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Structural disorders of the sperm chromatin. Pathophysiological aspects. Clinical relevance

https://doi.org/10.21886/2308-6424-2021-9-1-95-104

Abstract

The review provides an analysis of domestic and foreign sources devoted to the study of the sperm chromatin structure. The pathogenetic pathways of the sperm DNA fragmentation formation are described. The relationship between sperm DNA damage in pregnancy, live birth rate and the recurrent pregnancy losses in the assisted reproductive technique are presented. The prognostic determination's value of the sperm DNA fragmentation in male infertility cases is noted.

For citation:


Korshunov M.N., Korshunova E.S., Kyzlasov P.S., Korshunov D.M., Darenkov S.P. Structural disorders of the sperm chromatin. Pathophysiological aspects. Clinical relevance. Vestnik Urologii. 2021;9(1):95-104. (In Russ.) https://doi.org/10.21886/2308-6424-2021-9-1-95-104

Introduction

One in five couples in Western countries and one in four in the world suffer from infertility. According to WHO data, approximately 15% of sexually active couples seek help because of their inability to get pregnant during 12 months of regular sexual activity without contraception; 5% of them still do not have the opportunity to have biological children after treatment [1].

The infertility rate in Russia exceeds 17%. There has been a decrease in the birth rate in the Russian Federation since 2015 according to the Federal State Statistics Service. The number of Russians who died exceeded the number of those who were born in 2017-2018. The birth rate in 2018 equaled 10.7 births per 1000 people, ranking 184th in the world [2]. Thus, infertile marriage is considered to be an important medical, biological, and social problem.

The frequency of the male factor in the structure of infertile marriage is 20 ‒ 50% [1][3]. A mandatory laboratory test semen analysis is usually recommended to assess the fertility potential of a man. However, the results of the analysis reflecting quantitative and qualitative indicators of spermatogenesis are not an absolute predictor of the pregnancy probability and the birth of a healthy child [4].

The so-called non-web diagnostic tools that allow optimizing the process of overcoming infertility (to increase the frequency of pregnancy and childbirth) are getting more relevant ― under the conditions of natural impregnation and use of assisted reproductive technologies (ART). One such study is the determination of DNA fragmentation of sperm cells (DFSCC) [4][5][6][7].

Violation of DNA integrity is an indicator of cell damage which is considered to be a universal indicator of cellular lethality [6].

The structure of the sperm cell genome is recognized as a more accurate biological marker of male fertility since intact DNA is required for the transmission of healthy genetic material [5][6][7][8]. Therefore, the important role of natural selection is lost due to the widespread use of ART, the use of the intracytoplasmic sperm injection into the ovum (ICSI). This increases the risks of fertilization of the oocyte by a sperm with damaged chromatin and can possibly lead to the transmission of genetic defects and spontaneous abortions [5][7][6][7][8][9].

History of the DFSC study. Diagnostic tools

The beginning of the fundamental study of the sperm genome may be attributed to the middle of the twentieth century. Pollister and Mirsky discovered in 1946 that most of the protein complexes surrounding the DNA of trout sperm cells were represented by protamines [10].

A breakthrough associated with the discovery of the DNA duplex was made in 1953 [11]. Therefore, Watson and Crick were awarded the Nobel Prize for this contribution. In the same year, Leuchtenberger et al. published a work, which demonstrated that the structure of sperm cell DNA in infertile patients had large variations while compared with fertile men. The authors concluded that the assessment of the ejaculate quality should not be limited to the indicators of the number and motility of sperm cells [12].

The results of an experimental work by Alfert (1976) showed that in the post-meiotic phase of spermatogenesis, histones were replaced by protamines in nuclear chromatin [13].

The above studies marked the beginning of a continuous process of studying the sperm genome structure.

The Acridine Orange test (AO) was developed based on the sensitivity of damaged and undamaged DNA to acid denaturation. The ejaculate smears are fixed with a solution of methanol-acetic acid and stained with acridine orange (fluorochrome) after drying with atmospheric air. The more breaks in the chromatin structure are detected, the more active the denaturation will be. Therefore, a large proportion of the DNA will pass from the double-stranded form to the single-stranded one. The advantages of this method are economic accessibility and the minimal manipulative action with cells. However, the duration of the analysis leads to artifacts of the obtained results. This limits the use of AO in the research practice [14, 15].

