Male Infertility: From Genes to Genomes 2022

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 29224

Special Issue Editors


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Guest Editor Assistant
Department of Biochemistry and Biotechnology, University of Thessaly, 41221 Larissa, Greece
Interests: male infertility; animal genomics; evolution; genetics; non-coding RNAs

Special Issue Information

Dear Colleagues,

According to the WHO, infertility is the inability to conceive after at least 12 months of regular, unprotected sexual intercourse. It is an alarming global health issue, as it is estimated that 8–12% of couples of reproductive age suffer from infertility. The male factor interestingly contributes to 50% of all cases.

Male infertility is a complex disorder caused by interplay between genetic and environmental factors. A large proportion of male infertility cases are also idiopathic. Semen analysis remains the cornerstone for its diagnosis; however, today, in the era of genomics, next-generation sequencing (NGS) technologies, such as whole-exome and genome sequencing, offer the opportunity to simultaneously study numerous genes and identify new biomarkers. Additionally, it is estimated that approximately 10% of the human genome is involved in reproduction. Discoveries pertaining to the role of small RNAs and microRNAs in the spermatogenesis process are promising for the understanding of the mechanisms behind male infertility.

Thus, this Special Issue of Genes, entitled “Male Infertility: From Genes to Genomes”, aims to contribute to the identification of new genetic variants and genetic risk alleles associated with male infertility, as well as to provide readers with updated information regarding recent advances in the field. In this regard, original research articles and reviews are both welcome.

Prof. Dr. Zissis Mamuris
Guest Editor
Maria-Anna Kyrgiafini
Guest Editor Assistant

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Keywords

  • male infertility
  • biomarkers
  • semen analysis
  • spermatogenesis
  • genetic variants
  • next-generation sequencing (NGS)

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

4 pages, 202 KiB  
Editorial
Male Infertility: From Genes to Genomes 2022
by Maria-Anna Kyrgiafini and Zissis Mamuris
Genes 2023, 14(5), 959; https://doi.org/10.3390/genes14050959 - 23 Apr 2023
Cited by 4 | Viewed by 1661
Abstract
Infertility is defined as the inability to conceive after at least 12 months of regular, unprotected sexual intercourse and it is considered an alarming global health issue [...] Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)

