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Akhtarkhavari T, Behjati F. Role of Epigenetics in Male Infertility. SJMR 2018; 3 (3) :177-183
URL: http://saremjrm.com/article-1-74-en.html
URL: http://saremjrm.com/article-1-74-en.html
1- Sarem Cell Research Center (SCRC), Sarem Women’s Hospital, Tehran, Iran
2- “Sarem Fertility & Infertility Research Center (SAFIR)” and “Sarem Cell Research Center (SCRC), Sarem Women’s Hospital ,fbehjati@gmail.com
2- “Sarem Fertility & Infertility Research Center (SAFIR)” and “Sarem Cell Research Center (SCRC), Sarem Women’s Hospital ,
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/akhtarkhavari/2-4-8-3.png)
3- Chromatin state changes complexes
These complexes can alter the structure of location of nucleosomes on DNA, using the ATP hydrolysis energy and by this mechanism, the genes can be more easily transcribed or completely eliminated from transcription (Table 3) [10-11].
/akhtarkhavari/4.png)
/akhtarkhavari/2-4-8-5.png)
Figure 2) Epigenetic events during spermatogenesis
/akhtarkhavari/2-4-8-6.png)
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Introduction
Male infertility is a complex clinical condition that involves various causes, such as anatomical forms, infections, traumatic injuries, disorders in the endocrine, immune system problems, and genetic defects. So far, genetic roles have been studied in male infertility, and it has been estimated that genetic factors contribute to 15-30% of male infertility [1]. For example, chromosomal abnormalities such as Klinefelter syndrome, structural chromosome abnormalities such as Robertsonian translocation, Y chromosome deletions and sub-deletions, AZf mutations, cystic fibrosis disease, mutations in many genes such as AR, KAL-1, LGRS, MTHFR, SHBG, ESR, FSHR, LHR, USP26, TAF7L, as well as mutations in mitochondrial genes [1] are a number of genetic factors that lead to infertility in men. On the other hand, available treatments are not responsive to all patients and suggest something between 15-20% of men as infertile idiopathic people. Idiopathic infertility in men refers to infertile patients who do not have previous medical history and their semen analysis is also normal. One of the causes of this type of infertility is epigenetic disorder, which has recently been recognized as important in recent years [2]. Recent advances in technology have enabled humans to study epigenetic role in male infertility. Epigenetic changes are also a set of factors that affect the expression of genes, but do not affect the DNA sequence. The main epigenetic mechanisms are as follows (Fig.1) [3]:/akhtarkhavari/2-4-8-1.png)
The most important mechanisms among other epigenetic agents is hypermethylation and hypomethylation of DNA. Many human genes in the vicinity of their promoter region contain CpG islets. Hypermethylation in these areas suppresses the expression of the gene and hypomethylation of these areas leads to the expression of the genes. Many genes are involved in regulating this process which are a good candidate for the study of male epigenetic infertility (Table 1) [3-9]./akhtarkhavari/2-4-8-2.png)
Male infertility is a complex clinical condition that involves various causes, such as anatomical forms, infections, traumatic injuries, disorders in the endocrine, immune system problems, and genetic defects. So far, genetic roles have been studied in male infertility, and it has been estimated that genetic factors contribute to 15-30% of male infertility [1]. For example, chromosomal abnormalities such as Klinefelter syndrome, structural chromosome abnormalities such as Robertsonian translocation, Y chromosome deletions and sub-deletions, AZf mutations, cystic fibrosis disease, mutations in many genes such as AR, KAL-1, LGRS, MTHFR, SHBG, ESR, FSHR, LHR, USP26, TAF7L, as well as mutations in mitochondrial genes [1] are a number of genetic factors that lead to infertility in men. On the other hand, available treatments are not responsive to all patients and suggest something between 15-20% of men as infertile idiopathic people. Idiopathic infertility in men refers to infertile patients who do not have previous medical history and their semen analysis is also normal. One of the causes of this type of infertility is epigenetic disorder, which has recently been recognized as important in recent years [2]. Recent advances in technology have enabled humans to study epigenetic role in male infertility. Epigenetic changes are also a set of factors that affect the expression of genes, but do not affect the DNA sequence. The main epigenetic mechanisms are as follows (Fig.1) [3]:
Figure 1) Main epigenetic mechanisms
1-Hypermethylation and hypomethylationThe most important mechanisms among other epigenetic agents is hypermethylation and hypomethylation of DNA. Many human genes in the vicinity of their promoter region contain CpG islets. Hypermethylation in these areas suppresses the expression of the gene and hypomethylation of these areas leads to the expression of the genes. Many genes are involved in regulating this process which are a good candidate for the study of male epigenetic infertility (Table 1) [3-9].
