International Journal of Molecular Sciences

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12 pages, 5259 KiB

Open AccessArticle

The Effects of Mammary Gland ATIII Overexpression on the General Health of Dairy Goats and Their Anti-Inflammatory Response to LPS Stimulation

by Laiqing Yan, Hao Wu, Shengyu Guan, Wenkui Ma, Yao Fu, Pengyun Ji, Zhengxing Lian, Lu Zhang, Yiming Xing, Bingyuan Wang and Guoshi Liu

Int. J. Mol. Sci. 2023, 24(20), 15303; https://doi.org/10.3390/ijms242015303 - 18 Oct 2023

Viewed by 1187

Abstract

Antithrombin III is an important anticoagulant factor with anti-inflammatory properties. However, few studies have explored its anti-inflammatory actions in ATIII overexpressed transgenic animals. In this study, the dairy goats with mammary overexpression of ATIII were used to investigate their general health, milk quality [...] Read more.

Antithrombin III is an important anticoagulant factor with anti-inflammatory properties. However, few studies have explored its anti-inflammatory actions in ATIII overexpressed transgenic animals. In this study, the dairy goats with mammary overexpression of ATIII were used to investigate their general health, milk quality and particularly their response to inflammatory challenge. The results showed that transgenic goats have a normal phenotype regarding their physiological and biochemical parameters, including whole blood cells, serum protein levels, total cholesterol, urea nitrogen, uric acid, and total bilirubin, compared to the WT. In addition, the quality of milk also improved in transgenic animals compared to the WT, as indicated by the increased milk fat and dry matter content and the reduced somatic cell numbers. Under the stimulation of an LPS injection, the transgenic goats had elevated contents of IGA, IGM and superoxide dismutase SOD, and had reduced proinflammatory cytokine release, including IL-6, TNF-α and IFN-β. A 16S rDNA sequencing analysis also showed that the transgenic animals had a similar compositions of gut microbiota to the WT goats under the stimulation of LPS injections. Mammary gland ATIII overexpression in dairy goats is a safe process, and it did not jeopardize the general health of the transgenic animals; moreover, the compositions of their gut microbiota also improved with the milk quality. The LPS stimulation study suggests that the increased ATIII expression may directly or indirectly suppress the inflammatory response to increase the resistance of transgenic animals to pathogen invasion. This will be explored in future studies. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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14 pages, 2542 KiB

Open AccessArticle

Disorder of Biological Quality and Autophagy Process in Bovine Oocytes Exposed to Heat Stress and the Effectiveness of In Vitro Fertilization

by Marcjanna Wrzecińska, Alicja Kowalczyk, Władysław Kordan, Przemysław Cwynar and Ewa Czerniawska-Piątkowska

Int. J. Mol. Sci. 2023, 24(13), 11164; https://doi.org/10.3390/ijms241311164 - 6 Jul 2023

Cited by 5 | Viewed by 1645

Abstract

The main problem in dairy herds is reproductive disorders, which are influenced by many factors, including temperature. Heat stress reduces the quality of oocytes and their maturation through the influence of, e.g., mitochondrial function. Mitochondria are crucial during oocyte maturation as well as [...] Read more.

The main problem in dairy herds is reproductive disorders, which are influenced by many factors, including temperature. Heat stress reduces the quality of oocytes and their maturation through the influence of, e.g., mitochondrial function. Mitochondria are crucial during oocyte maturation as well as the process of fertilization and embryonic development. Disturbances related to high temperature will be increasingly observed due to global warming. In present studies, we have proven that exposure to high temperatures during the cleaving of embryos statistically significantly (at the level of p < 0.01) reduces the percentage of oocytes that cleaved and developed into blastocysts eight days after insemination. The study showed the highest percentage of embryos that underwent division in the control group (38.3 °C). The value was 88.10 ± 6.20%, while the lowest was obtained in the study group at 41.0 °C (52.32 ± 8.40%). It was also shown that high temperature has a statistically significant (p < 0.01) effect on the percentage of embryos that developed from the one-cell stage to blastocysts. The study showed that exposure to a temperature of 41.0 °C significantly reduced the percentage of embryos that split relative to the control group (38.3 °C; 88.10 ± 6.20%). Moreover, it was noted that the highest tested temperature limits the development of oocytes to the blastocyst stage by 5.00 ± 9.12% compared to controls (33.33 ± 7.10%) and cleaved embryos to blastocysts by 3.52 ± 6.80%; the control was 39.47 ± 5.40%. There was also a highly significant (p < 0.0001) effect of temperature on cytoplasmic ROS levels after 6 and 12 h IVM. The highest level of mitochondrial ROS was found in the group of oocytes after 6 h IVM at 41.0 °C and the lowest was found in the control group. In turn, at 41.0 °C after 12 h of IVM, the mitochondrial ROS level had a 2.00 fluorescent ratio, and the lowest in the group was 38.3 °C (1.08). Moreover, with increasing temperature, a decrease in the expression level of both LC3 and SIRT1 protein markers was observed. It was proved that the autophagy process was impaired as a result of high temperature. Understanding of the cellular and molecular responses of oocytes to elevated temperatures will be helpful in the development of heat resistance strategies in dairy cattle. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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18 pages, 8247 KiB

Open AccessArticle

The Uterine Melatonergic Systems of AANAT and Melatonin Membrane Receptor 2 (MT2) Are Essential for Endometrial Receptivity and Early Implantation in Mice

by Xiao Ma, Jing Wang, Likai Wang, Laiqing Yan, Yunjie Liu, Wenkui Ma, Pengyun Ji, Lu Zhang and Guoshi Liu

Int. J. Mol. Sci. 2023, 24(8), 7127; https://doi.org/10.3390/ijms24087127 - 12 Apr 2023

Cited by 3 | Viewed by 2090

Abstract

In the current study, using Aanat and Mt2 KO mice, we observed that the preservation of the melatonergic system is essential for successful early pregnancy in mice. We identified that aralkylamine N-acetyltransferase (AANAT), melatonin receptor 1A (MT1), and melatonin receptor 1B (MT2) were [...] Read more.

