Cigarette smoking by the male partner adversely affects assisted reproductive techniques, suggesting that it may damage sperm chromatin/DNA and consequently embryo development. The effects of graded concentrations of research cigarettes smoke extract (CSE) on motility, mitochondrial membrane potential (MMP), chromatin integrity and apoptosis were evaluated in spermatozoa obtained from 13 healthy, non-smoking men with normal sperm parameters, by flow cytometry. CSE suppressed sperm motility in a concentration- and time-dependent manner and increased the number of spermatozoa with low MMP, the main source of energy for sperm motility. In addition, CSE had a detrimental effect on sperm chromatin condensation and apoptosis. Indeed, it increased the number of spermatozoa with phosphatidylserine externalization, an early apoptotic sign, and fragmented DNA, a late apoptotic sign, in a concentration- and time-dependent manner. These effects of CSE were of similar or even greater magnitude to those obtained following incubation with tumour necrosis factor-alpha, a cytokine known for its negative impact on sperm function, used as positive control. Since transmission of smoking-induced sperm DNA alterations has been found in pre-implantation embryos, and this may predispose offspring to a greater risk of malformations, cancer and genetic diseases, men seeking to father a child are recommended to give up smoking.
The multifactorial pathological condition, that is, severe low sperm motility is a frequent cause of infertility. However, mechanisms underlying the development of this condition are not completely understood. Single abnormalities have been reported in sperm of patients with asthenozoospermia. In this study, we characterized, in 22 normozoospermic men and in 37 patients with asthenozoospermia, biochemical, molecular and genomic abnormalities that frequently occur in sperm of patients with asthenozoospermia. We evaluated a panel of sperm biomarkers that may affect the motility and fertilizing ability of sperm of patients with severe asthenozoospermia. Since reactive oxygen species (ROS) production is involved in the pathogenesis of such sperm abnormalities, we determined the association between ROS production and sperm abnormalities. High percentage of patients with severe asthenozoospermia showed increased basal and stimulated ROS production. Moreover, these patients showed increased mitochondrial DNA (mtDNA) copy number but decreased mtDNA integrity and they were associated with elevated ROS levels. Furthermore, mitochondrial membrane potential was also significantly decreased and again associated with high ROS production in these patients. However, the rate of nuclear DNA fragmentation was increased only in less than one-fifth of these patients. An important cohort of these patients showed multiple identical biochemical, molecular and genomic abnormalities, which are typical manifestations of oxidative stress. The most frequent association was found in patients with high ROS levels, increased mtDNA copy number and decreased integrity, and low MMP. A smaller cohort of the aforementioned patients also showed nDNA fragmentation. Therefore, patients with asthezoospermia likely present reduced fertilizing potential because of such composed abnormalities.
Progesterone stimulates sperm functions, e.g. hyperactivation, acrosome reaction, binding to oocyte zona pellucida and penetration rate into the hamster oocyte. The physiological relevance of these effects has been shown using female genital tract fluids which modulate sperm function according to their progesterone content. Progesterone interacts with specific sperm binding sites that, unlike the classic nuclear receptors, are located on the plasma membrane of the spermatozoon. Binding studies have revealed the presence of two classes of progesterone receptors in the human spermatozoon, one class has an elevated affinity constant (nanomolar) and is specific for progesterone, whereas the other class has an affinity constant in the micromolar range and binds equally well other hydroxylated progesterone derivatives. Following exposure to progesterone, the main event is a rapid (within seconds) increase of the intracellular free calcium concentration, followed by a sustained rise lasting for several minutes (plateau phase). Both these calcium transients are dependent upon entry of extracellular calcium. The nature of the calcium channel that mediates the effects of progesterone is, currently, unknown. It has been postulated that it may be: (i) part of the progesterone receptor; (ii) voltage-dependent; or (iii) operated by second messengers following activation of the progesterone receptor. Progesterone also modulates sperm function by stimulating a trypsin-like proteolytic activity, the biosynthesis of polyamine (putrescine and spermidine), phospholipase A2 activity and protein tyrosine kinase activity in the sperm cell. Recent studies have shown that chloride ion efflux is vital for progesterone to promote the acrosome reaction. This effect is achieved by interaction with a sperm membrane receptor which resembles the neuronal GABA(A) receptor. Accordingly, GABA(A) receptors have been found in the spermatozoon plasma membrane and GABA stimulates hyperactivation and promotes the acrosome reaction.
Various compounds have been used in the attempt to improve sperm motility, including pentoxifylline (PF), a methylxanthine derivative. It has been postulated that PF, being a phosphodiesterase inhibitor, increases sperm kinematic parameters and the number of spermatozoa exhibiting hyperactivated motility by raising the intracellular content of cAMP, a molecule involved in the generation of sperm energy. However, it has not been clarified whether the biological effects of PF on sperm motility correlate with its ability to increase intracellular cAMP levels. To examine this relationship, the kinematic parameters, hyperactivation, and intracellular cAMP content were evaluated in motile spermatozoa, obtained by discontinuous Percoll gradient and swim-up from 21 normozoospermic semen samples, incubated without and with PF for 0, 1, 2, and 4 h. PF increased beat cross frequency after 1 and 2 h of incubation, curvilinear velocity and lateral head displacement (ALH) after 4 h, and hyperactivation after 1, 2, and 4 h, and decreased linearity (LIN) after 1 h of incubation. The intracellular cAMP content of spermatozoa incubated with PF increased at all time-points examined. Both intracellular cAMP content and increase in hyperactivation in response to PF decreased with the length of incubation. In the absence of PF, cAMP content was unchanged and was correlated significantly only with ALH and the percentage of spermatozoa with hyperactivated motility. Following incubation with PF, cAMP content correlated with hyperactivation and all sperm kinematic parameters, with the exception of LIN and straightness. These findings suggest that the beneficial effects of PF on sperm kinematic parameters and hyperactivation are related to its ability to increase intracellular cAMP content.
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