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Biomedicines
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Molecular and Genetic Bases of Infertility
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Molecular and Genetic Bases of Infertility

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 11294

Special Issue Editor

Dr. Ranjha Khan

E-Mail Website
Guest Editor
Department of Pediatrics, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA
Interests: male Infertility; female Infertility; non-obstructive azoospermia; abnormal sperm morphology; MMAF

Special Issue Information

Dear Colleagues,

Abnormalities in any step of spermatogenesis and oogenesis can cause spermatogenic and oogenic disorders, leading to infertility in both genders. Infertility affects approximately 10–15% of human couples of reproductive age trying to conceive. Hormonal imbalance, immunological factors, previous surgeries, childhood mumps, varicocele, and genetic factors can cause human infertility. Genetic factors account for approximately 30–50% of cases, most of which are idiopathic.  Interestingly, the human testicular and follicular transcriptome comprises more than 30,000 transcripts, and theoretically, defects in any of these genes could lead to infertility. However,  the genetic basis of human infertility remains largely unknown, which limits the treatment or targeted therapeutic options.  This Special Issue covers all the molecular bases of spermatogenesis, oogenesis in mouse models, and genetic diagnosis of human infertility.

Dr. Ranjha Khan
Guest Editor

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Keywords

  • human infertility
  • spermatogenesis
  • oogenesis
  • non-obstructive azoospermia
  • MMAF
  • teratozoospermia
  • POI

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Published Papers (6 papers)

