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Molecular Biology of Human Fertility

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 21694

Special Issue Editors


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Guest Editor
Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, 21100 Varese, VA, Italy
Interests: women’s health; minimally invasive procedures; up-to-date management; gynecology; reproductive health; surgery
Special Issues, Collections and Topics in MDPI journals
Department of Surgery, Dentistry, Pediatrics, and Gynecology, AOUI Verona, University of Verona, 37126 Verona, Italy
Interests: infertility; fertility preservation; endometriosis; polycystic ovary syndrome; assisted reproduction technology; gynecologic surgical procedures; endometrial cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The idea of this special issue titled "Molecular biology of human fertility" derives from the desire to create a collection of manuscripts providing new evidence or summarizing the most recent available pieces of evidence on the molecular aspects of the complex mechanisms underlining human fertility. Live birth and before a clinical pregnancy result from a complex interaction of molecular pathways at the level of female and male gametes, their interaction during fecundation, and the development of the embryo before, during, and after implantation. All these mechanisms interact with the surrounding environment present at the level of gonads and male and female bodies, and later at the female genital tract level, from tubes to the endometrium and uterus. The knowledge of this molecular biology underlining human fertility is paramount to understand physiology and pathology, with the ultimate objective of successfully understanding and treating female and male infertility.

This Special Issue aims to publish groundbreaking research and review articles in basic and translational science (immunology, cell biology, genetics, and epigenetics) that may create new scenarios and change our perspective of the topic.

Dr. Antonio Simone Laganà
Dr. Simone Garzon
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Infertility
  • Gametes
  • Embryo
  • Implantation
  • Placenta
  • Endometrium
  • Gynecological endocrinology
  • Assisted Reproduction Technology
  • Ovaries
  • Inflammation
  • Endometriosis

Published Papers (9 papers)

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Editorial

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3 pages, 212 KiB  
Editorial
Molecular Biology of Human Fertility: Stepping towards a Tailored Approach
by Antonio Simone Laganà, Stefano Uccella, Vito Chiantera and Simone Garzon
Int. J. Mol. Sci. 2022, 23(14), 7517; https://doi.org/10.3390/ijms23147517 - 07 Jul 2022
Cited by 10 | Viewed by 1376
Abstract
Clinical pregnancies and live births result from a complex interaction of molecular pathways at the level of the female and male gametes during their development and interaction for fecundation, and the subsequent development of the embryo before, during, and after implantation [...] Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)