In the current study, using Aanat and Mt2 KO mice, we observed that the preservation of the melatonergic system is essential for successful early pregnancy in mice. We identified that aralkylamine N-acetyltransferase (AANAT), melatonin receptor 1A (MT1), and melatonin receptor 1B (MT2) were all expressed in the uterus. Due to the relatively weak expression of MT1 compared to AANAT and MT2, this study focused on AANAT and MT2. Aanat and Mt2 KO significantly reduced the early implantation sites and the abnormal morphology of the endometrium of the uterus. Mechanistical analysis indicated that the melatonergic system is the key player in the induction of the normal nidatory estrogen (E2) response for endometrial receptivity and functions by activating the STAT signaling pathway. Its deficiency impaired the interactions between the endometrium, the placenta, and the embryo. The reduction in melatonin production caused by Aanat KO and the impairment of signal transduction caused by Mt2 KO reduced the uterine MMP-2 and MMP-9 activity, resulting in a hyperproliferative endometrial epithelium. In addition, melatonergic system deficiency also increased the local immunoinflammatory reaction with elevated local proinflammatory cytokines leading to early abortion in the Mt2 KO mice compared to the WT mice. We believe that the novel data obtained from the mice might apply to other animals including humans. Further investigation into the interaction between the melatonergic system and reproductive effects in different species would be worthwhile. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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12 pages, 1279 KiB

Open AccessCommunication

Genome-Wide Association Study of Age at First Calving in U.S. Holstein Cows

by Dzianis Prakapenka, Zuoxiang Liang and Yang Da

Int. J. Mol. Sci. 2023, 24(8), 7109; https://doi.org/10.3390/ijms24087109 - 12 Apr 2023

Cited by 9 | Viewed by 1973

Abstract

A genome-wide association study (GWAS) of age at first calving (AFC) using 813,114 first lactation Holstein cows and 75,524 SNPs identified 2063 additive effects and 29 dominance effects with p-values < 10⁻⁸. Three chromosomes had highly significant additive effects in [...] Read more.

A genome-wide association study (GWAS) of age at first calving (AFC) using 813,114 first lactation Holstein cows and 75,524 SNPs identified 2063 additive effects and 29 dominance effects with p-values < 10⁻⁸. Three chromosomes had highly significant additive effects in the regions of 7.86–8.12 Mb of Chr15, 27.07–27.48 Mb and 31.25–32.11 Mb of Chr19, and 26.92–32.60 Mb of Chr23. Two of the genes in those regions were reproductive hormone genes with known biological functions that should be relevant to AFC, the sex hormone binding globulin (SHBG) gene, and the progesterone receptor (PGR) gene. The most significant dominance effects were near or in EIF4B and AAAS of Chr05 and AFF1 and KLHL8 of Chr06. All dominance effects were positive overdominance effects where the heterozygous genotype had an advantage, and the homozygous recessive genotype of each SNP had a very negative dominance value. Results from this study provided new evidence and understanding about the genetic variants and genome regions affecting AFC in U.S. Holstein cows. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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15 pages, 1519 KiB

Open AccessCommunication

Rhythm of the First Language: Dynamics of Extracellular Vesicle-Based Embryo–Maternal Communication in the Pre-Implantation Microenvironment

by Kasun Godakumara, Paul R. Heath and Alireza Fazeli

Int. J. Mol. Sci. 2023, 24(7), 6811; https://doi.org/10.3390/ijms24076811 - 6 Apr 2023

Cited by 4 | Viewed by 2275

Abstract

One of the most critical steps in mammalian reproduction is implantation. Embryos with an impaired capacity for embryo–maternal crosstalk are thought to have a reduced potential for implantation. One agent of embryo–maternal communication is extracellular vesicles (EV). EVs are lipid bilayer-bound biological nanoparticles [...] Read more.

One of the most critical steps in mammalian reproduction is implantation. Embryos with an impaired capacity for embryo–maternal crosstalk are thought to have a reduced potential for implantation. One agent of embryo–maternal communication is extracellular vesicles (EV). EVs are lipid bilayer-bound biological nanoparticles implicated in intercellular communication between many of the known cell types. In the current study, we isolated EVs from trophoblast analogue JAr spheroids and supplemented the EVs with receptive endometrium analogue RL95-2 cells to simulate pre-implantation embryo–maternal dialogue. The transcriptome of the endometrial cells was examined at 30 min, 4 h and 48 h intervals using Oxford Nanopore^® technology. At the time points, 30 min, 4 h and 48 h, the endometrial cells showed a significantly altered transcriptome. It seems trophoblast EVs induce a swift and drastic effect on the endometrial transcriptome. The effect peaks at around 4 h of EV supplementation, indicating a generalized effect on cell physiology. Alterations are especially apparent in biological pathways critical to embryonic implantation, such as extracellular matrix–receptor interactions and cytokine–receptor interactions. These observations can be helpful in elucidating the dynamics of embryo–maternal communication in the pre-implantation period. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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12 pages, 4549 KiB

Open AccessArticle

Sperm Meiotic Segregation Analysis of Reciprocal Translocations Carriers: We Have Bigger FISH to Fry

by Edgar Del Llano, Aurore Perrin, Frédéric Morel, Françoise Devillard, Radu Harbuz, Véronique Satre, Florence Amblard, Marie Bidart, Sylviane Hennebicq, Sophie Brouillet, Pierre F. Ray, Charles Coutton and Guillaume Martinez

Int. J. Mol. Sci. 2023, 24(4), 3664; https://doi.org/10.3390/ijms24043664 - 11 Feb 2023

Viewed by 2215

Abstract

Reciprocal translocation (RT) carriers produce a proportion of unbalanced gametes that expose them to a higher risk of infertility, recurrent miscarriage, and fetus or children with congenital anomalies and developmental delay. To reduce these risks, RT carriers can benefit from prenatal diagnosis (PND) [...] Read more.

