Infertility affected around 15% of couples all over the world, and estimated around half of all infertility cases (30% in the UK) due to reduce semen quality (Agarwal, 2012).
In a basic laboratory semen test, assessment relies on world health organisation (WHO) parameters like motility, sperm count and morphology. In general, a group of fertile men have higher mean sperm parameters compared to infertile group, although 15% of the infertile group had a normal semen analysis test according to WHO (Agarwal, 2012).
DNA integrity is another test highlighted recently. Sperm DNA can be used in determining individual semen quality which could be used in differentiating between fertile and infertile men or help to advise on best treatment options. Also is a good indicator of embryo quality, implantation, spontaneous miscarriage and, congenital abnormality.
Sperm DNA fragmentation index (DFI) as assessed by the flow cytometricsperm chromatin structure assay can be used for evaluation of sperm chromatin integrity. The biological reason behind abnormal DFI is not clearly known, however that data obtained recently shows that DFI was more than 30% was associated with reduced chances of people achieving pregnancy in the natural way or through insemination (Agarwal, 2012).
Justification for the study
Individuals use of assisted reproductive techniques has increased in the last decades. Intracytoplasmicsperm injection (ICSI) in being used today. Initially ICSI used to treat male with severe factor infertility. Now even couples with normal sperm quality are provided with ICSI . Ideally ICSI and IVF have been discovered as symptomatic treatment with about 25-30% resulting in a successful delivery.
The major reasons behind the limited success in individuals is lack of markers that could be used in determining the underlying cause of sub-fertility.
Attempts by medical practitioners
Clinics want to discover viable predictors of male fertility has driven people to focus on sperm DNA integrity . Currently, sperm chromatin integrity has been largely examined by majority of researchers including Agarwal, Carrell & Peterson (Carrell & Peterson, 2010; Agarwal, 2012). Even there is variation in the clinical value of different tests it was beyond the doubt that sperm chromatin structure assay was independent marker of fertility.
Standard semen parameters have been discovered to be inadequate predictors of fertility potential. Other than paternal karyotyping , sperm factors have not been evaluated as part of recurrent pregnancy loss. It is only in studies that are more recent that emphasis has been made on the role of sperm factors in assisting with early embryonic development because sperm creates genes that are important for early embryonic development.
Objectives if the study
To determine if sperm DNA integrity varies between couples who have experienced recurrent pregnancy loss and those that are fertile and have not.
To determine the biological reasons behind abnormal DNA fragmentation index
To look for factors that could be used as better indicators for male fertility
Could recurrent pregnancy loss affect individual DNA integrity ?Is there any biological reasons behind abnormal DNA fragmentation index?
What strategies could be employed in determining individual semen quality?
Sperm chromatin structure
Sperm chromatin structure is organised and also highly compacted and condensed (Agarwal, 2012). Chromatin structure protects the paternal genome in the event of being transported through reproductive tracts, and help to deliver the sperm to the ova in the right condition.
The DNA element found in the mammalian sperm is considered the most compacted eukaryotic DNA. Somatic cell nucleuses have a dissimilar DNA structure compared to that of the mammalian sperm DNA (Agarwal, 2012).The somatic cell nuclear is usually engulfed around an octamer of histones. The somatic cell nuclear DNA is further packaged into nucleosome and then coiled into a solenoid. This type of packaging in somatic cells adds histones that increase chromatin volume. Sperm cell nuclei undergo a different form of packaging owing to the certainty that nuclei do not have the volume required for the same type of packaging as somatic cells.
During the process of spermatogenesis, sperm chromatin goes through numerous modification processes, for example, loss and replacement of histones with transition proteins that are substituted with protamines, which are considered as approximately half the size of histones. The protamines assist with condensing DNA stands to formulate the basic packaging units for sperm chromatin ( toroids) (Agarwal, 2012). The toroids are further compacted by the intermolecular and intramolecular disulfide, which are cross interconnections between cystine residues that are found in protamines. All the aforementioned forms of compaction and organisation in the cells assist a great deal in the protection of sperm chromatin during their transportation through the reproductive tract
In addition, all these processes help in making sure that the paternal genome are conveyed in a form that would allow the developing embryo to adequately portray genetic information.
Even with it being that the human sperm chromatin is known to have a highly organised and compact structure, the sperm chromatin structure is regarded as less compact compared to that of the other mammals. One thing that makes the chromatin in human sperm chromatin less tightly compacted is that only an estimated 15% of histones are retained in the human sperm chromatin (Agarwal, 2012). Nevertheless, it has been discovered that infertile men have a higher histones to protamines ratio as part of their sperm chromatin. Most important, the human sperm is comprised of two types of protamines, P1 and P2 (Agarwal, 2012). The P2 protamines have less disulfide cross links and they contain reduced amounts of cysteine groups thus leaving individual DNA more susceptible to damage. Men with infertility cases were discovered to have altered P2 expression as a common trait.