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Research

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10 pages, 1968 KiB  
Article
The Identification of Molecular Ploidy Status of Abnormal Pronuclear Zygotes Reveals a Significant Number of Euploid Blastocysts Available for Conception
by Blair R. McCallie, Mary E. Haywood, Lauren N. Henry, Rachel M. Lee, William B. Schoolcraft and Mandy G. Katz-Jaffe
Biomedicines 2025, 13(1), 51; https://doi.org/10.3390/biomedicines13010051 - 28 Dec 2024
Viewed by 1127
Abstract
Objective: Abnormally fertilized embryos are often discarded during in vitro fertilization due to the fact that known chromosomal ploidy abnormalities lead to implantation failure or pregnancy loss. The objective of this study was to determine if pronuclear numeration (PN) observed at fertilization check [...] Read more.
Objective: Abnormally fertilized embryos are often discarded during in vitro fertilization due to the fact that known chromosomal ploidy abnormalities lead to implantation failure or pregnancy loss. The objective of this study was to determine if pronuclear numeration (PN) observed at fertilization check is representative of the true ploidy status of the subsequent developing blastocyst in order to maximize the number of viable embryos available for infertility patients and increase their chances of conception. Methods: Upon successful fertilization, pronuclear numeration was noted, and zygotes were cultured to the blastocyst stage. Biopsied trophectoderm cells were then lysed, and the isolated DNA was whole-genome amplified followed by library preparation. Next-generation sequencing was performed for PGT-A, and excess whole-genome amplified DNA was utilized for single nucleotide polymorphism beadchip array analysis. Results: At the time of fertilization check on day 1 of embryo development, when there were no visible pronuclei (n = 291), 56% of these 0PN blastocysts were confirmed to be diploid and normally fertilized. The remaining 41.9% were aneuploid, and 2.1% of the 0PN blastocysts contained only 23 haploid chromosomes. Upon analysis of the 1PN blastocysts (n = 217), just over a third (36.4%) only contained 23 haploid chromosomes (23XO), with another third (31.8%) identified as aneuploid, and surprisingly, the remaining third (31.8%) confirmed to be diploid and normally fertilized. In contrast, 50% of the 3PN blastocysts (n = 172) showed the presence of a third set of 23 parental chromosomes and were confirmed to be triploid (69XXY = 59.3% and 69XXX = 40.7%), with 41.9% identified as aneuploid and, interestingly, a small percentage (8.1%) confirmed to be diploid with normal fertilization. A very small proportion of biopsied blastocysts (0.63%) displaying the correct number of pronuclei for normal fertilization (2PN) were also identified as triploid with a third set of 23 parental chromosomes. To date, there have been 74 euploid embryo transfers from zygotes originally identified with an alternate pronuclear numeration, resulting in 16 ongoing pregnancies and 32 healthy live births, rates that match those typically observed with normally fertilized 2PN zygotes (>60%). Conclusions: A surprising number of blastocysts that were identified to have alternate pronuclear numeration at fertilization check on day 1 of embryo development were actually determined to be diploid with normal fertilization after molecular analysis. Accurate identification of haploid and tripoid zygotes is critical to prevent implantation failure and pregnancy loss and allows for the identification of all euploid embryos in a cohort, which has the potential to increase cumulative live birth rates for infertility patients. Full article
(This article belongs to the Special Issue Molecular and Genetic Bases of Infertility)
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17 pages, 289 KiB  
Article
CART (Cocaine- and Amphetamine-Regulated Transcript): A New Identified Intrafollicular Mediator in Ovulation Induction Protocols
by Charalampos Voros, Despoina Mavrogianni, Sofoklis Stavros, Myrto Papamentzelopoulou, Evangelia Dimitroulia, Dimitrios Doumplis, Dimitris Mathiopoulos and Dimitrios Loutradis
Biomedicines 2024, 12(11), 2598; https://doi.org/10.3390/biomedicines12112598 - 13 Nov 2024
Cited by 1 | Viewed by 834
Abstract
Background/Objectives: This study investigates the relationship between cocaine- and amphetamine-regulated transcript (CART) expression, leptin, and hormone profiles—specifically progesterone, testosterone, androstenedione, estradiol, follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG)—across four distinct ovulation induction protocols (HMG, HMG/hCG, rFSH, and rFSH/hCG). It also investigates the [...] Read more.
Background/Objectives: This study investigates the relationship between cocaine- and amphetamine-regulated transcript (CART) expression, leptin, and hormone profiles—specifically progesterone, testosterone, androstenedione, estradiol, follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG)—across four distinct ovulation induction protocols (HMG, HMG/hCG, rFSH, and rFSH/hCG). It also investigates the relationship between follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphisms, CART expression, and in vitro fertilization (IVF) results, with the goal of better understanding how CART and FSHR polymorphisms affect ovarian response and oocyte quality. Methods: Data were obtained from 94 women who underwent controlled ovarian stimulation (COS) as part of their IVF therapy. Hormone levels, CART expression, and FSHR polymorphisms were measured across all four ovulation induction procedures. Statistical studies were undertaken to investigate the relationships between CART expression, hormone levels, and IVF results. Results: The study found no significant difference in body mass index (BMI) amongst the four stimulation procedures (p-values varied from 0.244 to 0.909). CART expression did not show a significant correlation with hormone levels throughout the whole cohort (progesterone, testosterone, androstenedione, FSH, hCG, and estradiol; p > 0.05). However, CART levels were adversely linked with the number of follicles > 12 mm (r = −0.251, p = 0.018), total oocyte count (r = −0.247, p = 0.019), and oocyte maturity (r = −0.212, p = 0.048). Furthermore, there was a strong negative connection between CART expression and thyroid hormone T3 (r = −0.319, p = 0.048). Among FSHR polymorphisms, the SER/SER genotype was related to greater CART levels (mean 4.198 ± 2.257) than the SER/ASN and ASN/ASN genotypes (p = 0.031). Conclusions: These data indicate that CART expression and FSHR polymorphisms may influence ovarian response and oocyte quality in IVF patients, possibly acting as biomarkers for evaluating ovarian outcomes in various ovulation induction procedures. Full article
(This article belongs to the Special Issue Molecular and Genetic Bases of Infertility)
11 pages, 1535 KiB  
Article
The Human 8-oxoG DNA Glycosylase 1 (OGG1) Ser326Cys Polymorphism in Infertile Men
by César Antonio González-Díaz, María Antonieta Suárez-Souto, Elvia Pérez-Soto, Modesto Gómez-López, Jacobo Esteban Munguía-Cervantes, Nadia Mabel Pérez-Vielma and Virginia Sánchez-Monroy
Biomedicines 2024, 12(10), 2286; https://doi.org/10.3390/biomedicines12102286 - 9 Oct 2024
Cited by 1 | Viewed by 1422
Abstract
Background/Objectives: 8-hydroxy-2′-deoxyguanosine (8-OHdG) is a form of oxidative DNA damage caused by oxidative stress (OS), which is considered a major factor in male infertility. The cellular defense system against 8-OHdG involves base excision repair (BER) with the enzyme 8-Oxoguanine DNA glycosylase 1 (OGG1). [...] Read more.