Reciprocal translocation (RT) carriers produce a proportion of unbalanced gametes that expose them to a higher risk of infertility, recurrent miscarriage, and fetus or children with congenital anomalies and developmental delay. To reduce these risks, RT carriers can benefit from prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD). Sperm fluorescence in situ hybridization (spermFISH) has been used for decades to investigate the sperm meiotic segregation of RT carriers, but a recent report indicates a very low correlation between spermFISH and PGD outcomes, raising the question of the usefulness of spermFISH for these patients. To address this point, we report here the meiotic segregation of 41 RT carriers, the largest cohort reported to date, and conduct a review of the literature to investigate global segregation rates and look for factors that may or may not influence them. We confirm that the involvement of acrocentric chromosomes in the translocation leads to more unbalanced gamete proportions, in contrast to sperm parameters or patient age. In view of the dispersion of balanced sperm rates, we conclude that routine implementation of spermFISH is not beneficial for RT carriers. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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19 pages, 9531 KiB

Open AccessArticle

Integrative Proteomics and Phosphoproteomics Analysis of the Rat Adenohypophysis after GnRH Treatment

by Tian Wang, Hao-Qi Wang, Bao Yuan, Guo-Kun Zhao, Yi-Ran Ma, Pei-Sen Zhao, Wen-Yin Xie, Fei Gao, Wei Gao and Wen-Zhi Ren

Int. J. Mol. Sci. 2023, 24(4), 3339; https://doi.org/10.3390/ijms24043339 - 7 Feb 2023

Viewed by 1566

Abstract

The regulation of mammalian reproductive activity is tightly dependent on the HPG axis crosstalk, in which several reproductive hormones play important roles. Among them, the physiological functions of gonadotropins are gradually being uncovered. However, the mechanisms by which GnRH regulates FSH synthesis and [...] Read more.

The regulation of mammalian reproductive activity is tightly dependent on the HPG axis crosstalk, in which several reproductive hormones play important roles. Among them, the physiological functions of gonadotropins are gradually being uncovered. However, the mechanisms by which GnRH regulates FSH synthesis and secretion still need to be more extensively and deeply explored. With the gradual completion of the human genome project, proteomes have become extremely important in the fields of human disease and biological process research. To explore the changes of protein and protein phosphorylation modifications in the adenohypophysis after GnRH stimulation, proteomics and phosphoproteomics analyses of rat adenohypophysis after GnRH treatment were performed by using TMT markers, HPLC classification, LC/MS, and bioinformatics analysis in this study. A total of 6762 proteins and 15,379 phosphorylation sites contained quantitative information. Twenty-eight upregulated proteins and fifty-three downregulated proteins were obtained in the rat adenohypophysis after GnRH treatment. The 323 upregulated phosphorylation sites and 677 downregulated phosphorylation sites found in the phosphoproteomics implied that a large number of phosphorylation modifications were regulated by GnRH and were involved in FSH synthesis and secretion. These data constitute a protein–protein phosphorylation map in the regulatory mechanism of “GnRH-FSH,” which provides a basis for future studies on the complex molecular mechanisms of FSH synthesis and secretion. The results will be helpful for understanding the role of GnRH in the development and reproduction regulated by the pituitary proteome in mammals. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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15 pages, 1437 KiB

Open AccessArticle

Follicular Fluid Components in Reduced Ovarian Reserve, Endometriosis, and Idiopathic Infertility

by Giulia Collodel, Laura Gambera, Anita Stendardi, Fabiola Nerucci, Cinzia Signorini, Caterina Pisani, Marzia Marcheselli, Francesca Letizia Vellucci, Silvana Enrica Pizzasegale, Lucia Micheli and Elena Moretti

Int. J. Mol. Sci. 2023, 24(3), 2589; https://doi.org/10.3390/ijms24032589 - 30 Jan 2023

Cited by 10 | Viewed by 2844

Abstract

Follicular fluid (FF) molecules, and their increase or decrease, can contribute to appropriate follicular growth and oocyte maturation, thus being related to female infertility conditions. In this paper, we studied the changes and the relationships of some biochemical components, hormones, antioxidant enzymes, F [...] Read more.

Follicular fluid (FF) molecules, and their increase or decrease, can contribute to appropriate follicular growth and oocyte maturation, thus being related to female infertility conditions. In this paper, we studied the changes and the relationships of some biochemical components, hormones, antioxidant enzymes, F₂-Isoprostanes (F₂-IsoPs), and resolvin (Rv) D1 in the FF of infertile women with different reproductive conditions such as endometriosis, reduced ovarian reserve, and idiopathic infertility during assisted reproductive techniques (ART). In the whole population, positive correlations between albumin (ALB)/iron (Fe), ALB/beta-2-microglobulin (B2MG), and F₂-IsoPs/RvD1 were detected in the FF. In FF from aged women, increased levels of follicle stimulating hormone (FSH) and reduced anti-Müllerian hormone (AMH) levels were associated with a worse oocyte quality. The negative ART outcome was influenced by patient age and AMH, B2MG, and FSH levels. Moreover, the reduced ovarian reserve condition was characterised by a significant decrease in oocyte number and quality, AMH amount, and lactate dehydrogenase (LDH) activity, as well as by an increase in age and FSH levels. In the presence of endometriosis, high levels of MDA and RvD1 were detected in FF, with a decrease in luteinising hormone (LH). Finally, among the molecules examined, none characterised the condition of idiopathic infertility. These data could support the identification of new FF markers in different reproductive disorders, suggesting the need for personalised therapeutic approaches and optimised ART outcomes. In particular, the evaluation of resolvins and lipid mediators in FF could be a promising field of investigation with which to understand the entity of oxidative stress and inflammation in some female infertility conditions. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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12 pages, 8456 KiB

Open AccessArticle

New Mutations in DNHD1 Cause Multiple Morphological Abnormalities of the Sperm Flagella

by Guillaume Martinez, Anne-Laure Barbotin, Caroline Cazin, Zeina Wehbe, Angèle Boursier, Amir Amiri-Yekta, Abbas Daneshipour, Seyedeh-Hanieh Hosseini, Nathalie Rives, Aurélie Feraille, Nicolas Thierry-Mieg, Marie Bidart, Véronique Satre, Christophe Arnoult, Pierre F. Ray, Zine-Eddine Kherraf and Charles Coutton

Int. J. Mol. Sci. 2023, 24(3), 2559; https://doi.org/10.3390/ijms24032559 - 29 Jan 2023

Cited by 8 | Viewed by 2253

Abstract

Male infertility is a common and complex disease and presents as a wide range of heterogeneous phenotypes. Multiple morphological abnormalities of the sperm flagellum (MMAF) phenotype is a peculiar condition of extreme morphological sperm defects characterized by a mosaic of sperm flagellum defects [...] Read more.