Table 1) A number of the most important genes involved in the regulation of epigenetic processes
2- Changes in histones
Post-translation changes in histones are very important in the proper functioning of cells. The N-terminal region of histones is very important for the proper functioning of cellular processes, mitoses, and spermatogenesis. The N-terminal contains amino acids that can be affected by methylation, acetylation, phosphorylation, and ubiquitylation. The collection of the information that is transferred via this method is called histone code [10]. Acetylation, monomethylation, demethylation, trimethylation of lysins and serine phosphorylation are some of these common variations. Enzymes such as histone acetyltransferase, histone methyltransferases, histone kinases, histone deacetylases, histone demythylases, and histone phosphatase are number of common changes. Based on the type of change, chromatin is located in the group of heterochromatin and euchromatin. In heterochromatins, there are areas that are not active due to high compression. Euchromatins are also parts that are less compact and therefore they are transcriptionally active. The heterochromatin itself is divided into two parts: first, heterochromatin is building that cannot be converted to euchromatin and second, an optional heterochromatin capable of converting to euchromatin. A number of histone changes are noted in the regions of euchromatin and heterochromatin (Table 2) [10].
Post-translation changes in histones are very important in the proper functioning of cells. The N-terminal region of histones is very important for the proper functioning of cellular processes, mitoses, and spermatogenesis. The N-terminal contains amino acids that can be affected by methylation, acetylation, phosphorylation, and ubiquitylation. The collection of the information that is transferred via this method is called histone code [10]. Acetylation, monomethylation, demethylation, trimethylation of lysins and serine phosphorylation are some of these common variations. Enzymes such as histone acetyltransferase, histone methyltransferases, histone kinases, histone deacetylases, histone demythylases, and histone phosphatase are number of common changes. Based on the type of change, chromatin is located in the group of heterochromatin and euchromatin. In heterochromatins, there are areas that are not active due to high compression. Euchromatins are also parts that are less compact and therefore they are transcriptionally active. The heterochromatin itself is divided into two parts: first, heterochromatin is building that cannot be converted to euchromatin and second, an optional heterochromatin capable of converting to euchromatin. A number of histone changes are noted in the regions of euchromatin and heterochromatin (Table 2) [10].
Table 2) A number of histone changes in the areas of euchromatin and heterochromatin
3- Chromatin state changes complexes
These complexes can alter the structure of location of nucleosomes on DNA, using the ATP hydrolysis energy and by this mechanism, the genes can be more easily transcribed or completely eliminated from transcription (Table 3) [10-11].
Table 3) A number of chromatin-modifying complexes
Epigenetic events during spermatogenesis
During the production of sex cells, epigenetic reprogramming occurs in these cells. This means that epigenetic symptoms are erased once and then repositioned with respect to the individual`s gender. At each stage of spermatogenesis, epigenetic events occur. For example, primordial sexual cells are subjected to DNA and histone demethylation to remove the positioned areas. Removal of histone methylation, especially in H3K4 and H3K9 is very important. At the same time, the histone H4 becomes deacetylated and on the other hand, the genes DNMT3A, DNMT3B and DNMT3L become expressed. In spermatognia, paternal methylation reoccurs and in the spermatocyte there is also methylation if H3K4 and H3K9. In the next step, H4 hyperacetylation occurs in circular spermatozoa and the DNMT1 gene is expressed. Also, in this stage, histones are replaced by the temporary proteins. In spermatids, while the methylation state is preserved, H3K9 is subjected to demythylation, and replacement of protamins with temporary proteins happens, and ultimately, genomic placement with be stabilized in spermatozoa [12]. In general, this process activates or suppresses the expression of genes that play a role in the developmental and maturing processes of gametes. The interesting point about spermatogenesis is that when chromatin is re-packed, 85% of histones are replaced with protamine [13], and the addition of protamine to sperm chromatin causes compression of DNA which is crucial for spermatogenesis [14, 15]. These steps are summarized (Fig. 2) [16].