Research

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15 pages, 1982 KiB  
Article
Semen Thresholds of Normality Established by the WHO Do Not Reveal Genome Instability—A Potential Occult Male Factor
by Usha Punjabi, Ilse Goovaerts, Kris Peeters and Diane De Neubourg
Genes 2023, 14(2), 239; https://doi.org/10.3390/genes14020239 - 17 Jan 2023
Cited by 1 | Viewed by 1912
Abstract
Semen parameters are unable to inform on the function or fertilizing capacity of the male gamete. Standardized methods are provided by the WHO but, the lower reference limits have reduced sensitivity to predict chances of conception. Subfertile men may be falsely classified as [...] Read more.
Semen parameters are unable to inform on the function or fertilizing capacity of the male gamete. Standardized methods are provided by the WHO but, the lower reference limits have reduced sensitivity to predict chances of conception. Subfertile men may be falsely classified as “normal” and a male factor contributing to genome instability may be overlooked. Semen parameters, sperm DNA fragmentation (SDF), sperm chromatin maturity and stability, and sperm aneuploidy were assessed in fertile (F), subfertile normozoospermic (SN) and subfertile non-normozoospermic males (SN-N). Standardized assays employing flow cytometry were used to detect genome instability. Sperm DNA fragmentation did not differ significantly whether the semen samples were from a fertile (F), subfertile normozoospermic (SN) or subfertile non-normozoospermic male (SN-N). Chromatin decondensation was significantly reduced and hyperstability significantly increased in the SN group as compared to the F group. The frequency of diploidy was significantly different in the three study groups with significance between F and SN and between F and SN-N groups. Subfertile men with normal semen parameters are often excluded from extensive genetic testing. Genome instability might be an independent attribute of semen quality detecting problems not seen with semen analysis alone. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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15 pages, 7036 KiB  
Article
Absence of Testicular Estrogen Leads to Defects in Spermatogenesis and Increased Semen Abnormalities in Male Rabbits
by Aurélie Dewaele, Emilie Dujardin, Marjolaine André, Audrey Albina, Hélène Jammes, Frank Giton, Eli Sellem, Geneviève Jolivet, Eric Pailhoux and Maëlle Pannetier
Genes 2022, 13(11), 2070; https://doi.org/10.3390/genes13112070 - 8 Nov 2022
Cited by 6 | Viewed by 1787
Abstract
Estrogens are steroid hormones produced by the aromatization of androgens by the aromatase enzyme, encoded by the CYP19A1 gene. Although generally referred to as “female sex hormones”, estrogen is also produced in the adult testes of many mammals, including humans. To better understand [...] Read more.
Estrogens are steroid hormones produced by the aromatization of androgens by the aromatase enzyme, encoded by the CYP19A1 gene. Although generally referred to as “female sex hormones”, estrogen is also produced in the adult testes of many mammals, including humans. To better understand the function of estrogens in the male, we used the rabbit model which is an important biomedical model. First, the expression of CYP19A1 transcripts was localized mainly in meiotic germ cells. Thus, testicular estrogen appears to be produced inside the seminiferous tubules. Next, the cells expressing ESR1 and ESR2 were identified, showing that estrogens could exert their function on post-meiotic germ cells in the tubules and play a role during sperm maturation, since ESR1 and ESR2 were detected in the cauda epididymis. Then, CRISPR/Cas9 CYP19A1−/− genetically modified rabbits were analyzed. CYP19A1−/− males showed decreased fertility with lower sperm count associated with hypo-spermatogenesis and lower spermatid number. Germ/sperm cell DNA methylation was unchanged, while sperm parameters were affected as CYP19A1−/− males exhibited reduced sperm motility associated with increased flagellar defects. In conclusion, testicular estrogens could be involved in the spermatocyte–spermatid transition in the testis, and in the acquisition of sperm motility in the epididymis. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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21 pages, 2267 KiB  
Article
Whole-Genome Profile of Greek Patients with Teratozοοspermia: Identification of Candidate Variants and Genes
by Maria-Anna Kyrgiafini, Themistoklis Giannoulis, Alexia Chatziparasidou, Nikolaos Christoforidis and Zissis Mamuris
Genes 2022, 13(9), 1606; https://doi.org/10.3390/genes13091606 - 8 Sep 2022
Cited by 3 | Viewed by 1839
Abstract
Male infertility is a global health problem that affects a large number of couples worldwide. It can be categorized into specific subtypes, including teratozoospermia. The present study aimed to identify new variants associated with teratozoospermia in the Greek population and to explore the [...] Read more.
Male infertility is a global health problem that affects a large number of couples worldwide. It can be categorized into specific subtypes, including teratozoospermia. The present study aimed to identify new variants associated with teratozoospermia in the Greek population and to explore the role of genes on which these were identified. For this reason, whole-genome sequencing (WGS) was performed on normozoospermic and teratozoospermic individuals, and after selecting only variants found in teratozoospermic men, these were further prioritized using a wide range of tools, functional and predictive algorithms, etc. An average of 600,000 variants were identified, and of them, 61 were characterized as high impact and 153 as moderate impact. Many of these are mapped in genes previously associated with male infertility, yet others are related for the first time to teratozoospermia. Furthermore, pathway enrichment analysis and Gene ontology (GO) analyses revealed the important role of the extracellular matrix in teratozoospermia. Therefore, the present study confirms the contribution of genes studied in the past to male infertility and sheds light on new molecular mechanisms by providing a list of variants and candidate genes associated with teratozoospermia in the Greek population. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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12 pages, 2792 KiB  
Article
Hyaluronidase 6 Does Not Affect Cumulus–Oocyte Complex Dispersal and Male Mice Fertility
