Infertility a novel and promising approach to the diagnosis,

Infertility is one of thereproductive-related disorders that there are several causes in itsdevelopment, and both genders can play a role in the disorder.

Despite theefforts made, in many cases, the cause remains idiopathic. In male infertility, epigenetic factors play an important role,one of which is piRNAs that are considered as a class of non-coding RNAs andplay a crucial role in spermatogenesis. Therefore, these non-coding RNAs canserve as a novel and promising approach to the diagnosis, treatment, andprognosis of this disorder, although this still requires much research.

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Ourstudy is one of the first studies that reviewed the most recent investigationsperformed on the potential role of piRNAs in male infertility and in humanpopulation and it can help to better understand the etiology of this disorderand diagnosis of patientsInfertilityInfertility is described asthe disability to conceive after 1 year of unprotected intercourse, which ithas a general prevalence of 9% (1). Primaryand secondary infertility is defined as childlessness and failure to conceiveor carry for a woman who had already had one or more children. Infertility can occur in different ways in both genders (2). This is areproductive disease that can occur from many causes.

Genetic, anatomical,immunological and endocrinological abnormalities can lead to infertility (3). Malefactors contributing to infertility, included quality, motility,sperm counts and ejaculatory dysfunctions (3).  Male Infertility In 20% of infertile couples, there is adefect inmale fertility, and it can reach over 40% (4). The main causes of male infertility are varicocele (37%), semen disorders (10%), testicular insufficiency(9%), obstruction (6%), cryptorchidism (6%),and other abnormality (7%). Additionally, the causeof male infertility remained unclear in approximately 25% of cases that is called as idiopathicinfertility (5). Many studies haveexamined the genetic causes of male infertility, but so far they have only beenable to identify about 15% of infertility cases (6). Consequently, there isstill a need for a better understanding of it, and we must consider otherapproaches to understanding its causes. The epigenetic is one of thesepromising approaches that can partly explain the causes of idiopathic cases.

Therefore, the understanding of the epigeneticbasis of male infertility can be essential to appropriatelymanage an infertile patients.  The role of the epigeneticfactors in male infertility In fact, the epigenetic modifications arealterations in phenotype caused by mechanisms that do not change the DNA sequence (7). These modificationsin sperm are excluded fortwo reasons. First, in primordial germ cells (PGCs) occur, eliminating theepigenetic marks. Second, in male germ cell nuclei occurs a reorganization anda condensation of its genome (8). The most common of thesechanges includeDNA methylation, Histones modifications, transition from canonical histones toprotamines and non-coding RNAs (ncRNAs) (9). The most importantncRNAs are miRNA, siRNA and piRNA, the differences of which are presented inthe following table (10, 11) :  The piRNAs as a non-coding RNA In 2006, the first, a novel class of small noncoding RNA wasisolated from the mouse testis and Drosophila germ cells that were called piRNAs(PIWI interacting RNAs) (12, 13). The length of the piRNAis about 26-33 nucleotides which about 86% of them, there is a uracildeflection at the 5′ end and play a crucial role in spermatogenesis (14).

  Biogenesis of piRNA The main distribution sites piRNA are the animal testesspermatogonial cells and ovarian oocytes and in drosophila follicle cells(somatic cells). There are two main pathways of the piRNA biogenesis: In germcells, the AUB dependent piRNA pathway (secondary piRNA processing) is active,while in somatic cells, only pathway for producing piRNAs is the PIWI dependentpathway (primary piRNA processing) (15). The primary antisensetranscripts of piRNA are preferably binds to PIWI protein. This complex iscalled as piRISCs (piRNA-induced silencing complexes) which breaks the sensetranscript of transposons at positions 10 and 11 and generate the 5′ end of asense Ago3-associated piRNA. In the secondary piRNA processing that is known as thePing-Pong cycle, proteins of AUB and Argonaute 3 (AGO3) are involved (16). The AUB protein plays asimilar role to PIWI and forms the 5? end of piRNAs that associated with AGO3 (17).