Aetiology and mechanisms of sperm DNA damage
Sperm chromatin abnormalities occur at different level.. For example, there can be nuclear protein defects that may interfere with histone to protamine conversion and subsequent DNA compaction, destruction to the actual DNA physical integrity , which would occur in the form of double stranded and single stranded DNA strand breaks, and chromatin structural deformities that would result to transformed tertiary chromatin configuration. Events such as gene mutations, environmental stress , and chromosomal abnormalities could all interfere with biochemical events that take place during process of spermatogenesis (Gillman & Poston, 2012).This could result to abnormal chromatin structure that is incompatible with fertility .
Repair DNA damage could only be carried out to a minimal extent by the ova. However, if it happened that the sperm DNA damage was extensive the ovum proponent of the female cells will not have the repair capacity that would allow normal development of the embryo after conception (Gillman & Poston, 2012).
Quite a number of etiologic factors have been associated with sperm DNA fragmentation or impaired chromatin integrity . Sperm DNA fragmentation or impaired chromatin integrity can be caused by several factors that range depending on environments condition such as irradiation, cigarette smoking , and chemotherapy (Gillman & Poston, 2012). The pathophysiologic condition the result to DNA fragmentation includeleukocytospermia, cancer and varicocele.Other factors that have also been associated with sperm DNA damage include iatrogenic cause such as sperm cryopreservation (Gillman & Poston, 2012).
Specialised clinicaltests on semen and sperm
It has been discovered that there were times when the analysis of the semen proponent of individual body did not sufficiently help with predicting a mans fertility. As such, specialised clinical tests should be sidelined for cases in which the identification of the grounds for male infertility would direct treatment (Gillman & Poston, 2012).
DNA evaluation process have been utilised to a great degree in determining the degree of sperm DNA fragmentation. Individuals study of sperm DNA integrity has been conducted with the aim of establishing the aforementioned proponents correlation with individuals ability to conceive by intercourse, IVF, IUI and IVF by use of ICSI (Gillman & Poston, 2012).
Research conducted in the past years has shown that patients who had impaired DNA integrity were the majority when it came to determining lower pregnancy rates (Gillman & Poston, 2012). Nevertheless, it was also unraveled that a good number of couples who had impaired sperm DNA integrity were able to conceive through sexual intercourse.
Repair and prevention of sperm chromatin damage
The processes involved in the manufacture of sperms would in one way or another influence the manner in which individuals would select the healthy population of spermatozoa. Ideally, the chromatin integrity of mature sperm cells is usually more than that of unprepared semen. However, with simple preparation techniques such as density gradient centrifugation in place individuals would be able to enrich sperm normal morphology and the normal nuclear integrity (Gillman & Poston, 2012). Antioxidant therapy has been discovered as one of the most profound methods that could be put to play in protecting sperm chromatin integrity.
DNA or chromatin integrity
DNA integrity in sperm is considered the most researched molecular feature in the sperm cell. Although sperm cells with abnormal DNA or chromatin integrity subsist in ejaculates, the fact remains that the clinical viability of such piece of information is controversial. Intrauterine insemination (IUI) is largely similar to the sperm journey when one compared such process with natural conception processes. One of the most intriguing facts about chromatin or sperm DNA is that they link best with the outcomes of IUI and natural conception and to a lesser degree to with the ICSI and IVF .Increased levels of DNA fragmentation are mainly associated with recurring pregnancy loss in human beings., It could be proclaimed that there is the possibility of compromised DNA cells having issues with their arrival at the egg and fertilizing the egg in the process. However, if it happened that the DNA compromised cells fertilize the egg then the resulting fetus may be compromised in its development process.
Sperm DNA fragmentation can originate from multiple points that may be exogenous or endogenous. Damages to individuals DNA may result from a series of factors that would include abortive apoptosis, defective spermatogenesis, reactive oxygen species attack, protamine defects, diverse kinds of medical pathologies (varicocele, infections, cancer), working conditions or life recreational habits and age among several other factors.
Most of the tests that are used in the current times are only able to show gross anomalies making them less capable of picking up minor anomalies. Researchers have come to a common agreement concerning the link that existed between sperm DNA fragmentation and male infertility. In addition, scientists have reached a common point of agreement when it comes to the possibility of inadvertently microinjecting a DNA-damaged sperm during ICSI thus leading to the development of a worse embryo quality. Scientists have also agreed to the fact that the aforementioned occurrences generally lower reproductive outcomes when it comes to individuals miscarriage rates and persons degree of pregnancy achievement, which may eventually affect the health of children born of parents with worse embryo quality.
Based on th...
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