During the production of sex cells, epigenetic reprogramming occurs in these cells. This means that epigenetic symptoms are erased once and then repositioned with respect to the individual`s gender. At each stage of spermatogenesis, epigenetic events occur. For example, primordial sexual cells are subjected to DNA and histone demethylation to remove the positioned areas. Removal of histone methylation, especially in H3K4 and H3K9 is very important. At the same time, the histone H4 becomes deacetylated and on the other hand, the genes DNMT3A, DNMT3B and DNMT3L become expressed. In spermatognia, paternal methylation reoccurs and in the spermatocyte there is also methylation if H3K4 and H3K9. In the next step, H4 hyperacetylation occurs in circular spermatozoa and the DNMT1 gene is expressed. Also, in this stage, histones are replaced by the temporary proteins. In spermatids, while the methylation state is preserved, H3K9 is subjected to demythylation, and replacement of protamins with temporary proteins happens, and ultimately, genomic placement with be stabilized in spermatozoa [12]. In general, this process activates or suppresses the expression of genes that play a role in the developmental and maturing processes of gametes. The interesting point about spermatogenesis is that when chromatin is re-packed, 85% of histones are replaced with protamine [13], and the addition of protamine to sperm chromatin causes compression of DNA which is crucial for spermatogenesis [14, 15]. These steps are summarized (Fig. 2) [16].
Figure 2) Epigenetic events during spermatogenesis
Relationship between RNA types and male infertility
Several studies have shown that infertile sperm compared to fertile one has significant changes in terms of RNA types [17]. One of these changes is the change in miRNA, mRNA, and piRNA. This study was conducted in more than 50 articles published in the Pubmed Scientific Database. All articles until June 20, 2016 which had the key terms of epigenetic, epimutation, epigenetic science, epigenetic and epimedical, male infertility, azoospermia and oligosperma were studied.
For each epigenetic mechanism, several changes related to infertility have been reported, including:
1- Methylation changes associated with male infertility
Various changes have been reported for various genes [3, 5, 18-26]:
MTHFR: it is the most important gene in the methylation mechanism that is reported in numerous studies related to infertility. Initially, the promoter hyperthermia of this gene was considered in association with the human seminal fluid by creating poor sperm parameters [3]. In another study, men with non-obstructive azoospermia were compared with those with obstructive azoospermia and found that hypermethylation of the MTHFR promoter was present only in those with non-obstructive azoospermia [18]. Waugh et al. have also shown that hypermethylation of this gene is involved in the induction of male idiopathic infertility [19]. In another study, Chen et al. described the hypermethylation of this gene in relation to the low quality of semen and male infertility [20].
SFN: Rajender et al. have reported the promoter hypermethylation of this gene by creating weaking parameters in semen in humans [3]. On the other hand, Hooshdaran et al. have associated the hypermethylation of this gene with low sperm concentration in semen, and acknowledge that this process has a negative effect on morphology and sperm motility [21].
H19, MEST, IGF2: first, the abnormal methylation of H19 and MEST, both of which were imprinted, were reported with oligosperma [22].in another study, fertile and infertile men were compared and it was shown that the three IGF2, H19 and MEST locus, which are imprinted, had abnormal methylation pattern in infertile persons [23]. In studies, it has been shown that hypermethylation of IGF2 and H19 is associated with low sperm concentration in semen [23]. In another study by Hooshdaran et al., MEST was found to be associated with poor semen parameters in semen [21]. There are some contradictions in these three locusts. For example, it has been shown in a study that these three locus were hypermethylated in some fertile people, and they were hypomethylated in some other fertile people [23].
LIT1: Rajender et al. have shown that the hypermethylation of LIT1 promoter in humans is associated with poor sperm parameters [3], and another study showed that the methylation pattern of CpG islets in this gene is different in infertile individuals [24].
SNRPN, PLAG1: initially, the abnormal methylation pattern of these two genes was reported among infertile individuals [24], and in another study, their hypermethylation was associated with poor sperm parameters [3, 24].
GTL2, KCNQ1, RASGRF1, D1RAS3: different reports of promoter hypermethylation have been provided by these four genes in connection with poor spermatic parameters [3, 21, 24, 26].