Male infertility is a common and complex disease and presents as a wide range of heterogeneous phenotypes. Multiple morphological abnormalities of the sperm flagellum (MMAF) phenotype is a peculiar condition of extreme morphological sperm defects characterized by a mosaic of sperm flagellum defects to a total asthenozoospermia. At this time, about 40 genes were associated with the MMAF phenotype. However, mutation prevalence for most genes remains individually low and about half of individuals remain without diagnosis, encouraging us to pursue the effort to identify new mutations and genes. In the present study, an a cohort of 167 MMAF patients was analyzed using whole-exome sequencing, and we identified three unrelated patients with new pathogenic mutations in DNHD1, a new gene recently associated with MMAF. Immunofluorescence experiments showed that DNHD1 was totally absent from sperm cells from DNHD1 patients, supporting the deleterious effect of the identified mutations. Transmission electron microscopy reveals severe flagellum abnormalities of sperm cells from one mutated patient, which appeared completely disorganized with the absence of the central pair and midpiece defects with a shortened and misshapen mitochondrial sheath. Immunostaining of IFT20 was not altered in mutated patients, suggesting that IFT may be not affected by DNHD1 mutations. Our data confirmed the importance of DNHD1 for the function and structural integrity of the sperm flagellum. Overall, this study definitively consolidated its involvement in MMAF phenotype on a second independent cohort and enriched the mutational spectrum of the DNHD1 gene. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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14 pages, 2762 KiB

Open AccessArticle

The Effects of the Follicle-Stimulating Hormone on Human Follicular Fluid-Derived Stromal Cells

by Giedrė Skliutė, Brigita Vaigauskaitė-Mažeikienė, Algirdas Kaupinis, Mindaugas Valius, Edita Kazėnaitė and Rūta Navakauskienė

Int. J. Mol. Sci. 2023, 24(3), 2450; https://doi.org/10.3390/ijms24032450 - 26 Jan 2023

Cited by 1 | Viewed by 2057

Abstract

The prevalence of infertility is getting higher over the years. The increasing age of first-time parents, although economically more desirable, can cause various biological problems from low natural conception rate to poor pregnancy outcomes. The growing demand for assisted reproductive technology procedures worldwide [...] Read more.

The prevalence of infertility is getting higher over the years. The increasing age of first-time parents, although economically more desirable, can cause various biological problems from low natural conception rate to poor pregnancy outcomes. The growing demand for assisted reproductive technology procedures worldwide draws medical specialists’ and scientists’ attention to various elements which could lead to successful conception, such as follicular fluid (FF) and hormones. In this study, we analyzed the effects of exposure to follicle-stimulating hormone (FSH) on FF-derived stromal cells isolated from females admitted for treatment due to infertility, participating in assisted reproductive technologies procedures. We demonstrated that FF stromal cells are positive for mesenchymal stromal cell surface markers (CD90⁺, CD44⁺, CD166⁺) and showed that FSH has no impact on FF stromal cell morphology yet lowers proliferation rate. Using a real-time polymerase chain reaction method, we indicated that the expression of PTGS2 is significantly downregulated in FF sediment cells of patients who did not conceive; furthermore, we showed that FSH can affect the expression of ovarian follicle development and FSH response-related genes differentially depending on the length of exposure and that levels of ovulatory cascade genes differ in conceived and not-conceived patients’ FF stromal cells. Using mass spectrometry analysis, we identified 97 proteins secreted by FF stromal cells. The identified proteins are related to stress response, positive regulation of apoptotic cell clearance and embryo implantation. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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11 pages, 1035 KiB

Open AccessArticle

The Polymorphism Asn680Ser on the FSH Receptor and Abnormal Ovarian Response in Patients with Normal Values of AMH and AFC

by Giorgio Maria Baldini, Assunta Catino, Simone Palini, Romualdo Sciorio, Daniele Ferri, Marina Vinciguerra and Domenico Baldini

Int. J. Mol. Sci. 2023, 24(2), 1080; https://doi.org/10.3390/ijms24021080 - 5 Jan 2023

Cited by 7 | Viewed by 2634

Abstract

After the controlled ovarian stimulation (COS), the number of cumulus oocyte complexes collected is lower than predicted. The aim of this study is to understand if there is a possible reason for that deficient ovarian response. It was hypothesized that this is associated [...] Read more.

After the controlled ovarian stimulation (COS), the number of cumulus oocyte complexes collected is lower than predicted. The aim of this study is to understand if there is a possible reason for that deficient ovarian response. It was hypothesized that this is associated with the SNP (single-nucleotide polymorphism) of the FSH receptor (FSHr), specifically c.2039A > G, resulting in Asn680Ser. Two groups of patients were enrolled for this purpose: the normal (n = 36) and abnormal responses (n = 31). To predict the number of retrievable oocytes, according to the anti-Mũllerian hormone (AMH) and the antral follicle count (AFC), the following formula was applied in a log scale: the number of oocytes retrieved = 2.584 − 0.015 × (age) − 0.035 × (FSH) + 0.038 × (AMH) + 0.026 × (AFC). Then, when the number of oocytes collected was less than 50% of the calculated value, it was proposed that the patients result in an abnormal response. DNA sample blood was collected from the women, and then the genetic assessment for the Asn680Ser of the FSHr was evaluated in both groups. The differences between the two categories were statistically analyzed with an independent samples t test, a Mann–Whitney U test and a Chi-squared test. In a patient with an abnormal response, a significant prevalence of the amino acid serine at position 680 of the FSHr compared to the counterpart group (p < 0.05) was detected. In conclusion, according to the results, the genetic evaluation of the FSHr could represent an accurate and predictive feature for patients undergoing assisted reproductive technology treatment. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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22 pages, 3430 KiB

