For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

The lipocalin protein family is a large group of small extracellular proteins. The family demonstrates great diversity at the sequence level; however, most lipocalins share three characteristic conserved sequence motifs, the kernel lipocalins, while a group of more divergent family members, the outlier lipocalins, share only one. Belying this sequence dissimilarity, lipocalin crystal structures are highly conserved and comprise a single eight-stranded continuously hydrogen-bonded antiparallel beta-barrel, which encloses an internal ligand-binding site. Together with two other families of ligand-binding proteins, the fatty-acid-binding proteins (FABPs) and the avidins, the lipocalins form part of an overall structural superfamily: the calycins. Members of the lipocalin family are characterized by several common molecular-recognition properties: the ability to bind a range of small hydrophobic molecules, binding to specific cell-surface receptors and the formation of complexes with soluble macromolecules. The varied biological functions of the lipocalins are mediated by one or more of these properties. In the past, the lipocalins have been classified as transport proteins; however, it is now clear that the lipocalins exhibit great functional diversity, with roles in retinol transport, invertebrate cryptic coloration, olfaction and pheromone transport, and prostaglandin synthesis. The lipocalins have also been implicated in the regulation of cell homoeostasis and the modulation of the immune response, and, as carrier proteins, to act in the general clearance of endogenous and exogenous compounds.

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The lipocalin protein family: structure and function

https://www.clevelandclinic.org/ReproductiveResearchCenter/docs/agradoc114.pdf

Role of reactive oxygen species in the pathophysiology of human reproduction

At coitus, human sperm are deposited into the anterior vagina, where, to avoid vaginal acid and immune responses, they quickly contact cervical mucus and enter the cervix. Cervical mucus filters out sperm with poor morphology and motility and as such only a minority of ejaculated sperm actually enter the cervix. In the uterus, muscular contractions may enhance passage of sperm through the uterine cavity. A few thousand sperm swim through the uterotubal junctions to reach the Fallopian tubes (uterine tubes, oviducts) where sperm are stored in a reservoir, or at least maintained in a fertile state, by interacting with endosalpingeal (oviductal) epithelium. As the time of ovulation approaches, sperm become capacitated and hyperactivated, which enables them to proceed towards the tubal ampulla. Sperm may be guided to the oocyte by a combination of thermotaxis and chemotaxis. Motility hyperactivation assists sperm in penetrating mucus in the tubes and the cumulus oophorus and zona pellucida of the oocyte, so that they may finally fuse with the oocyte plasma membrane. Knowledge of the biology of sperm transport can inspire improvements in artificial insemination, IVF, the diagnosis of infertility and the development of contraceptives.

/pdf/sperm-transport-in-the-female-reproductive-tract-1wd76o2ooi.pdf

Sperm transport in the female reproductive tract

Role of reactive oxygen species in male infertility.

Identification of placental protein 14 as an immunosuppressive factor in human reproduction.

Summary. Peroxidative damage induced by reactive oxygen species (ROS) has been proposed as one of the major causes of defective sperm function. In previous studies of the production of ROS in semen, the contribution of contaminating leucocytes was not assessed. We determined the levels of ROS in 60 semen samples from men attending our infertility clinic and demonstrated by performing extraction experiments with antibody-coated magnetic beads that, within this unselected population of patients, leucocytes were the major source of ROS in the low-density Percoll fraction. Of the sperm motion parameters examined using computerized semen analysis, beat-cross frequency was the only one significantly affected by the ROS in semen.

/pdf/origin-of-reactive-oxygen-species-in-human-semen-spermatozoa-539qmci2dy.pdf

Origin of reactive oxygen species in human semen: spermatozoa or leucocytes?

A preliminary investigation was undertaken further to determine the function of the leukocytic cells found in semen. We performed semen analysis and quantified leukocyte subsets using immunocytochemical staining techniques in ejaculates of 351 patients. Leukocyte profiles were examined in relation to sperm morphological data for evidence of a sperm removal/selection process. Three types of seminal phagocytic cell were found to contain spermatozoa: small polymorphonuclear leukocytes (approximately 10-12 microns), monocytes of similar size and much larger (30-40 microns) macrophages capable of engulfing multiple sperm heads. The total leukocyte count (P less than 0.01), the numbers of phagocytic cells i.e. polymorphonuclear leukocytes (P less than 0.05), monocyte/macrophages (P less than 0.01) and HLA-DR positive cells (P less than 0.01), were significantly higher in those samples with greater than 50% ideal sperm forms. Significantly fewer of these same cell types were observed in samples with greater than 50% head defects. There was no difference in the number of tail or midpiece defects between leukocytospermic (greater than 10(6)/ml) and non-leukocytospermic semen samples. Oligozoospermic samples contained significantly fewer leukocytes (P less than 0.005), although above a concentration of 5 x 10(6)/ml, the sperm number was not correlated with leukocyte number. These data, along with repeated observation of spermatozoa or sperm fragments within phagocytic cells, support the hypothesis that leukocytes have a role in the removal of abnormal spermatozoa from the ejaculate.

The removal of morphologically abnormal sperm forms by phagocytes: a positive role for seminal leukocytes?

The functional significance of white blood cells in the modulation of an anti-sperm antibody response, prevention of infection (including HIV) sperm transport/storage and sperm function is extensively discussed. A critical review of the existing literature is presented with future experimental lines of investigation outlined. A lack of controlled clinical studies in the human to validate data from animal species--for example--the involvement of white blood cells in the transport and storage of sperm in the female tract and the possible adverse effect of pathology (i.e. endometriosis) on these functions are presented. In conclusion, with the advent of modern techniques, e.g. monoclonal antibodies and sophisticated sperm function tests, many of the questions raised should be answered in the near future.

Functional significance of white blood cells in the male and female reproductive tract

PROBLEM: Sperm interaction with the immune system of the human cervix is poorly understood.



METHOD: The leukocytic response of the human cervix to sperm was examined in a closely monitored patient population (N = 10), using monoclonal antibody cell identification techniques. Baseline data were collected from both cervical mucus and smears sampled before treatment by donor insemination. Donor insemination was timed to coincide with ovulation by monitoring plasma LH concentrations twice daily. Following insemination the numbers of leukocytes were recorded in cervical mucus and smear samples taken over a 24-h period relative to the time of treatment. Controls treated with “pure sperm,” seminal plasma, cryopreservative, and cervical smearing alone were also included in the study.



RESULTS: Only those women treated with sperm cells exhibited substantial elevations in leukocyte numbers following inseminations. Additionally, serial cervical smearing induced an inflammatory response of the cervix. In all the women, the neutrophil was the predominant leukocyte of the cervix both during the baseline and treatment periods (median values ranged from 77 to 86%). Macrophages, T-helper lymphocytes, and T-suppressor lymphocytes were also detected, but only in low numbers (2–10.6%). Two patients and one control (“pure sperm”) became pregnant during their study cycle.



CONCLUSIONS: We conclude that the leukocytic reaction is a physiological response of the cervix to sperm, the function of which remains to be established.

A.E. Bolton

Papers

Identification of placental protein 14 as an immunosuppressive factor in human reproduction.

Origin of reactive oxygen species in human semen: spermatozoa or leucocytes?

The removal of morphologically abnormal sperm forms by phagocytes: a positive role for seminal leukocytes?

Functional significance of white blood cells in the male and female reproductive tract

The leukocytic reaction of the human uterine cervix.