PAX8: Hypermethylation of this gene is associated with a low concentration of sperm in semen and also negatively affects morphology and sperm mobility [21]. Also, hypermethylation promoter is associated with poor sperm parameters [3].
PAX 8: Rajender et al. have suggested the promoter hypermethylation of this gene by establishing weak sperm parameters [3].
NTF3: Chan et al. relate hypermethylation of this gene to low sperm concentration in semen, and stated that hypermethylation in this region has a negative effect on morphology and sperm motility [3].
2- Changes in histone associated with male infertility
The study on mice revealed the vital role of Jhmd2a during the spermatogenesis. In this study, it was found that this demethylated histone is involved in regulating the expression of two genes called Prm1 and Tnp1, which are involved in correct packaging of chromatin in sperm [27, 28].
3. Relationship between chromatin changes and male infertility
It is known that protamins begin to be phosphorylated before binding to the DNA, and they become re-phosphorylated at the same time as the maturation of the nucleoprotein. Camrk4 is a protein that phosphorylates protamine type II. Mutation in this protein cause defective spermatogenesis and infertility in men [29]. Because type one and type two protamine are critical to sperm function, the inadequate state for these two genes make the chromatin structure unnatural, damage DNA, and cause infertility [3]. In addition, it has been shown that the ratio of protamine type one to protamine type two is also very important [30]. This ratio is between 0.8 and 1.2 in fertile men and deviations from this amount result in infertility. These deviations also affect the quality of semen and maintain the stability of DNA, and the decrease in this proportion results in low sperm concentration in semen and changes in its morphology and mobility [30, 31].
Several studies have shown that infertile sperm compared to fertile one has significant changes in terms of RNA types [17]. One of these changes is the change in miRNA, mRNA, and piRNA. This study was conducted in more than 50 articles published in the Pubmed Scientific Database. All articles until June 20, 2016 which had the key terms of epigenetic, epimutation, epigenetic science, epigenetic and epimedical, male infertility, azoospermia and oligosperma were studied.
For each epigenetic mechanism, several changes related to infertility have been reported, including:
1- Methylation changes associated with male infertility
Various changes have been reported for various genes [3, 5, 18-26]:
MTHFR: it is the most important gene in the methylation mechanism that is reported in numerous studies related to infertility. Initially, the promoter hyperthermia of this gene was considered in association with the human seminal fluid by creating poor sperm parameters [3]. In another study, men with non-obstructive azoospermia were compared with those with obstructive azoospermia and found that hypermethylation of the MTHFR promoter was present only in those with non-obstructive azoospermia [18]. Waugh et al. have also shown that hypermethylation of this gene is involved in the induction of male idiopathic infertility [19]. In another study, Chen et al. described the hypermethylation of this gene in relation to the low quality of semen and male infertility [20].
SFN: Rajender et al. have reported the promoter hypermethylation of this gene by creating weaking parameters in semen in humans [3]. On the other hand, Hooshdaran et al. have associated the hypermethylation of this gene with low sperm concentration in semen, and acknowledge that this process has a negative effect on morphology and sperm motility [21].
H19, MEST, IGF2: first, the abnormal methylation of H19 and MEST, both of which were imprinted, were reported with oligosperma [22].in another study, fertile and infertile men were compared and it was shown that the three IGF2, H19 and MEST locus, which are imprinted, had abnormal methylation pattern in infertile persons [23]. In studies, it has been shown that hypermethylation of IGF2 and H19 is associated with low sperm concentration in semen [23]. In another study by Hooshdaran et al., MEST was found to be associated with poor semen parameters in semen [21]. There are some contradictions in these three locusts. For example, it has been shown in a study that these three locus were hypermethylated in some fertile people, and they were hypomethylated in some other fertile people [23].
LIT1: Rajender et al. have shown that the hypermethylation of LIT1 promoter in humans is associated with poor sperm parameters [3], and another study showed that the methylation pattern of CpG islets in this gene is different in infertile individuals [24].
SNRPN, PLAG1: initially, the abnormal methylation pattern of these two genes was reported among infertile individuals [24], and in another study, their hypermethylation was associated with poor sperm parameters [3, 24].
GTL2, KCNQ1, RASGRF1, D1RAS3: different reports of promoter hypermethylation have been provided by these four genes in connection with poor spermatic parameters [3, 21, 24, 26].