Research

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17 pages, 2482 KiB  
Article
Molecular Background of Toxic-Substances-Induced Morphological Alterations in the Umbilical Cord Vessels and Fetal Red Blood Cells
by Szabolcs Zahorán, Ágnes Márton, Krisztina Dugmonits, Payal Chakraborty, Ali Khamit, Péter Hegyi, Hajnalka Orvos and Edit Hermesz
Int. J. Mol. Sci. 2022, 23(23), 14673; https://doi.org/10.3390/ijms232314673 - 24 Nov 2022
Cited by 1 | Viewed by 1346
Abstract
The relationship between smoking and human health has been investigated mostly in adults, despite the fact that the chemicals originating from sustained maternal smoking disrupt the carefully orchestrated regulatory cascades in the developing fetus. In this study, we followed molecular alterations in the [...] Read more.
The relationship between smoking and human health has been investigated mostly in adults, despite the fact that the chemicals originating from sustained maternal smoking disrupt the carefully orchestrated regulatory cascades in the developing fetus. In this study, we followed molecular alterations in the umbilical cord (UC) vessels and fetal red blood cells (RBCs), which faithfully reflect the in vivo status of the fetus. We showed evidence for the decreased level of DNA-PKcs-positive nuclei in samples with smoking origin, which is associated with the impaired DNA repair system. Furthermore, we pointed out the altered ratio of MMP-9 metalloproteinase and its endogenous inhibitor TIMP-1, which might be a possible explanation for the morphological abnormalities in the UC vessels. The presented in vivo dataset emphasizes the higher vulnerability of the veins, as the primary target for the toxic materials unfiltered by the placenta. All these events become amplified by the functionally impaired fetal RBC population via a crosstalk mechanism between the vessel endothelium and the circulating RBCs. In our ex vivo approach, we looked for the molecular explanation of metal-exposure-induced alterations, where expressions of the selected genes were upregulated in the control group, while samples with smoking origin showed a lack of response, indicative of prior long-term in utero exposure. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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22 pages, 3446 KiB  
Article
Global 5mC and 5hmC DNA Levels in Human Sperm Subpopulations with Differentially Protaminated Chromatin in Normo- and Oligoasthenozoospermic Males
by Marta Olszewska, Oliwia Kordyl, Marzena Kamieniczna, Monika Fraczek, Piotr Jędrzejczak and Maciej Kurpisz
Int. J. Mol. Sci. 2022, 23(9), 4516; https://doi.org/10.3390/ijms23094516 - 19 Apr 2022
Cited by 5 | Viewed by 2306
Abstract
Epigenetic modifications play a special role in the male infertility aetiology. Published data indicate the link between sperm quality and sperm chromatin protamination. This study aimed to determine the relationship between methylation (5mC) and hydroxymethylation (5hmC) in sperm DNA, with respect to sperm [...] Read more.
Epigenetic modifications play a special role in the male infertility aetiology. Published data indicate the link between sperm quality and sperm chromatin protamination. This study aimed to determine the relationship between methylation (5mC) and hydroxymethylation (5hmC) in sperm DNA, with respect to sperm chromatin protamination in three subpopulations of fertile normozoospermic controls and infertile patients with oligo-/oligoasthenozoospermia. For the first time, a sequential staining protocol was applied, which allowed researchers to analyse 5mC/5hmC levels by immunofluorescence staining, with a previously determined chromatin protamination status (aniline blue staining), using the same spermatozoa. TUNEL assay determined the sperm DNA fragmentation level. The 5mC/5hmC levels were diversified with respect to chromatin protamination status in both studied groups of males, with the highest values observed in protaminated spermatozoa. The linkage between chromatin protamination and 5mC/5hmC levels in control males disappeared in patients with deteriorated semen parameters. A relationship between 5mC/5hmC and sperm motility/morphology was identified in the patient group. Measuring the 5mC/5hmC status of sperm DNA according to sperm chromatin integrity provides evidence of correct spermatogenesis, and its disruption may represent a prognostic marker for reproductive failure. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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13 pages, 14258 KiB  
Article
Immunofluorescence and High-Resolution Microscopy Reveal New Insights in Human Globozoospermia
by Paula Sáez-Espinosa, Laura Robles-Gómez, Leonor Ortega-López, Jon Aizpurua and María José Gómez-Torres
Int. J. Mol. Sci. 2022, 23(3), 1729; https://doi.org/10.3390/ijms23031729 - 02 Feb 2022
Cited by 2 | Viewed by 2315
Abstract
Globozoospermia is a rare and severe type of teratozoospermia characterized by the presence of round-headed, acrosomeless spermatozoa with cytoskeleton defects. Current data support a negative relationship between globozoospermia and intracytoplasmic sperm injection (ICSI) outcomes, revealing the need to perform exhaustive studies on this [...] Read more.
Globozoospermia is a rare and severe type of teratozoospermia characterized by the presence of round-headed, acrosomeless spermatozoa with cytoskeleton defects. Current data support a negative relationship between globozoospermia and intracytoplasmic sperm injection (ICSI) outcomes, revealing the need to perform exhaustive studies on this type of sperm disorder. The aim of this study was to evaluate different structural, functional and molecular sperm biomarkers in total globozoospermia with proper embryo development after ICSI. The combination of field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) allowed us to identify and correlate eight morphological patterns with both types of microscopy. Additionally, results reported a high percentage of coiled forms, with cytoplasmic retentions around the head and midpiece. By fluorescent microscopy, we detected that most of the sperm showed tubulin in the terminal piece of the flagellum and less than 1% displayed tyrosine phosphorylation in the flagellum. Moreover, we did not detect chaperone Heat shock-related 70 kDa protein 2 (HSPA2) in 85% of the cells. Overall, these findings provide new insights into globozoospermia, which could have potential implications in improving sperm selection methods for assisted reproductive techniques. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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17 pages, 1499 KiB  
Article
Fibronectin Molecular Status in Plasma of Women with Endometriosis and Fertility Disorders
by Jolanta Lis-Kuberka, Paulina Kubik, Agnieszka Chrobak, Jarosław Pająk, Anna Chełmońska-Soyta and Magdalena Orczyk-Pawiłowicz
Int. J. Mol. Sci. 2021, 22(21), 11410; https://doi.org/10.3390/ijms222111410 - 22 Oct 2021
Cited by 4 | Viewed by 1809
Abstract
The diagnosis of endometriosis and fertility disorders is difficult; therefore, it is necessary to look for reliable biomarkers. Analysis of the molecular status of fibronectin as a key player in repair and wound healing processes, as well as in coagulation and fibrinolysis pathways, [...] Read more.