Open AccessArticle

Proteome Mapping of Cervical Mucus and Its Potential as a Source of Biomarkers in Female Tract Disorders

by Tomáš Oždian, Jan Vodička, Jiří Dostál, Dušan Holub, Jana Václavková, Michal Ješeta, Barbora Hamerníková, Pavla Kouřilová, Ondřej Malchar, Vladimír Dvořák, Pavel Hejtmánek, Kateřina Sobková, Pavel Ventruba, Radovan Pilka, Petr Džubák and Marián Hajdúch

Int. J. Mol. Sci. 2023, 24(2), 1038; https://doi.org/10.3390/ijms24021038 - 5 Jan 2023

Cited by 5 | Viewed by 3457

Abstract

Cervical mucus (CM) is a viscous fluid that is produced by the cervical glands and functions as a uterine cervix plug. Its viscosity decreases during ovulation, providing a window for non-invasive sampling. This study focuses on proteomic characterization of CM to evaluate its [...] Read more.

Cervical mucus (CM) is a viscous fluid that is produced by the cervical glands and functions as a uterine cervix plug. Its viscosity decreases during ovulation, providing a window for non-invasive sampling. This study focuses on proteomic characterization of CM to evaluate its potential as a non-invasively acquired source of biomarkers and in understanding of molecular (patho)physiology of the female genital tract. The first objective of this work was to optimize experimental workflow for CM processing and the second was to assess differences in the proteomic composition of CM during natural ovulatory cycles obtained from intrauterine insemination (IUI) cycles and in vitro fertilization (IVF) cycles with controlled ovarian hyperstimulation. Proteomic analysis of CM samples revealed 4370 proteins involved in processes including neutrophil degranulation, cellular stress responses, and hemostasis. Differential expression analysis revealed 199 proteins enriched in IUI samples and 422 enriched in IVF. The proteins enriched in IUI were involved in phosphatidic acid synthesis, responses to external stimulus, and neutrophil degranulation, while those enriched in IVF samples were linked to neutrophil degranulation, formation of a cornified envelope and hemostasis. Subsequent analyses clarified the protein composition of the CM and how it is altered by hormonal stimulation of the uterus. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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27 pages, 5626 KiB

Open AccessArticle

Integrative Proteomics and Transcriptomics Profiles of the Oviduct Reveal the Prolificacy-Related Candidate Biomarkers of Goats (Capra hircus) in Estrous Periods

by Zhipeng Sun, Yufang Liu, Xiaoyun He, Ran Di, Xiangyu Wang, Chunhuan Ren, Zijun Zhang and Mingxing Chu

Int. J. Mol. Sci. 2022, 23(23), 14888; https://doi.org/10.3390/ijms232314888 - 28 Nov 2022

Cited by 4 | Viewed by 2727

Abstract

The oviduct is a dynamic reproductive organ for mammalian reproduction and is required for gamete storage, maturation, fertilization, and early embryonic development, and it directly affects fecundity. However, the molecular regulation of prolificacy occurring in estrous periods remain poorly understood. This study aims [...] Read more.

The oviduct is a dynamic reproductive organ for mammalian reproduction and is required for gamete storage, maturation, fertilization, and early embryonic development, and it directly affects fecundity. However, the molecular regulation of prolificacy occurring in estrous periods remain poorly understood. This study aims to gain a better understanding of the genes involved in regulating goat fecundity in the proteome and transcriptome levels of the oviducts. Twenty female Yunshang black goats (between 2 and 3 years old, weight 52.22 ± 0.43 kg) were divided into high- and low-fecundity groups in the follicular (FH and FL, five individuals per group) and luteal (LH and LL, five individuals per group) phases, respectively. The DIA-based high-resolution mass spectrometry (MS) method was used to quantify proteins in twenty oviducts. A total of 5409 proteins were quantified, and Weighted gene co-expression network analysis (WGCNA) determined that the tan module was highly associated with the high-fecundity trait in the luteal phase, and identified NUP107, ANXA11, COX2, AKP13, and ITF140 as hub proteins. Subsequently, 98 and 167 differentially abundant proteins (DAPs) were identified in the FH vs. FL and LH vs. LL comparison groups, respectively. Parallel reaction monitoring (PRM) was used to validate the results of the proteomics data, and the hub proteins were analyzed with Western blot (WB). In addition, biological adhesion and transporter activity processes were associated with oviductal function, and several proteins that play roles in oviductal communication with gametes or embryos were identified, including CAMSAP3, ITGAM, SYVN1, EMG1, ND5, RING1, CBS, PES1, ELP3, SEC24C, SPP1, and HSPA8. Correlation analysis of proteomics and transcriptomic revealed that the DAPs and differentially expressed genes (DEGs) are commonly involved in the metabolic processes at the follicular phase; they may prepare the oviductal microenvironment for gamete reception; and the MAP kinase activity, estrogen receptor binding, and angiotensin receptor binding terms were enriched in the luteal phase, which may be actively involved in reproductive processes. By generating the proteome data of the oviduct at two critical phases and integrating transcriptome analysis, we uncovered novel aspects of oviductal gene regulation of fecundity and provided a reference for other mammals. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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10 pages, 1313 KiB

Open AccessArticle

Down-Regulation of Neogenin Decreases Proliferation and Differentiation of Spermatogonia during the Early Phase of Spermatogenesis

by Jin Woo Park, Yu Jin Kim, Sang Jin Lee, Jung Jae Ko, Dae Keun Kim and Jae Ho Lee

Int. J. Mol. Sci. 2022, 23(23), 14761; https://doi.org/10.3390/ijms232314761 - 25 Nov 2022

Viewed by 1706

Abstract

Non-obstructive azoospermia is a major clinical issue associated with male infertility that remains to be addressed. Although neogenin is reportedly abundantly expressed in the testis, its role in mammalian spermatogenesis is unknown. We systematically investigated the role of neogenin during spermatogenesis by performing [...] Read more.

