek

Kurpisz

2015

Folia Histochem Cytobiol.

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The invasion of the male reproductive tract by microorganisms, and its subsequent consequences for sperm fertilizing potential, has been intensely discussed. The role of the bacteria that are responsible for the colonization and contamination of the male urogenital tract, rather than its infection, in diminished sperm parameters raises the most controversy. There are numerous premises suggesting that bacterial semen infection is associated with male infertility. However, the molecular mechanism by which the fertility is affected is complex and multifactorial, and still presents a puzzle. Some authors have suggested that direct interactions between bacteria and human spermatozoa facilitate sperm immobilization, affect sperm morphology, and thus weaken the ability of sperm to fertilize. On the other hand, the massive infiltration of activated leukocytes into the inflammatory site may be associated with impairment of sperm fertilizing potential, due to oxidative, apoptotic, and immune processes. This review presents current research trends and aims to summarize the present knowledge of semen inflammation and causative bacterial agents in the male urogenital tract, with its consequence on seminological parameters, and male fertility status.

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Section: Apoptosis/necrosismentioning

confidence: 99%

“…One novel concept suggests that mitochondrial ROS generation may decide whether spermatozoon remains alive or enters an apoptotic state; its role in the aetiology of male infertility has most recently been postulated in the literature [96].…”

Section: Role Of Oxidative Stressmentioning

confidence: 99%

Mechanisms of the harmful effects of bacterial semen infection on ejaculated human spermatozoa: potential inflammatory markers in semen

Frączek

Kurpisz

2015

Folia Histochem Cytobiol.

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“…L-amino acid oxidase mitochondrial ROS generation ( Fig. 7; Koppers et al 2011, Aitken et al 2012. The ability of aromatic amino acids, such as phenylalanine, to stimulate the sustained generation of low levels of ROS in human spermatozoa may be of significance in an assisted conception context for the enhancement of IVF rates.…”

Section: Discussionmentioning

confidence: 99%

“…6). This loss of functionality after prolonged exposure to high doses (10 mM) of phenylalanine was associated with the induction of sperm apoptosis as evidenced by statistically significant increases in two hallmarks of this process, mitochondrial ROS generation (Koppers et al 2011), and caspase activation (Fig. 7).…”

Section: Functional Consequences Of Laao Activitymentioning

confidence: 99%

Human spermatozoa possess an IL4I1 l-amino acid oxidase with a potential role in sperm function

Houston¹,

Curry²,

Aitken³

2015

Reproduction

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Reactive oxygen species (ROS) are known to play an important role in the regulation of human sperm function. In this study, we demonstrate for the first time that human spermatozoa possess interleukin-induced gene 1 (IL4I1), an L-amino acid oxidase (LAAO) which is capable of generating ROS on exposure to aromatic amino acids in the presence of oxygen. The preferred substrates were found to be phenylalanine and tryptophan while the enzyme was located in the acrosomal region and midpiece of these cells. In contrast to equine and bovine spermatozoa, enzyme activity was lost as soon as the spermatozoa became non-viable. On a cell-to-cell basis human spermatozoa were also shown to generate lower levels of hydrogen peroxide than their equine counterparts on exposure to phenylalanine. Stimulation of LAAO activity resulted in the induction of several hallmarks of capacitation including tyrosine phosphorylation of the sperm flagellum and concomitant activation of phospho-SRC expression. In addition, stimulation of LAAO resulted in an increase in the levels of acrosomal exocytosis in both the presence and absence of progesterone stimulation, via mechanisms that could be significantly reversed by the presence of catalase. As is often the case with free radical-mediated phenomena, prolonged exposure of human spermatozoa to phenylalanine resulted in the stimulation of apoptosis as indicated by significant increases in mitochondrial superoxide generation and the activation of intracellular caspases. These results confirm the existence of an LAAO in human spermatozoa with a potential role in driving the redox regulation of sperm capacitation and acrosomal exocytosis.

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“…OGG1 removes these base adducts creating an abasic site that so destabilises the DNA backbone that fragmentation occurs. Endonuclease-mediated cleavage of DNA cannot occur in spermatozoa because the sperm nucleus is physically separated from the mitochondria and a majority of the cytoplasm (Koppers et al 2011).…”

Section: Obesitymentioning

confidence: 99%

Age, the environment and our reproductive future: bonking baby boomers and the future of sex

Aitken

2014

Reproduction

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There has never been a greater need for scientists trained in reproductive science. Most developed countries are witnessing unprecedented rates of recourse to assisted conception sitting cheek-by-jowl with high rates of induced abortion. This article addresses these two incongruous faces of reproductive healthcare. Every year at least 44 million abortions are performed worldwide, many under unsafe and insanitary conditions that carry a significant risk to the lives of women deprived of safe, effective methods for controlling their fertility. Although birth control is a complex issue involving myriad social and political factors, the technical vacuum in this area is significant. Through no fault of the family planning authorities, there have been no radically new methods of fertility control since the oral contraceptive pill was introduced in 1960 and even this contribution to planned parenthood has its roots in the biochemistry of the 1920s and 1930s. Moreover, the pharmaceutical industry has, by and large, turned its back on fundamental research activities in this area. At present, our major investment in reproductive healthcare involves treating ever-increasing numbers of couples with assisted reproductive technologies (ART). However, these treatments are often delivered without critically considering the underlying causes of this condition or seriously contemplating the long-term consequences of the current enthusiasm for such therapy. Significantly, the clinical factors underpinning the commitment of couples to ART include advanced maternal age and a variety of lifestyle factors, such as smoking and obesity, which are known to compromise the developmental potential of the oocyte and DNA integrity in spermatozoa.

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Phosphoinositide 3-kinase signalling pathway involvement in a truncated apoptotic cascade associated with motility loss and oxidative DNA damage in human spermatozoa

Cited by 212 publications

References 60 publications

Mechanisms of the harmful effects of bacterial semen infection on ejaculated human spermatozoa: potential inflammatory markers in semen

Mechanisms of the harmful effects of bacterial semen infection on ejaculated human spermatozoa: potential inflammatory markers in semen

Human spermatozoa possess an IL4I1 l-amino acid oxidase with a potential role in sperm function

Age, the environment and our reproductive future: bonking baby boomers and the future of sex

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