by Hyewon Bang, Sujin Lee, Pil-Soo Jeong, Dong-Won Seol, Daeun Son, Young-Hyun Kim, Bong-Seok Song, Bo-Woong Sim, Soojin Park, Dong-Mok Lee, Gabbine Wee, Joon-Suk Park, Sun-Uk Kim and Ekyune Kim
Genes 2022, 13(5), 753; https://doi.org/10.3390/genes13050753 - 25 Apr 2022
Cited by 1 | Viewed by 1916
Abstract
Glycosylphosphatidylinositol-anchored sperm hyaluronidases (HYAL) assist sperm penetration through the cumulus–oocyte complex (COC), but their role in mammalian fertilization remains unclear. Previously, we demonstrated that sperm from HYAL 5 and 7 double-knockout (dKO) mice produced significantly less offspring than sperm from wild-type mice due [...] Read more.
Glycosylphosphatidylinositol-anchored sperm hyaluronidases (HYAL) assist sperm penetration through the cumulus–oocyte complex (COC), but their role in mammalian fertilization remains unclear. Previously, we demonstrated that sperm from HYAL 5 and 7 double-knockout (dKO) mice produced significantly less offspring than sperm from wild-type mice due to defective COC dispersal. However, the HYAL6 gene remained active in the sperm from the dKO mice, indicating that they were not entirely infertile. This study explored the role of HYAL6 in fertilization by analyzing HYAL6-mutant mice. In this mouse model, HYAL5 and HYAL7 were present in the HYAL6-knockout sperm, and they could disperse hyaluronic acid. We found that HYAL6 was present on the surface of sperm. However, male mice lacking the HYAL6 gene had normal fertility, testicular integrity, and sperm characteristics. Furthermore, in vitro fertilization assays demonstrated that HYAL6-deficient epididymal sperm functioned normally. Therefore, HYAL6 is dispensable for fertilization. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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13 pages, 2870 KiB  
Article
Changes in Expression of Specific mRNA Transcripts after Single- or Re-Irradiation in Mouse Testes
by Kenta Nagahori, Ning Qu, Miyuki Kuramasu, Yuki Ogawa, Daisuke Kiyoshima, Kaori Suyama, Shogo Hayashi, Kou Sakabe, Takayuki Yoshimoto and Masahiro Itoh
Genes 2022, 13(1), 151; https://doi.org/10.3390/genes13010151 - 15 Jan 2022
Cited by 4 | Viewed by 2207
Abstract
Alkylating agents and irradiation induce testicular damage, which results in prolonged azoospermia. Even very low doses of radiation can significantly impair testis function. However, re-irradiation is an effective strategy for locally targeted treatments and the pain response and has seen important advances in [...] Read more.
Alkylating agents and irradiation induce testicular damage, which results in prolonged azoospermia. Even very low doses of radiation can significantly impair testis function. However, re-irradiation is an effective strategy for locally targeted treatments and the pain response and has seen important advances in the field of radiation oncology. At present, little is known about the relationship between the harmful effects and accumulated dose of irradiation derived from continuous low-dose radiation exposure. In this study, we examined the levels of mRNA transcripts encoding markers of 13 markers of germ cell differentiation and 28 Sertoli cell-specific products in single- and re-irradiated mice. Our results demonstrated that re-irradiation induced significantly decreased testicular weights with a significant decrease in germ cell differentiation mRNA species (Spo11, Tnp1, Gfra1, Oct4, Sycp3, Ddx4, Boll, Crem, Prm1, and Acrosin). In the 13 Sertoli cell-specific mRNA species decreased upon irradiation, six mRNA species (Claudin-11,Espn, Fshr, GATA1, Inhbb, and Wt1) showed significant differences between single- and re-irradiation. At the same time, different decreases in Sertoli cell-specific mRNA species were found in single-irradiation (Aqp8, Clu, Cst12, and Wnt5a) and re-irradiation (Tjp1, occludin,ZO-1, and ZO-2) mice. These results indicate that long-term aspermatogenesis may differ after single- and re-irradiated treatment. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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14 pages, 1459 KiB  
Article
Yeast Two-Hybrid Screen Identifies PKA-Riα Interacting Proteins during Mouse Spermiogenesis
by Kunyu Shi, Lele Yang, Xueqing Zhuang, Lan Zhang and Huayu Qi
Genes 2021, 12(12), 1941; https://doi.org/10.3390/genes12121941 - 30 Nov 2021
Cited by 2 | Viewed by 2908
Abstract
cAMP-dependent protein kinase (PKA) signaling plays various roles during mammalian spermatogenesis, ranging from the regulation of gene expression to the modulation of sperm motility. However, the molecular mechanisms that govern the multifaceted functions of PKA during spermatogenesis remain largely unclear. We previously found [...] Read more.
cAMP-dependent protein kinase (PKA) signaling plays various roles during mammalian spermatogenesis, ranging from the regulation of gene expression to the modulation of sperm motility. However, the molecular mechanisms that govern the multifaceted functions of PKA during spermatogenesis remain largely unclear. We previously found that PKA regulatory subunit I α (RIα) and catalytic subunit α (Cα) co-sediment with polyribosomal fractions of mouse testis lysate on sucrose gradient and the stimulation of PKA activity facilitates protein synthesis in post-meiotic elongating spermatids, indicating that type I PKA is intricately associated with protein translation machinery and regulates protein synthesis during mouse spermiogenesis. Since PKA activity is often regulated by interacting proteins that form complexes with its regulatory subunits, the identification of PKA-RIα interacting proteins in post-meiotic spermatogenic cells will facilitate our understanding of its regulatory roles in protein synthesis and spermiogenesis. In the present study, we applied a yeast two-hybrid screen to identify PKA-Riα-binding proteins using a cDNA library generated from mouse round and elongating spermatids. Numerous proteins were found to potentially interact with PKA-RIα, including proteostasis modulators, metabolic enzymes, cytoskeletal regulators, and mitochondrial proteins, many of which are specifically expressed in testes. Consistently, the examination of MENA (mouse ENA/VASP homolog) in developing mouse testes suggested that post-meiotic spermatogenic cells express a short isoform of MENA that interacts with PKA-RIα in yeast two-hybrid assay. The identification of PKA-RIα interacting proteins provides us solid basis to further explore how PKA signaling regulates protein synthesis and cellular morphogenesis during mouse spermatogenesis. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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Review