Non-obstructive azoospermia is a major clinical issue associated with male infertility that remains to be addressed. Although neogenin is reportedly abundantly expressed in the testis, its role in mammalian spermatogenesis is unknown. We systematically investigated the role of neogenin during spermatogenesis by performing loss-of-function studies. Testis-specific neogenin conditional knock-out (cKO) mice were generated using CRISPR/Cas9 and neogenin-targeting guide RNAs. We analyzed the expression profiles of germ cell factors by RT-PCR and Western blotting. Neogenin localized mainly to spermatogonia in seminiferous tubules of mouse testes. RT-PCR and Western blot analyses further demonstrated that neogenin expression varied during spermatogenesis and was dramatically increased at postnatal day 12–25 during the pubertal stage. In neogenin-cKO mouse testes, the ratio of primary and secondary spermatocytes was significantly decreased compared with the control, while the number of apoptotic testicular cells was significantly increased. Taken together, these results suggest that neogenin plays a pivotal role in the maintenance and proliferation of spermatogonia during the early stage of spermatogenesis in mice. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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14 pages, 2014 KiB

Open AccessArticle

Correlation between Sperm Micro Ribonucleic Acid-34b and -34c Levels and Clinical Outcomes of Intracytoplasmic Sperm Injection in Men with Male Factor Infertility

by Ling-Yu Yeh, Robert Kuo-Kuang Lee, Ming-Huei Lin, Chih-Hung Huang and Sheng-Hsiang Li

Int. J. Mol. Sci. 2022, 23(20), 12381; https://doi.org/10.3390/ijms232012381 - 16 Oct 2022

Cited by 5 | Viewed by 1693

Abstract

Few studies have examined the correlation between sperm miRNA levels and clinical outcomes of intracytoplasmic sperm injection (ICSI). In this study, we aimed to assess the correlation of sperm miR-34b, miR-34c, miR-122, and miR-429 levels with ICSI outcomes in men with teratozoospermia and [...] Read more.

Few studies have examined the correlation between sperm miRNA levels and clinical outcomes of intracytoplasmic sperm injection (ICSI). In this study, we aimed to assess the correlation of sperm miR-34b, miR-34c, miR-122, and miR-429 levels with ICSI outcomes in men with teratozoospermia and asthenozoospermia. TaqMan microRNA quantitative polymerase chain reaction was used to evaluate the relative expression of miRNAs in sperm. The relative miRNA levels quantified using a comparative method found that the four miRNAs were not associated with fertilization rate and early embryo development. However, revels of miR-34b and miR-34c in teratozoospermia sperm of the live birth group were significantly higher than those in the non-live birth group. Receiver operating characteristic curve analysis revealed that the optimal cut-off delta cycle threshold values of miR-34b and miR-34c were 8.630 and 7.883, respectively. Statistical analysis found that the levels of miR-34b and the miR-34c in teratozoospermic and asthenozoospermic sperm above the thresholds were not associated with the fertilization rate and the high-quality embryo rate above 50%; however, they were more likely to exhibit higher implantation, pregnancy, and live birth rates. miR-34b and miR-34c were significantly associated with ICSI clinical outcomes in male factor infertility, especially teratozoospermia. Further validation is required before it becomes a clinically valid reference indicator. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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12 pages, 2272 KiB

Open AccessArticle

Identification and Characterization of Piwi-Interacting RNAs for Early Testicular Development in Yak

by Yongfu La, Xiaoming Ma, Pengjia Bao, Min Chu, Ping Yan, Xian Guo and Chunnian Liang

Int. J. Mol. Sci. 2022, 23(20), 12320; https://doi.org/10.3390/ijms232012320 - 14 Oct 2022

Cited by 9 | Viewed by 1791

Abstract

Normal testicular development plays a crucial role in male reproduction and is the precondition for spermatogenesis. PIWI-interacting RNAs (piRNAs) are novel noncoding RNAs expressed in animal germ cells that form complexes with PIWI family proteins and are involved in germ cell development, differentiation, [...] Read more.

Normal testicular development plays a crucial role in male reproduction and is the precondition for spermatogenesis. PIWI-interacting RNAs (piRNAs) are novel noncoding RNAs expressed in animal germ cells that form complexes with PIWI family proteins and are involved in germ cell development, differentiation, and spermatogenesis. However, changes in piRNA expression profiles during early testicular development in yak have not been investigated. In this study, we used small RNA sequencing to evaluate the differences and potential functions of piRNA expression profiles in 6-, 18-, and 30-month-old yak testis tissues. Differential expression analysis found 109, 293, and 336 differentially expressed piRNAs in M30 vs. M18, M18 vs. M6, and M30 vs. M6, respectively, and found 30 common differentially expressed piRNAs in the three groups of M6, M18, and M30. In addition, the functional enrichment analysis of differentially expressed piRNAs target genes indicated that they were related to testicular development and spermatogenesis. Finally, we detected the expression of the PIWI protein family in the yak testis at different developmental stages and found that PIWIL1, PIWIL2, PIWIL3, and PIWIL4 were highly expressed in 18- and 30-month-old yak testis and almost not expressed in 6-month-old yak testis. In conclusion, this study summarizes the changes of piRNA expression patterns during the early development of yak testis and provides new clues for the regulatory role of piRNA in yak testis. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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9 pages, 1105 KiB

Open AccessArticle

Development of the Connecting Piece in ODF1-Deficient Mouse Spermatids

by Sigrid Hoyer-Fender

Int. J. Mol. Sci. 2022, 23(18), 10280; https://doi.org/10.3390/ijms231810280 - 7 Sep 2022

Cited by 6 | Viewed by 1669

Abstract

ODF1 is a major protein of the accessory fibres of the mammalian sperm tail. In addition, ODF1 is found in the connecting piece, a complex structure located at the posterior end of the nucleus that connects the sperm head and tail. The tight [...] Read more.