PAX8: Hypermethylation of this gene is associated with a low concentration of sperm in semen and also negatively affects morphology and sperm mobility [21]. Also, hypermethylation promoter is associated with poor sperm parameters [3].
PAX 8: Rajender et al. have suggested the promoter hypermethylation of this gene by establishing weak sperm parameters [3].
NTF3: Chan et al. relate hypermethylation of this gene to low sperm concentration in semen, and stated that hypermethylation in this region has a negative effect on morphology and sperm motility [3].
2- Changes in histone associated with male infertility
The study on mice revealed the vital role of Jhmd2a during the spermatogenesis. In this study, it was found that this demethylated histone is involved in regulating the expression of two genes called Prm1 and Tnp1, which are involved in correct packaging of chromatin in sperm [27, 28].
3. Relationship between chromatin changes and male infertility
It is known that protamins begin to be phosphorylated before binding to the DNA, and they become re-phosphorylated at the same time as the maturation of the nucleoprotein. Camrk4 is a protein that phosphorylates protamine type II. Mutation in this protein cause defective spermatogenesis and infertility in men [29]. Because type one and type two protamine are critical to sperm function, the inadequate state for these two genes make the chromatin structure unnatural, damage DNA, and cause infertility [3]. In addition, it has been shown that the ratio of protamine type one to protamine type two is also very important [30]. This ratio is between 0.8 and 1.2 in fertile men and deviations from this amount result in infertility. These deviations also affect the quality of semen and maintain the stability of DNA, and the decrease in this proportion results in low sperm concentration in semen and changes in its morphology and mobility [30, 31].
4- RNA changes in male fertility
A) mRNA changes: studies have shown that HSPA2 which plays a role in the maturation of sperms and their function, has been found much higher spermatogenesis in people with low concentration of sperms with low mobility and abnormal shape [32]. BONF-specific mRNA is also lower in subjects with low motility sperm compared to those with normal sperm. The GP130, which binds to IL-6 and play role in sperm motility, has shown high level of mRNA in men with low sperm motility. In oligospermic individuals, DDX4 and VASA transcripts that are essential for the development of sex are reported to be low [33].
B) miRNA changes in the sperm: human sperm has 7% miRNA and 17% piRNA [34]. These small RNAs regulate gene expression at the transcriptional, post-transcriptional, and chromatin levels [35], and so far it has been determined that one-third of human genes are regulated by miRNA [36]. In terms of number, more than 200 miRNA has been found in human sperm that this high number expresses the very important role of this type of RNA in morphogenesis and sperm maturation [10]. A number of miRNA associated with infertility in men are described below; for example, in mice, the miRNA is miR-18 which is required for natural spermatogenesis [37]. miR-34c and miRNA34b also play a role in the production of sex cells during spermatogenesis [38]. Another case is miR-122, which is an RNA and it regulates a gene called Tnp2. This gene is specific to testicular tissue and is thought to be involved in the function of complexes that alter the state of chromatin during testicular spermatogenesis [39]. The miR-17-92 cluster is also effective in the regulation of apoptosis in the spermatogenesis process [40]. It is noteworthy that the presence of mutations such as deletions in miRNA processing machine that includes Dicer and Drosha, can lead to problems with spermatogenesis and infertility. The method for detecting and investigating miRNA in RT-qPCR semen is based on the assumption that this type of RNA is transmitted from semen sexual cells to semen via apoptosis [41].
C) piRNA association and male infertility: This type of RNA is the largest and most complex RNA class that has recently been discovered. These RNAs in the cell are not translated into proteins. Some of them are MIW, MIWI2, HIWI, PRG-1, and piRNA. PRG-2 is produced in the clean stage of spermatocytes and studies on mice have shown that it protects sex-grade cells against transposons [42]. In General, experiments on the mouse model have been performed for some of the epigenetic regulators involved in the mammalian gametogenesis (Table 4) [7, 43-55].
A) mRNA changes: studies have shown that HSPA2 which plays a role in the maturation of sperms and their function, has been found much higher spermatogenesis in people with low concentration of sperms with low mobility and abnormal shape [32]. BONF-specific mRNA is also lower in subjects with low motility sperm compared to those with normal sperm. The GP130, which binds to IL-6 and play role in sperm motility, has shown high level of mRNA in men with low sperm motility. In oligospermic individuals, DDX4 and VASA transcripts that are essential for the development of sex are reported to be low [33].