The 1980s were marked by the development of molecular biology technologies. Evenson et al. developed a test for the detection of DFSC by flow cytometry. This analysis was called the Sperm Chromatin Structure Assay (SCSA). Sperm DNA is denatured with acid at the sites of DNA strand breaks and stained with the fluorescent cationic dye ― acridine orange. Such a test makes it possible to determine single- and double-stranded DNA breaks. It also helps to identify the percentage of sperm cells with an immature nucleus that possesses an abnormal chromatin structure [16].

A new diagnostic tool “Comet Assau” was introduced in the 1990s. It allows determining the content of high- and low-molecular-weight DNA according to the area of the latter, which resembles the tail of a comet, obtained by the mini-electrophoresis of cells. Literature data indicate a high clinical and diagnostic value of this test [17].

The DFSC identification by TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) is based on direct labeling of breaks with fluorochrome and measurement of luminescence intensity. Terminal deoxynucleotidyl transferase indicates single- and double-stranded DNA damage. Various clinical observations demonstrated high sensitivity of the TUNEL method [5][6][7][8][18].

An indirect method for DFSC identification is the sperm chromatin dispersion test (SCD). The dispersed DNA is viewed as a halo surrounding the nucleus through using specific DNA fluorochromes and a fluorescent microscope. If the DNA is fragmented, there is a small dispersion, resulting in a small “halo”. A special feature of SCD is the possibility of dividing cells into categories according to the degree of DFSC, depending on the intensity of the glow [19].

The SCD modification (Halosperm kit) is based on the properties of the chromatin density of sperm cells, which allows evaluating the results of microscopy in a light field with the possibility of identifying an intact tail. This facilitates the differentiation of male gametes from other cell types found in the ejaculate [20].

Li et al. developed the ɣH2AX analysis for determining double-stranded breaks in the gamete DNA in 2006. The results of clinical work demonstrated a significant correlation between the values of ɣH2AX and the frequency of pregnancy. This technique turned out to be labor-intensive and time-consuming to perform [21].

DW1 is a method for determining single- and double-stranded breaks in the DNA of sperm cells. It is based on the use of a synthetic peptide consisting of 21 amino acids and bound with the fluorescent dye ― rhodamine B. The further improvement of this technique, according to the authors, will allow the selection of gametes with intact DNA to perform the ICSI procedure, although the detergent removes the sperm membrane [22][23].

Gametogenesis. Chromatin condensation. DFSC mechanisms

Reproductive gametes are highly differentiated cells with a definitive ultrastructural morphology that makes their DNA compact and protected from damaging factors.

The genome damage can occur during spermatogenesis, spermiogenesis, transit through the sperm ducts, or after ejaculation [3][24][25][26]. The types of structural changes in sperm cells chromatin are represented by DFSC, nuclear protein defects, and rearrangements of the sequence of DNA sections [5][24][27][28][29].

Specific changes in chromatin at different stages of spermatogenesis (premeiotic, meiotic, post-meiotic) may turn out to be a source of DNA breaks [5][24][27][28][29].

The spermatogonial cell undergoes mitotic division during the premeiotic proliferative phase, as a result, one of the daughter cells remains a stem one, and the other enters the path of spermatogenesis. Therefore, active DNA synthesis occurs during this period [24][27][28].

Chromosomes undergo a process of homologous recombination in the pachytene of meiosis, and somatic histones are replaced by testis-specific ones. At this stage, the unformed gametes are particularly sensitive to external toxicants, and unrepaired DNA changes may be fixed after replication in the form of mutations [24][25][26][28][29][30].

Chromatin remodeling occurs in the post-meiotic haploid phase, which is associated with the loss of histones and their replacement with specific transient proteins. The latter ones are subsequently replaced by protamines ― arginine-rich proteins bound by disulfide bonds. This leads to chromatin thickening. At this stage, the DNA breaks are repaired by the remodeling, but some of them remain unrepaired, resulting in DFSC [24][25][26][27][28][30].

The sperm cell DNA is 85 ‒ 90% represented by protamines. The remaining 10 ‒ 15% of the elements are histones. This ensures the availability of chromatin for transcription during ovum fertilization [24][25][26][28][29][30].