ODF1 is a major protein of the accessory fibres of the mammalian sperm tail. In addition, ODF1 is found in the connecting piece, a complex structure located at the posterior end of the nucleus that connects the sperm head and tail. The tight coupling of the sperm head and tail is critical for the progressive motility of the sperm to reach the oocyte for fertilisation. The depletion of ODF1 by homologous recombination in mice led to male infertility. Although sperm tails were present in the epididymis, no intact spermatozoa were found. Instead, the depletion of ODF1 resulted in sperm decapitation, suggesting that ODF1 is essential for the formation of the coupling apparatus and the tight linkage of the sperm head and tail. However, the development of the linkage complex in the absence of ODF1 has never been investigated. Here, I analysed the fine structure of the developing connecting piece by transmission electron microscopy. I show that the connecting piece develops as in wild-type spermatids. Structural abnormalities were not observed when ODF1 was absent. Thus, ODF1 is dispensable for the development of the connecting piece. However, the decapitation of ODF1-deficient spermatozoa indicates that the heads and tails of the spermatozoa are not linked, so that they separate when force is applied. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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21 pages, 3634 KiB

Open AccessArticle

Endometrial Epithelial ARID1A Is Required for Uterine Immune Homeostasis during Early Pregnancy

by Ryan M. Marquardt, Soo Hyun Ahn, Jake J. Reske, Ronald L. Chandler, Margaret G. Petroff, Tae Hoon Kim and Jae-Wook Jeong

Int. J. Mol. Sci. 2022, 23(11), 6067; https://doi.org/10.3390/ijms23116067 - 28 May 2022

Cited by 1 | Viewed by 3159

Abstract

A growing body of work suggests epigenetic dysregulation contributes to endometriosis pathophysiology and female infertility. The chromatin remodeling complex subunit AT-rich interaction domain 1A (ARID1A) must be properly expressed to maintain normal uterine function. Endometrial epithelial ARID1A is indispensable for pregnancy establishment in [...] Read more.

A growing body of work suggests epigenetic dysregulation contributes to endometriosis pathophysiology and female infertility. The chromatin remodeling complex subunit AT-rich interaction domain 1A (ARID1A) must be properly expressed to maintain normal uterine function. Endometrial epithelial ARID1A is indispensable for pregnancy establishment in mice through regulation of endometrial gland function; however, ARID1A expression is decreased in infertile women with endometriosis. We hypothesized that ARID1A performs critical operations in the endometrial epithelium necessary for fertility besides maintaining gland function. To identify alterations in uterine gene expression resulting from loss of epithelial ARID1A, we performed RNA-sequencing analysis on pre-implantation uteri from Ltf^iCre/+Arid1a^f/f and control mice. Differential expression analysis identified 4181 differentially expressed genes enriched for immune-related ingenuity canonical pathways including agranulocyte adhesion and diapedesis and natural killer cell signaling. RT-qPCR confirmed an increase in pro-inflammatory cytokine and macrophage-related gene expression but a decrease in natural killer cell signaling. Immunostaining confirmed a uterus-specific increase in macrophage infiltration. Flow cytometry delineated an increase in inflammatory macrophages and a decrease in uterine dendritic cells in Ltf^iCre/+Arid1a^f/f uteri. These findings demonstrate a role for endometrial epithelial ARID1A in suppressing inflammation and maintaining uterine immune homeostasis, which are required for successful pregnancy and gynecological health. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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32 pages, 27166 KiB

Open AccessArticle

Understanding the Underlying Molecular Mechanisms of Meiotic Arrest during In Vitro Spermatogenesis in Rat Prepubertal Testicular Tissue

by Justine Saulnier, Frédéric Chalmel, Marion Delessard, Laura Moutard, Tony Pereira, François Fraissinet, Ludovic Dumont, Aurélie Rives-Feraille, Christine Rondanino and Nathalie Rives

Int. J. Mol. Sci. 2022, 23(11), 5893; https://doi.org/10.3390/ijms23115893 - 24 May 2022

Cited by 5 | Viewed by 2949

Abstract

In vitro spermatogenesis appears to be a promising approach to restore the fertility of childhood cancer survivors. The rat model has proven to be challenging, since germ cell maturation is arrested in organotypic cultures. Here, we report that, despite a meiotic entry, abnormal [...] Read more.

In vitro spermatogenesis appears to be a promising approach to restore the fertility of childhood cancer survivors. The rat model has proven to be challenging, since germ cell maturation is arrested in organotypic cultures. Here, we report that, despite a meiotic entry, abnormal synaptonemal complexes were found in spermatocytes, and in vitro matured rat prepubertal testicular tissues displayed an immature phenotype. RNA-sequencing analyses highlighted up to 600 differentially expressed genes between in vitro and in vivo conditions, including genes involved in blood-testis barrier (BTB) formation and steroidogenesis. BTB integrity, the expression of two steroidogenic enzymes, and androgen receptors were indeed altered in vitro. Moreover, most of the top 10 predicted upstream regulators of deregulated genes were involved in inflammatory processes or immune cell recruitment. However, none of the three anti-inflammatory molecules tested in this study promoted meiotic progression. By analysing for the first time in vitro matured rat prepubertal testicular tissues at the molecular level, we uncovered the deregulation of several genes and revealed that defective BTB function, altered steroidogenic pathway, and probably inflammation, could be at the origin of meiotic arrest. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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Review

Jump to: Research, Other

14 pages, 827 KiB

Open AccessReview

The Role of Inositols in the Hyperandrogenic Phenotypes of PCOS: A Re-Reading of Larner’s Results

by Valeria Fedeli, Angela Catizone, Alessandro Querqui, Vittorio Unfer and Mariano Bizzarri

Int. J. Mol. Sci. 2023, 24(7), 6296; https://doi.org/10.3390/ijms24076296 - 27 Mar 2023

Cited by 10 | Viewed by 4759

Abstract

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers—myo-Inositol and D-Chiro-Inositol—have recently been pharmacologically effective in managing many PCOS [...] Read more.