Background/Objectives: 8-hydroxy-2′-deoxyguanosine (8-OHdG) is a form of oxidative DNA damage caused by oxidative stress (OS), which is considered a major factor in male infertility. The cellular defense system against 8-OHdG involves base excision repair (BER) with the enzyme 8-Oxoguanine DNA glycosylase 1 (OGG1). However, studies on the single-nucleotide polymorphism (SNP) OGG1 Ser326Cys have demonstrated that the Cys326Cys genotype could be the cause of an increment in oxidative DNA damage. In this study, the OGG1 Ser326Cys polymorphism and its effect on DNA oxidation were evaluated in 118 infertile men. Methods: Polymorphic screening was performed using TaqMan allelic discrimination assays, and oxidative DNA damage was evaluated through the quantification of 8-OHdG and total antioxidant capacity (TAC); in addition, electrical bioimpedance spectroscopy (EBiS) measurements were used as a reference for different electrical properties associated with 8-OHdG concentrations. Results: The detected Cys (G) allele frequency (0.4) was higher compared to the allele frequency reported in the “Allele Frequency Aggregator” (ALFA) and “Haplotype Map” (HapMap) projects for American populations (0.21–0.29), suggesting that the Cys (G) allele carrier could be a factor associated with American infertile populations. The values of 8-OHdG were twofold higher in carriers of the Cys326Cys (GG) genotype than the other genotypes and, in concordance, the TAC levels were threefold lower in Cys326Cys (GG) genotype carriers compared to the other genotypes. Moreover, the EBiS magnitude exhibited potential for the detection of different oxidative damage in DNA samples between genotypes. Conclusions: The Cys326Cys (GG) genotype is associated with oxidative DNA damage that could contribute to male infertility. Full article
(This article belongs to the Special Issue Molecular and Genetic Bases of Infertility)
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17 pages, 5065 KiB  
Article
The Potential Mechanisms Involved in the Disruption of Spermatogenesis in Mice by Nanoplastics and Microplastics
by Yixian Wen, Jing Cai, Huilian Zhang, Yi Li, Manyao Yu, Jinyi Liu and Fei Han
Biomedicines 2024, 12(8), 1714; https://doi.org/10.3390/biomedicines12081714 - 1 Aug 2024
Cited by 2 | Viewed by 1731
Abstract
Background: Plastic-based products are ubiquitous due to their tremendous utility in our daily lives. Nanoplastic (NP) and microplastic (MP) pollution has become a severe threat to the planet and is a growing concern. It has been widely reported that polystyrene (PS) MPs are [...] Read more.
Background: Plastic-based products are ubiquitous due to their tremendous utility in our daily lives. Nanoplastic (NP) and microplastic (MP) pollution has become a severe threat to the planet and is a growing concern. It has been widely reported that polystyrene (PS) MPs are severely toxic to the male reproduction system, with effects including decreased sperm parameters, impaired spermatogenesis, and damaged testicular structures. However, the molecular mechanisms for impaired spermatogenesis remain poorly understood. Methods: C57BL/6 male mice were treated with PS-NPs (80 nm) and PS-MPs (5 μm) by oral gavage every day for 60 days. A series of morphological analyses were completed to explore the influence of PS-NP and PS-MP exposure on the testes. Compared to other cell types in the seminiferous tubule, PS-NP and PS-MP exposure can lead to decreased spermatocytes. Then, more refined molecular typing was further performed based on gene expression profiles to better understand the common and specific molecular characteristics after exposure to PS-NPs and PS-MPs. Results: There were 1794 common DEGs across the PS-NP groups at three different doses and 1433 common DEGs across the PS-MP groups at three different doses. GO and KEGG analyses of the common DEGs in the PS-NP and PS-MP groups were performed to enrich the common and specific functional progress and signaling pathways, including 349 co-enriched GO entries and 13 co-enriched pathways. Moreover, 348 GO entries and 33 pathways were specifically enriched in the PS-NP group, while 526 GO entries and 15 pathways were specifically enriched in the PS-MPs group. Conclusions: PS-NPs were predominantly involved in regulating retinoic acid metabolism, whereas PS-MPs primarily influenced pyruvate metabolism and thyroid hormone metabolism. Our results highlight the different molecular mechanisms of PS-NPs and PS-MPs in the impairment of spermatogenesis in male mammals for the first time, providing valuable insights into the precise mechanisms of PS-NPs and PS-MPs in male reproduction. Full article
(This article belongs to the Special Issue Molecular and Genetic Bases of Infertility)
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11 pages, 1691 KiB  
Article
Exome Sequencing to Identify Novel Variants Associated with Secondary Amenorrhea and Premature Ovarian Insufficiency (POI) in Saudi Women
by Ahmed M. Almatrafi, Ali M. Hibshi and Sulman Basit
Biomedicines 2024, 12(4), 785; https://doi.org/10.3390/biomedicines12040785 - 3 Apr 2024
Cited by 1 | Viewed by 2155
Abstract
Background and objectives: Post-pubertal disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion is a heterogeneous condition. Patients with this disease have low levels of gonadal hormones and high levels of gonadotropins. It is one of the causes of female infertility [...] Read more.
Background and objectives: Post-pubertal disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion is a heterogeneous condition. Patients with this disease have low levels of gonadal hormones and high levels of gonadotropins. It is one of the causes of female infertility and a strong genetic component is attributed as an underlying cause of this condition. Although variants in several genes have been associated with the condition, the cause of the disease remains undetermined in the vast majority of cases. Methodology and Materials: Ten Saudi married women experiencing secondary amenorrhea were referred to a center for genetics and inherited diseases for molecular investigation. A family-based study design was used. Intensive clinical examinations, including pelvic ultra-sonography (U/S) and biochemical evaluations, were carried out. Karyotypes were normal in all cases and polycystic ovarian syndrome (PCOS) was excluded by using Rotterdam consensus criteria. Patients’ DNA samples were whole-exome sequenced (WES). Bidirectional Sanger sequencing was then utilized to validate the identified candidate variants. The pathogenicity of detected variants was predicted using several types of bioinformatics software. Results: Most of the patients have a normal uterus with poor ovarian reserves. Exome sequence data analysis identified candidate variants in genes associated with POI in 60% of cases. Novel variants were identified in HS6ST1, MEIOB, GDF9, and BNC1 in POI-associated genes. Moreover, a homozygous variant was also identified in the MMRN1 gene. Interestingly, mutations in MMRN1 have never been associated with any human disease. The variants identified in this study were not present in 125 healthy Saudi individuals. Conclusions: WES is a powerful tool to identify the underlying variants in genetically heterogeneous diseases like secondary amenorrhea and POI. In this study, we identified six novel variants and expanded the genotype continuum of POI. Unravelling the genetic landscape of POI will help in genetic counselling, management, and early intervention. Full article
(This article belongs to the Special Issue Molecular and Genetic Bases of Infertility)
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Review