The remodeling of sperm chromatin leads to the production of temporary nicks in the DNA. The trigger mechanism is the modification of histones, namely, specific methylation, acetylation, phosphorylation, ubiquitinylation, and hyperacetylation [24][25][28][29][30].

The activation of endogenous nucleases (topoisomerase ― types I and II) catalyzes the unwinding of the DNA chain, breaks of the superspiral with a subsequent repair. Topoisomerase I induces multiple single-and double-stranded breaks in the sperm chromosomes. This allows solving the problem of DNA supercoiling and facilitates the removal of histones during protamination. Topoisomerase II is the main enzyme during the DNA repair in elongated spermatids. It is inhibited by the polyenzyme (ADP-ribose-polymerase), which is, in turn, activated due to the DNA breaks. Apoptosis is used to eliminate cells with unrepaired DNA [24][25][26][28][29].

The beginning of chromatin condensation is accompanied by an increase in the number of DNA breaks, which are then repaired, and their ligation is provided by embedded transition nuclear protein (TNP) TP1 ‒ TP4. They bind to DNA, promoting the interaction with protamines. Their function is to facilitate the remodeling and condensation of chromatin, the repair of DNA breaks [24][25][26][29]. Thiol groups of protamines are oxidized at the final stage of compaction (during the process of epididymal transport of sperm cells). It forms numerous internal and external disulfide bonds between cysteine residues, they compact the chromatin and stabilize the sperm nucleus. It plays an important role in the formation of the sperm cell head, inactivation of genome transcription, protection and stabilization of DNA [24, 25, 26, 29]. Temporary nicks are restored until the completion of spermatogenesis. Otherwise, an extra piece of DNA may appear in the sperm. The unrepaired DNA breaks that occur during chromatin remodeling are considered as one of the main sources of DFSC, and their presence indicates incomplete spermatogenesis.

One of the mechanisms of sperm DNA damage is abortive (incomplete) apoptosis during spermatogenesis. The elimination of germ cells with various disorders and injuries occurs with the help of apoptosis, which is a physiological process [5][24][25][26][27]. It is assumed that apoptosis can perform two functions – numerical restriction of the spermatogonial cell population and selective death of abnormal sperm cells. The mechanism of apoptosis in spermiogenesis is less associated with cell death, but it also plays a significant role in the process of cytoplasm separation at the last stages of sperm maturation. Therefore, the suppression of this process due to various reasons can lead to the risks of DFSC [5][24][25][26][28][29][30].

The presence of apoptotic bodies (testicular origin) in the sperm of an infertile patient indicates that apoptosis is triggered mainly in the testicle [24][31]. However, the detection of more fragmented DNA in ejaculatory sperm cells, in comparison with testicular sperm cells, indicates the possible presence of apoptotic stimuli during the transit of gametes along the sperm ducts [24][27][28][29][31].

Thus, the chromatin of male gametes has a unique ultrastructure formed by complex biochemical processes. The superspiralization of sperm cell DNA provides stability, transcriptional inertia, and protection during passage through the sperm ducts.

Oxidative stress (OS). Antioxidant system

The role of OS in the pathogenesis of DFSC has been established by numerous studies [3, 4, 6, 32, 33]. The reactive oxygen species (ROS) belong to the class of free radicals (FRs). Being highly reactive oxidants, they are continuously generated in the process of cell metabolism and are required in physiological quantities for chromatin condensation, acrosome reaction formation, and sperm hyperactivation [5, 24, 32, 33, 34, 35].

The immature gametes, neutrophilic white blood cells, and structurally altered sperm cells are considered to be the main sources of FRs in sperm. The retention of residual cytoplasm can also lead to the hyperproduction of ROS.

Normally, the genome of sperm cells is protected from damage by dense DNA packaging and the antioxidant system of seminal plasma. The excessive OS is a consequence of the imbalance between the production of ROS and seed antioxidants [5, 24, 32, 33, 34, 35].

The seed antioxidant system is represented by non-enzymatic (vitamins A, C, E, ascorbate, pyruvate, glutathione, glycine, zinc, etc.) and enzymatic antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT)) [32, 33, 34, 35].