B) miRNA changes in the sperm: human sperm has 7% miRNA and 17% piRNA [34]. These small RNAs regulate gene expression at the transcriptional, post-transcriptional, and chromatin levels [35], and so far it has been determined that one-third of human genes are regulated by miRNA [36]. In terms of number, more than 200 miRNA has been found in human sperm that this high number expresses the very important role of this type of RNA in morphogenesis and sperm maturation [10]. A number of miRNA associated with infertility in men are described below; for example, in mice, the miRNA is miR-18 which is required for natural spermatogenesis [37]. miR-34c and miRNA34b also play a role in the production of sex cells during spermatogenesis [38]. Another case is miR-122, which is an RNA and it regulates a gene called Tnp2. This gene is specific to testicular tissue and is thought to be involved in the function of complexes that alter the state of chromatin during testicular spermatogenesis [39]. The miR-17-92 cluster is also effective in the regulation of apoptosis in the spermatogenesis process [40]. It is noteworthy that the presence of mutations such as deletions in miRNA processing machine that includes Dicer and Drosha, can lead to problems with spermatogenesis and infertility. The method for detecting and investigating miRNA in RT-qPCR semen is based on the assumption that this type of RNA is transmitted from semen sexual cells to semen via apoptosis [41].
C) piRNA association and male infertility: This type of RNA is the largest and most complex RNA class that has recently been discovered. These RNAs in the cell are not translated into proteins. Some of them are MIW, MIWI2, HIWI, PRG-1, and piRNA. PRG-2 is produced in the clean stage of spermatocytes and studies on mice have shown that it protects sex-grade cells against transposons [42]. In General, experiments on the mouse model have been performed for some of the epigenetic regulators involved in the mammalian gametogenesis (Table 4) [7, 43-55].
Table 4) Results of inactivation experiments of epigenetic regulators involved in mammalian gametogenesis
Effect of assisted reproductive technology on epigenetic profile
Studies on humans and mice have shown that oocytes taken by hormal induction as well as fetus created in test tubes are different in terms of gene expression and methylation pattern [10]. For example, methylation of the MEST/PEG1 maternal methylation site on the 7q33 chromosomal region and the acquisition of methylation in the different regions of H19 motility region on the chromosomal region of 11p15.5 in oocytes can be noted [10].
A number of recent studies have also shown that the prevalence of epigenetic abnormalities among children resulting from assistant reproductive technology has been higher than that of children who were result of a natural fertility [10]. This increased prevalence has been reported for angelman syndrome with an odd ratio of 6 to 12 and for Beckwith-Wiedmann with an odd ration of 6 to 17. An interesting point about these two syndromes is that both of these diseases can cause problems in naming the maternal allele [10]. Among these children, the loss of methylation in different regions of maternal methylation in 15q11 for angelman syndrome is 8 times higher and for Beckwith-Widemann syndrome in 11p15 is 9.1 times higher than normal fertility [10]. An interesting point about epigenetic studies is that environment conditions can also cause these changes in human fetus. This hypothesis was first proposed by David Barker. He stated that maternal pregnancy stress such as inappropriate nutrition, exposure to toxic substances, and physiological stress can induce persistent epigenetic changes in the fetus and may later reflect these changes in cardiovascular, metabolic and psychological illnesses [56].
For many years, the role of epigenetic factors in the incidence of infertility as well as the effect of assistant reproductive methods on the fetus epigenetic pattern was not considered, but in recent years, it has been determined that epigenetic factors are one of the most important and measurable factors in male fertility, and therefore these factors should be investigated in the diagnosis methods of infertility in men. On the other hand, it is obvious today that stimulation of artificial ovulation, which is stage in the treatment of infertility, is associated with marking disorders in maternal and paternal alleles. However, it is still unclear that whether epigenetic problems themselves are involved in infertility or that they are the complication of artificial ovulation. Therefore, further studies are needed to determine the precise outbreak of epigenetic abnormalities among children from artificial insemination. Also, the effect of artificial insemination on the epigenetic pattern of fetus should be investigated.