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19 pages, 1776 KiB  
Review
Decoding the Genes Orchestrating Egg and Sperm Fusion Reactions and Their Roles in Fertility
by Ranjha Khan, Muhammad Azhar and Muhammad Umair
Biomedicines 2024, 12(12), 2850; https://doi.org/10.3390/biomedicines12122850 - 15 Dec 2024
Viewed by 1753
Abstract
Mammalian fertilization is a complex and highly regulated process that has garnered significant attention, particularly with advancements in assisted reproductive technologies such as in vitro fertilization (IVF). The fusion of egg and sperm involves a sequence of molecular and cellular events, including capacitation, [...] Read more.
Mammalian fertilization is a complex and highly regulated process that has garnered significant attention, particularly with advancements in assisted reproductive technologies such as in vitro fertilization (IVF). The fusion of egg and sperm involves a sequence of molecular and cellular events, including capacitation, the acrosome reaction, adhesion, and membrane fusion. Critical genetic factors, such as IZUMO1, JUNO (also known as FOLR4), CD9, and several others, have been identified as essential mediators in sperm–egg recognition and membrane fusion. Additionally, glycoproteins such as ZP3 within the zona pellucida are crucial for sperm binding and triggering the acrosome reaction. Recent gene-editing technologies, such as CRISPR/Cas9 and conditional knockout models, have facilitated the functional annotation of genes such as SPAM1 and ADAM family members, further elucidating their roles in capacitation and adhesion. Furthermore, the integration of CRISPR-Cas9 with omics technologies, including transcriptomics, proteomics, and lipidomics, has unlocked new avenues for identifying previously unknown genetic players and pathways involved in fertilization. For instance, transcriptomics can uncover gene expression profiles during gamete maturation, while proteomics identifies key protein interactions critical for processes such as capacitation and the acrosome reaction. Lipidomics adds another dimension by revealing how membrane composition influences gamete fusion. Together, these tools enable the discovery of novel genes, pathways, and molecular mechanisms involved in fertility, providing insights that were previously unattainable. These approaches not only deepen our molecular understanding of fertility mechanisms but also hold promise for refining diagnostic tools and therapeutic interventions for infertility. This review summarizes the current molecular insights into genes orchestrating fertilization and highlights cutting-edge methodologies that propel the field toward novel discoveries. By integrating these findings, this review aims to provide valuable knowledge for clinicians, researchers, and technologists in the field of reproductive biology and assisted reproductive technologies. Full article
(This article belongs to the Special Issue Molecular and Genetic Bases of Infertility)
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