The balance of the oxidative profile is determined by the activities of SOD, GPX, CAT, and the biomarker of lipid peroxidation (LP) — malondialdehyde [32, 33]. The lack of antioxidants and the increased concentration of malondialdehyde correlate with DFSC [32].

In contrast to somatic cells, reproductive cells are more vulnerable to LP due to the lack of the necessary cytoplasmic enzyme repair system. In addition, the cytoplasmic membrane contains a large amount of polyunsaturated fatty acids and membrane-bound Nicotinamide Adenosine Dinucleotide Phosphate (NADPH)-oxidase 5, which makes gametes susceptible to ROS attacks. The consequence of excessive OS is a violation of the membrane integrity, which ultimately leads to a decrease in the mobility and fertilizing ability of sperm cells [5, 24, 32, 33, 34, 35]. The damage to the FR genome can manifest itself in the form of chromatin denaturation, base modification, point mutations, gene polymorphism, deletions, reading frame shift, single- and double-stranded breaks in DNA strands [5, 24, 32, 33, 34, 35].

Etiology of DFSC

The damage to the structure of sperm cell chromatin is polyethiological in nature. The main causes are recognized as varicocele [36, 37], older paternal age [38, 39, 40], infectious and inflammatory diseases of the reproductive tract [41], ionizing radiation, sexual abstinence, Wi-Fi waves influence [5, 42], chemo-and radiotherapy, oncological processes, contact with heavy metals, metabolic disorders, diabetes, gametotoxic drugs [43], spinal cord injuries, hyperthermia [5]. The negative effect of smoking and excessive alcohol consumption on chromatin integrity was established [5, 36] as well. According to Boeri et al., the presence of human papillomavirus in the ejaculate may negatively affect sperm motility and be a risk factor for DFSC [44].

It is important to note that in subfertile men, the risk of increased DFSC is directly proportional to the severity of pathospermia [29].

Up to 20% of cases of idiopathic infertility can be associated with DFSC. The frequency of detection of chromatin structure disorders in normozoospermia, including sperm donors, ranges from 0 to 25% [4, 5]. The breadth of this range can be explained by national and ethnic affiliation, age, requirements for somatic status, terms of sexual abstinence, and differences in methods for determining DFSC.

The damage to the sperm genome is possible while manipulating actions with the ejaculate in ART laboratories (cryopreservation, storage conditions of biomaterial, violations of the procedure for collecting, filling and pretreatment of sperm). The spermoplasm is rich in antioxidants, vitamins, trace elements, and enzymes and it is removed while washing the sperm. The centrifugation and prolonged incubation of sperm cells increase the likelihood of aggressive action of FR on DNA. This is particularly important, since the fresh or thawed sperm cells used in ART procedures may possess a damaged chromatin structure [45].

Clinical relevance of DFSC

The ovum can repair up to 8% of sperm DNA damage. However, error-based repair results in point mutations and deletions. The oocytes may be subject to an “oxidative attack” by sperm cells during natural conception or intrauterine insemination/in vitro fertilization (IVF) procedures. This may lead to impaired ovum functionality and loss of compensatory mechanisms for restoring mechanical chromatin defects. Double-chain injuries are almost impossible to be repaired unlike single-chain breaks [7, 8, 24, 46, 47, 48].

The high fragmentation of gametes can be one of the reasons for a decrease in a man's fertility potential, which leads to difficulties in achieving a natural pregnancy. In addition, there may be violations of embryonic development, stopping and elimination of the embryo at the early stages of embryo- and ontogenesis. The frequency of spontaneous termination of pregnancy reaches 40% with a high percentage of DFSC, and at standard values, the risks of habitual miscarriage are reduced to 10% [6, 7, 8, 24, 46, 47, 48, 49].

Neubourg et al. published the data of a systematic literature review on the assessment of the DFSC indicator significance in predicting the clinical outcome of intrauterine insemination. The work included nine studies for qualitative analysis and four for meta-analysis (940 cycles). A low correlation was found between the values of DFSC and the frequency of pregnancy. The combined sensitivity and specificity of the analysis were 94% (95% CI: 0.88; 0.97) and 19% (95% CI: 0.14; 0.26), respectively. The conclusion was made about the limited value of DFSC in evaluating the effectiveness of intrauterine insemination programs. The authors noted the need for further observations to assess the threshold values, the stability of the DFSC index in the time interval, as well as the effect of ejaculate processing and density gradient centrifugation on chromatin integrity [50].