Conclusion
Currently, infertility diagnosis and available therapies do not address all cases of male infertility. Epigenetic factors are among the factors contributing to this type of infertility. To this end, this aspect should be considered for the examination of infertile people. Moreover, due to the dynamicity of epigenetic pattern, correction of these factors is much easier than the genetic modification of individuals. Therefore, studying these factors in near future will enable us to build epimedical drugs to correct epigenetic processes in infertile people.
Acknowledgements
All people who helped us with this article are appreciated.
Ethical permissions
Non-declared
Conflict of interests
Non-declared
Financial support
Non-declared
Contribution of authors
Tara Akhtar Khavari (First author), author of the article/methodology/main author or helper/statistical analysis/author of discussion (%...); Farkhondeh Behjati (Second author), author of the article/methodology/main author or helper/statistical analysis/author of discussion (%...); (Select the role of each person in the production of the article from among specified roles. Select the appropriate role for each person and avoid the selection of all items for all authors, as it will not be acceptable).
Studies on humans and mice have shown that oocytes taken by hormal induction as well as fetus created in test tubes are different in terms of gene expression and methylation pattern [10]. For example, methylation of the MEST/PEG1 maternal methylation site on the 7q33 chromosomal region and the acquisition of methylation in the different regions of H19 motility region on the chromosomal region of 11p15.5 in oocytes can be noted [10].
A number of recent studies have also shown that the prevalence of epigenetic abnormalities among children resulting from assistant reproductive technology has been higher than that of children who were result of a natural fertility [10]. This increased prevalence has been reported for angelman syndrome with an odd ratio of 6 to 12 and for Beckwith-Wiedmann with an odd ration of 6 to 17. An interesting point about these two syndromes is that both of these diseases can cause problems in naming the maternal allele [10]. Among these children, the loss of methylation in different regions of maternal methylation in 15q11 for angelman syndrome is 8 times higher and for Beckwith-Widemann syndrome in 11p15 is 9.1 times higher than normal fertility [10]. An interesting point about epigenetic studies is that environment conditions can also cause these changes in human fetus. This hypothesis was first proposed by David Barker. He stated that maternal pregnancy stress such as inappropriate nutrition, exposure to toxic substances, and physiological stress can induce persistent epigenetic changes in the fetus and may later reflect these changes in cardiovascular, metabolic and psychological illnesses [56].
For many years, the role of epigenetic factors in the incidence of infertility as well as the effect of assistant reproductive methods on the fetus epigenetic pattern was not considered, but in recent years, it has been determined that epigenetic factors are one of the most important and measurable factors in male fertility, and therefore these factors should be investigated in the diagnosis methods of infertility in men. On the other hand, it is obvious today that stimulation of artificial ovulation, which is stage in the treatment of infertility, is associated with marking disorders in maternal and paternal alleles. However, it is still unclear that whether epigenetic problems themselves are involved in infertility or that they are the complication of artificial ovulation. Therefore, further studies are needed to determine the precise outbreak of epigenetic abnormalities among children from artificial insemination. Also, the effect of artificial insemination on the epigenetic pattern of fetus should be investigated.
Conclusion
Currently, infertility diagnosis and available therapies do not address all cases of male infertility. Epigenetic factors are among the factors contributing to this type of infertility. To this end, this aspect should be considered for the examination of infertile people. Moreover, due to the dynamicity of epigenetic pattern, correction of these factors is much easier than the genetic modification of individuals. Therefore, studying these factors in near future will enable us to build epimedical drugs to correct epigenetic processes in infertile people.
Acknowledgements
All people who helped us with this article are appreciated.
Ethical permissions
Non-declared
Conflict of interests
Non-declared
Financial support
Non-declared
Contribution of authors
Tara Akhtar Khavari (First author), author of the article/methodology/main author or helper/statistical analysis/author of discussion (%...); Farkhondeh Behjati (Second author), author of the article/methodology/main author or helper/statistical analysis/author of discussion (%...); (Select the role of each person in the production of the article from among specified roles. Select the appropriate role for each person and avoid the selection of all items for all authors, as it will not be acceptable).
Article Type: Analytical Review |
Subject:
Reproduction
Received: 2017/04/4 | Accepted: 2017/10/21 | Published: 2018/11/22
Received: 2017/04/4 | Accepted: 2017/10/21 | Published: 2018/11/22
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