Jump to: Editorial, Research

23 pages, 1197 KiB  
Review
Impact of Advanced Paternal Age on Fertility and Risks of Genetic Disorders in Offspring
by Aris Kaltsas, Efthalia Moustakli, Athanasios Zikopoulos, Ioannis Georgiou, Fotios Dimitriadis, Evangelos N. Symeonidis, Eleftheria Markou, Theologos M. Michaelidis, Dung Mai Ba Tien, Ioannis Giannakis, Eleni Maria Ioannidou, Athanasios Papatsoris, Panagiota Tsounapi, Atsushi Takenaka, Nikolaos Sofikitis and Athanasios Zachariou
Genes 2023, 14(2), 486; https://doi.org/10.3390/genes14020486 - 14 Feb 2023
Cited by 27 | Viewed by 10638
Abstract
The average age of fathers at first pregnancy has risen significantly over the last decade owing to various variables, including a longer life expectancy, more access to contraception, later marriage, and other factors. As has been proven in several studies, women over 35 [...] Read more.
The average age of fathers at first pregnancy has risen significantly over the last decade owing to various variables, including a longer life expectancy, more access to contraception, later marriage, and other factors. As has been proven in several studies, women over 35 years of age have an increased risk of infertility, pregnancy problems, spontaneous abortion, congenital malformations, and postnatal issues. There are varying opinions on whether a father’s age affects the quality of his sperm or his ability to father a child. First, there is no single accepted definition of old age in a father. Second, much research has reported contradictory findings in the literature, particularly concerning the most frequently examined criteria. Increasing evidence suggests that the father’s age contributes to his offspring’s higher vulnerability to inheritable diseases. Our comprehensive literature evaluation shows a direct correlation between paternal age and decreased sperm quality and testicular function. Genetic abnormalities, such as DNA mutations and chromosomal aneuploidies, and epigenetic modifications, such as the silencing of essential genes, have all been linked to the father’s advancing years. Paternal age has been shown to affect reproductive and fertility outcomes, such as the success rate of in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), and premature birth rate. Several diseases, including autism, schizophrenia, bipolar disorders, and paediatric leukaemia, have been linked to the father’s advanced years. Therefore, informing infertile couples of the alarming correlations between older fathers and a rise in their offspring’s diseases is crucial, so that they can be effectively guided through their reproductive years. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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13 pages, 321 KiB  
Review
A Systematic Review of the Impact of Mitochondrial Variations on Male Infertility
by Houda Amor and Mohamad Eid Hammadeh
Genes 2022, 13(7), 1182; https://doi.org/10.3390/genes13071182 - 30 Jun 2022
Cited by 8 | Viewed by 3345
Abstract
According to current estimates, infertility affects one in four couples trying to conceive. Primary or secondary infertility can be due either to both partners or only to the man or the woman. Up to 15% of infertility cases in men can be attributed [...] Read more.
According to current estimates, infertility affects one in four couples trying to conceive. Primary or secondary infertility can be due either to both partners or only to the man or the woman. Up to 15% of infertility cases in men can be attributed to genetic factors that can lead to irreversible partial or complete spermatogenic arrest. The increased use of assisted reproductive technology (ART) has provided not only insights into the causes of male infertility but also afforded a diagnostic tool to detect and manage this condition among couples. Genes control a variety of physiological attributes, such as the hypothalamic–pituitary–gonadal axis, development, and germ cell differentiation. In the era of ART, it is important to understand the genetic basis of infertility so as to provide the most tailored therapy and counseling to couples. Genetic factors involved in male infertility can be chromosome abnormalities or single-gene disorders, mitochondrial DNA (mtDNA) mutations, Y-chromosome deletions, multifactorial disorders, imprinting disorders, or endocrine disorders of genetic origin. In this review, we discuss the role of mitochondria and the mitochondrial genome as an indicator of sperm quality and fertility. Full article
(This article belongs to the Special Issue Male Infertility: From Genes to Genomes 2022)
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