The diagnosis of endometriosis and fertility disorders is difficult; therefore, it is necessary to look for reliable biomarkers. Analysis of the molecular status of fibronectin as a key player in repair and wound healing processes, as well as in coagulation and fibrinolysis pathways, is justified. ELISA and SDS-agarose immunoblotting were applied to determine the fibronectin concentration and presence and occurrence of soluble FN-fibrin complexes in the blood plasma of women with endometriosis (n = 38), fertility disorders (n = 28) and the healthy group (n = 25). The concentration of fibronectin in the blood plasma of women with endometriosis (292.61 ± 96.17 mg/L) and fertility disorders (287.53 ± 122.68 mg/L) was significantly higher than in the normal group (226.55 ± 91.98 mg/L). The presence of FN-fibrin complexes of 750, 1000, 1300, 1600 and 1900 kDa in the plasma of women with endometriosis and fertility disorders was shown. The presence of FN-fibrin complexes with a molecular mass of more than 1300 kDa in women with endometriosis and infertility and the complete absence of these complexes in healthy women may indicate an increased and chronic activation of coagulation mechanisms in these patients. The presence of complexes of high molecular mass may be one of the biomarkers of fertility disorders in women. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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10 pages, 1295 KiB  
Article
Lower Spermatozoal PIWI-LIKE 1 and 2 Transcript Levels Are Significantly Associated with Higher Fertilization Rates in IVF
by Maria Giebler, Thomas Greither, Diana Handke, Gregor Seliger and Hermann M. Behre
Int. J. Mol. Sci. 2021, 22(21), 11320; https://doi.org/10.3390/ijms222111320 - 20 Oct 2021
Cited by 3 | Viewed by 1486
Abstract
The four human PIWI-LIKE gene family members PIWI-LIKE 1–4 play a pivotal role in stem cell maintenance and transposon repression in the human germline. Therefore, dysregulation of these genes negatively influences the genetic stability of the respective germ cell and subsequent development and [...] Read more.
The four human PIWI-LIKE gene family members PIWI-LIKE 1–4 play a pivotal role in stem cell maintenance and transposon repression in the human germline. Therefore, dysregulation of these genes negatively influences the genetic stability of the respective germ cell and subsequent development and maturation. Recently, we demonstrated that a lower PIWI-LIKE 2 mRNA expression in ejaculated spermatozoa is more frequent in men with oligozoospermia. In this study, we analysed how PIWI-LIKE 1–4 mRNA expression in ejaculated spermatozoa predicts ART outcome. From 160 IVF or ICSI cycles, portions of swim-up spermatozoa used for fertilization were collected, and the total RNA was isolated. PIWI-LIKE 1–4 mRNA expression was measured by qPCR using TaqMan probes with GAPDH as a reference gene. PIWI-LIKE 1 and 2 transcript levels in the spermatozoa of the swim-up fraction were positively correlated to each other (rS = 0.78; p < 0.001). Moreover, lower PIWI-LIKE 2 mRNA levels, as well as lower PIWI-LIKE 1 mRNA levels, in these spermatozoa were positively associated with a fertilization rate ≥ 50% in the respective ART cycles (p = 0.02 and p = 0.0499, Mann–Whitney U-Test). When separately analysing IVF and ICSI cycles, PIWI-LIKE 1 and 2 transcript levels were only significantly associated to increased fertilization rates in IVF, yet not in ICSI cycles. Spermatozoal PIWI-LIKE 3 and 4 transcript levels were not significantly associated to fertilization rates in ART cycles. In conclusion, lower levels of spermatozoal PIWI-LIKE 1 and 2 mRNA levels are positively associated with a higher fertilization rate in IVF cycles. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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13 pages, 3164 KiB  
Article
CCNE1 Is a Putative Therapeutic Target for ARID1A-Mutated Ovarian Clear Cell Carcinoma
by Naoki Kawahara, Yuki Yamada and Hiroshi Kobayashi
Int. J. Mol. Sci. 2021, 22(11), 5869; https://doi.org/10.3390/ijms22115869 - 30 May 2021
Cited by 8 | Viewed by 2939
Abstract
Background: Ovarian clear cell carcinoma (OCCC) is resistant to platinum chemotherapy and is characterized by poor prognosis. Today, the use of poly (ADP-ribose) polymerase (PARP) inhibitor, which is based on synthetic lethality strategy and characterized by cancer selectivity, is widely used for new [...] Read more.
Background: Ovarian clear cell carcinoma (OCCC) is resistant to platinum chemotherapy and is characterized by poor prognosis. Today, the use of poly (ADP-ribose) polymerase (PARP) inhibitor, which is based on synthetic lethality strategy and characterized by cancer selectivity, is widely used for new types of molecular-targeted treatment of relapsed platinum-sensitive ovarian cancer. However, it is less effective against OCCC. Methods: We conducted siRNA screening to identify synthetic lethal candidates for the ARID1A mutation; as a result, we identified Cyclin-E1 (CCNE1) as a potential target that affects cell viability. To further clarify the effects of CCNE1, human OCCC cell lines, namely TOV-21G and KOC7c (ARID1A mutant lines), and RMG-I and ES2 (ARID1A wild type lines) were transfected with siRNA targeting CCNE1 or a control vector. Results: Loss of CCNE1 reduced proliferation of the TOV-21G and KOC7c cells but not of the RMG-I and ES2 cells. Furthermore, in vivo interference of CCNE1 effectively inhibited tumor cell proliferation in a xenograft mouse model. Conclusion: This study showed for the first time that CCNE1 is a synthetic lethal target gene to ARID1A-mutated OCCC. Targeting this gene may represent a putative, novel, anticancer strategy in OCCC treatment. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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11 pages, 33381 KiB  
Article
Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure
by Nicola Tempest, Elizabeth Batchelor, Christopher J. Hill, Hannan Al-Lamee, Josephine Drury, Andrew J. Drakeley and Dharani K. Hapangama
Int. J. Mol. Sci. 2021, 22(8), 3835; https://doi.org/10.3390/ijms22083835 - 07 Apr 2021
Cited by 7 | Viewed by 1944
Abstract
Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) are distressing conditions without effective treatments. The luminal epithelium (LE) is integral in determining receptivity of the endometrium, whereas functionalis glands and stroma aid in nurturing early embryo development. Calcium signalling pathways are known [...] Read more.
Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) are distressing conditions without effective treatments. The luminal epithelium (LE) is integral in determining receptivity of the endometrium, whereas functionalis glands and stroma aid in nurturing early embryo development. Calcium signalling pathways are known to be of vital importance to embryo implantation and pregnancy establishment, and anterior gradient protein 3 (AGR3) and S100 calcium-binding protein P (S100P) are involved with these pathways. We initially examined 20 full-thickness endometrial biopsies from premenopausal women across the menstrual cycle to characterize levels of AGR3 protein in each endometrial sub-region at the cellular level. A further 53 endometrial pipelle biopsies collected in the window of implantation were subsequently assessed to determine differential endometrial AGR3 and S100P levels relevant to RIF (n = 13) and RPL (n = 10) in comparison with parous women (n = 30) using immunohistochemistry. Significantly higher AGR3 and S100P immunostaining was observed in ciliated cells of the LE of women with recurrent reproductive failure compared with parous women, suggesting aberrant subcellular location-associated pathophysiology for these conditions. The nuclear localisation of S100P may allow transcriptional regulatory function, which is necessary for implantation of a viable pregnancy. Further work is thus warranted to assess their utility as diagnostic/therapeutic targets. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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Review