The literature data indicate that under in vitro conditions during IVF and ICSI procedures, a high DFSC index is associated with risks of impaired embryogenesis during cultivation: with abortion, fragmentation, and poor embryo quality. This reduces the likelihood of implantation and clinical pregnancy [6, 7, 8, 46, 48, 49]. However, sperm cells with DNA damage retain the ability to fertilize. This fact explains the effect of fertilization in ART programs. However, the risk of spontaneous abortions in this case significantly increases, both when performing the IVF procedure and selection by the ICSI method [7, 8, 24, 46, 47, 48, 49, 51].

The increased DFSC is a risk factor for the development of fetal birth defects, chromosomal disorders in children, possible delay in physical and mental development, and predisposition to cancer [52]. Jin et al. described the risks of lymphomas and leukemia development in children born to fathers considered to be “long-term smokers”. Therefore, a direct relationship between tobacco smoking and disorders of the sperm chromatin structure was established [53].

Conclusion

The data from the literature review indicate the diagnostic value of determining DFSC in various forms of infertility, including habitual miscarriage. However, the introduction of gamete DNA integrity tests into routine clinical practice often requires expensive equipment and trained staff. In addition, an important problem is the lack of reliable, clinically significant threshold values of DFSC while using certain detection methods.

The above-mentioned information highlights the need to optimize the standard of male infertility screening (including miscarriage) to increase the global birth rate.

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About the Authors

M. N. Korshunov
Central State Medical Academy, The Administrative Directorate of the President of the Russian Federation
Russian Federation

Maxim N. Korshunov — M.D., Cand.Sc.(M); Assoc. Prof. (Docent), Dept. of Urology, Central State Medical Academy.

121359, Moscow, 19 bldg. 1A Marshal Tymoshenko st. ; tel.: +7 (905) 749 64-57


Competing Interests: no conflict of interest


E. S. Korshunova
Central State Medical Academy, The Administrative Directorate of the President of the Russian Federation; Research Center of Neurology; A.I. Yevdokimov Moscow State University of Medicine and Dentistry
Russian Federation

Ekaterina S. Korshunova — M.D., Cand.Sc.(M); Assoc. Prof. (Docent), Central Medical Academy Administration of the President of Russian Federation; Physician, Research Center of Neurology; Physician, A.I. Yevdokimov MSUMD.

121359, Moscow, 19 bldg. 1A Marshal Tymoshenko st.; 125367, Moscow, 80 Volokolamskoe hwy; 127473, Moscow, 20 bldg. 1 Delegatskaya st.


Competing Interests: no conflict of interest


P. S. Kyzlasov
State Research Center of the Russian Federation - A. I. Burnazyan Federal Medical Biophysical Center
Russian Federation

PavelS. Kyzlasov — M.D., Dr.Sc.(M); Prof., Dept. of Urology and Andrology.

123098, Moscow, 23 Marshal Novikov st.


Competing Interests: no conflict of interest


D. M. Korshunov
A.I. Yevdokimov Moscow State University of Medicine and Dentistry
Russian Federation

Danila M. Korshunov — Student.

127473, Moscow, 20 bldg. 1 Delegatskaya st.


Competing Interests: no conflict of interest


S. P. Darenkov
Central State Medical Academy, The Administrative Directorate of the President of the Russian Federation
Russian Federation

Sergey P. Darenkov — M.D., Dr.Sc.(M); Full Prof.; Head, Dept. of Urology.

121359, Moscow, 19 bldg. 1A Marshal Tymoshenko st.


Competing Interests: no conflict of interest


For citation:


Korshunov M.N., Korshunova E.S., Kyzlasov P.S., Korshunov D.M., Darenkov S.P. Structural disorders of the sperm chromatin. Pathophysiological aspects. Clinical relevance. Vestnik Urologii. 2021;9(1):95-104. (In Russ.) https://doi.org/10.21886/2308-6424-2021-9-1-95-104

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