This complex has tworoles: On the one hand, it produces the 5? end of the antisense piRNAs by thecleavage of antisense piRNA precursors and then these are loaded onto AUB, andon the other hand, it produces secondary piRNAs (Figure 1). The HEN1 protein mediated2??O-methylationof the 3? end of piRNA. Also, Mili and Miwi2 are two members of the mouse Piwiproteins that by processing of transposable elements (TEs) produce piRNAs. Thisoccurs in cytoplasmic granules called pi-bodies and piP-bodies (18).

  The role of piRNAs inmale infertility The piRNAs can play different roles inbiological processes, including:Sex Determination, Gene Silencing, Epigenetic Regulation and Cancer.Their most important role is to protect the gametes genome from the transposoninvasion and is performed by PIWI-piRNA complexes with silencing theirtranscripts (17).Consequently, piRNAs are usually used in the genome, but the aberrantexpression of each of the genes involved in biogenesis and function can lead tomodifications in the genome and different disorders. One of these disorders ismale infertility. In Figure 2, the most importantresearch performed on male infertility and piRNAs is summarized:The Moloney leukemia virus 10-like 1 (MOV10L1) gene is apiRNA biogenesis- relatedgene that plays a role in the primary and secondary processing (19). It can help to primarypiRNAs for binding to the PIWI protein. Some studies have confirmed thatseveral polymorphisms of this gene have a remarkable increase in infertile men (20). In human, theassociation of four human PIWI proteins (HIWI, HILI, HIWI2 and PIWIL3) in malefertility has been shown.

In 2010 and 2017, investigations on Chinese andIranian populations with non-obstructive azoospermia revealed independently arelationship between HIWI2 rs508485 (T>C) and non-obstructive azoospermiaand this variant can be considered as a risk factor for male infertility (21, 22).A recent study on peripheral blood samples of 30 infertile men, showed that rs10773767 and rs6982089 were two singlenucleotide polymorphisms (SNPs) in PIWIL1 and PIWIL2 respectively. These polymorphisms were allele-specificmethylation-sensitive and suggests that DNA methylation changes in these genesare associated with spermatogenesis disorders (23).

Furthermore, Transposons are repetitive elements that usethe genome of a host cell to survive and amplification. For protecting of thegenomes of gametes from their invasion, PIWI-piRNA complexes target them tosilence of their transcripts. LINE-1 (L1) is one of the transposons studiedthat by performing the examinations on patients with cryptorchidism revealed thata consequence of alterations in the Piwi-pathway and derepression oftransposable elements in these patients is infertility (24). These studies indicatethat piRNAs may play a crucial role in male infertility.  The potential role of piRNAs as a diagnostic biomarker formale infertility According to the WHO, diagnosis of male infertility is basedon the semen parameters, which include the following: motility,sperm concentration, seminal volume, pH and morphology (25).

some studies have shownthat sperm analysis cannot be used accurately for diagnosis between fertile andinfertile men (26). Therefore,identification of non-Invasive seminal Biomarkers, can solve this problem. In2015, Hong and colleagues identified 5 piRNAs by examining seminal plasmasamples in infertile patients, which can be used as diagnostic biomarkers forthe detection of infertile men (Figure 3) (27). Also, another study in patientswith idiopathic male infertility who experienced the first ICSI course, suggestedthat there is a relationship between spermatozoa piRNA levels (piR-31704 andpiR-39888)  and sperm concentration (28). Thus, these piRNAs mayplay an important role in the fertilization process.

 One of the benefits of understanding the epigeneticabnormalities is that epigenetic modifications, unlike genetic mutations, canbe modified using specific drugs. Therefore, with a complete understanding ofthese modifications, treatment for epigenetic-related diseases can be achieved.The ncRNAs are the most common epigenetic regulators that their role has beenidentified in many disorders. Among ncRNAs, piRNAs play an important role inspermatogenesis and are candidates for further research on male infertility.

Thestudies presented in this review showed that investigating the role of piRNAsin male infertility could be useful for multiple causes. First, determine anon-invasive biomarker for early detection of male infertility. Second,discover the causes of idiopathic male infertility. Also, piRNAs can be used todiagnose different types of infertile patients.

For example, piR-30198 is oneof piRNAs used for this purpose. This biomarker is able to distinguish betweentwo disorders related to male infertility, namely, azoospermia andasthenozoospermia (27).