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12 pages, 1625 KiB  
Review
The Role of Mutant p63 in Female Fertility
by Yi Luan, Pauline Xu, Seok-Yeong Yu and So-Youn Kim
Int. J. Mol. Sci. 2021, 22(16), 8968; https://doi.org/10.3390/ijms22168968 - 20 Aug 2021
Cited by 8 | Viewed by 3189
Abstract
The transcription factor p63, one of the p53 family members, plays an essential role in regulating maternal reproduction and genomic integrity as well as epidermal development. TP63 (human)/Trp63 (mouse) produces multiple isoforms: TAp63 and ΔNp63, which possess a different N-terminus depending [...] Read more.
The transcription factor p63, one of the p53 family members, plays an essential role in regulating maternal reproduction and genomic integrity as well as epidermal development. TP63 (human)/Trp63 (mouse) produces multiple isoforms: TAp63 and ΔNp63, which possess a different N-terminus depending on two different promoters, and p63a, p63b, p63g, p63δ, and p63ε as products of alternative splicing at the C-terminus. TAp63 expression turns on in the nuclei of primordial germ cells in females and is maintained mainly in the oocyte nuclei of immature follicles. It has been established that TAp63 is the genomic guardian in oocytes of the female ovaries and plays a central role in determining the oocyte fate upon oocyte damage. Lately, there is increasing evidence that TP63 mutations are connected with female infertility, including isolated premature ovarian insufficiency (POI) and syndromic POI. Here, we review the biological functions of p63 in females and discuss the consequences of p63 mutations, which result in infertility in human patients. Full article
(This article belongs to the Special Issue Molecular Biology of Human Fertility)
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