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers—myo-Inositol and D-Chiro-Inositol—have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association—according to the physiological ratio of 40:1—patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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21 pages, 1618 KiB

Open AccessReview

Bypassing Mendel’s First Law: Transmission Ratio Distortion in Mammals

by Gaëlle Friocourt, Aurore Perrin, Paul A. Saunders, Elvira Nikalayevich, Cécile Voisset, Charles Coutton, Guillaume Martinez and Frédéric Morel

Int. J. Mol. Sci. 2023, 24(2), 1600; https://doi.org/10.3390/ijms24021600 - 13 Jan 2023

Cited by 2 | Viewed by 3639

Abstract

Mendel’s law of segregation states that the two alleles at a diploid locus should be transmitted equally to the progeny. A genetic segregation distortion, also referred to as transmission ratio distortion (TRD), is a statistically significant deviation from this rule. TRD has been [...] Read more.

Mendel’s law of segregation states that the two alleles at a diploid locus should be transmitted equally to the progeny. A genetic segregation distortion, also referred to as transmission ratio distortion (TRD), is a statistically significant deviation from this rule. TRD has been observed in several mammal species and may be due to different biological mechanisms occurring at diverse time points ranging from gamete formation to lethality at post-natal stages. In this review, we describe examples of TRD and their possible mechanisms in mammals based on current knowledge. We first focus on the differences between TRD in male and female gametogenesis in the house mouse, in which some of the most well studied TRD systems have been characterized. We then describe known TRD in other mammals, with a special focus on the farmed species and in the peculiar common shrew species. Finally, we discuss TRD in human diseases. Thus far, to our knowledge, this is the first time that such description is proposed. This review will help better comprehend the processes involved in TRD. A better understanding of these molecular mechanisms will imply a better comprehension of their impact on fertility and on genome evolution. In turn, this should allow for better genetic counseling and lead to better care for human families. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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22 pages, 1970 KiB

Open AccessReview

Translational Bioinformatics for Human Reproductive Biology Research: Examples, Opportunities and Challenges for a Future Reproductive Medicine

by Kun Liu, Yingbo Zhang, César Martin, Xiaoling Ma and Bairong Shen

Int. J. Mol. Sci. 2023, 24(1), 4; https://doi.org/10.3390/ijms24010004 - 20 Dec 2022

Cited by 6 | Viewed by 3878

Abstract

Since 1978, with the first IVF (in vitro fertilization) baby birth in Manchester (England), more than eight million IVF babies have been born throughout the world, and many new techniques and discoveries have emerged in reproductive medicine. To summarize the modern technology and [...] Read more.

Since 1978, with the first IVF (in vitro fertilization) baby birth in Manchester (England), more than eight million IVF babies have been born throughout the world, and many new techniques and discoveries have emerged in reproductive medicine. To summarize the modern technology and progress in reproductive medicine, all scientific papers related to reproductive medicine, especially papers related to reproductive translational medicine, were fully searched, manually curated and reviewed. Results indicated whether male reproductive medicine or female reproductive medicine all have made significant progress, and their markers have experienced the progress from karyotype analysis to single-cell omics. However, due to the lack of comprehensive databases, especially databases collecting risk exposures, disease markers and models, prevention drugs and effective treatment methods, the application of the latest precision medicine technologies and methods in reproductive medicine is limited. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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20 pages, 2452 KiB

Open AccessReview

Proteoglycans: Systems-Level Insight into Their Expression in Healthy and Diseased Placentas

by Orsolya Oravecz, Andrea Balogh, Roberto Romero, Yi Xu, Kata Juhasz, Zsolt Gelencser, Zhonghui Xu, Gaurav Bhatti, Roger Pique-Regi, Balint Peterfia, Petronella Hupuczi, Ilona Kovalszky, Padma Murthi, Adi L. Tarca, Zoltan Papp, Janos Matko and Nandor Gabor Than

Int. J. Mol. Sci. 2022, 23(10), 5798; https://doi.org/10.3390/ijms23105798 - 21 May 2022

Cited by 8 | Viewed by 3358

Abstract

Proteoglycan macromolecules play key roles in several physiological processes (e.g., adhesion, proliferation, migration, invasion, angiogenesis, and apoptosis), all of which are important for placentation and healthy pregnancy. However, their precise roles in human reproduction have not been clarified. To fill this gap, herein, [...] Read more.

Proteoglycan macromolecules play key roles in several physiological processes (e.g., adhesion, proliferation, migration, invasion, angiogenesis, and apoptosis), all of which are important for placentation and healthy pregnancy. However, their precise roles in human reproduction have not been clarified. To fill this gap, herein, we provide an overview of the proteoglycans’ expression and role in the placenta, in trophoblast development, and in pregnancy complications (pre-eclampsia, fetal growth restriction), highlighting one of the most important members of this family, syndecan-1 (SDC1). Microarray data analysis showed that of 34 placentally expressed proteoglycans, SDC1 production is markedly the highest in the placenta and that SDC1 is the most upregulated gene during trophoblast differentiation into the syncytiotrophoblast. Furthermore, placental transcriptomic data identified dysregulated proteoglycan genes in pre-eclampsia and in fetal growth restriction, including SDC1, which is supported by the lower concentration of syndecan-1 in maternal blood in these syndromes. Overall, our clinical and in vitro studies, data analyses, and literature search pointed out that proteoglycans, as important components of the placenta, may regulate various stages of placental development and participate in the maintenance of a healthy pregnancy. Moreover, syndecan-1 may serve as a useful marker of syncytialization and a prognostic marker of adverse pregnancy outcomes. Further studies are warranted to explore the role of proteoglycans in healthy and complicated pregnancies, which may help in diagnostic or therapeutic developments. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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12 pages, 499 KiB

Open AccessReview

Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism

by Decio Armanini, Marco Boscaro, Luciana Bordin and Chiara Sabbadin

Int. J. Mol. Sci. 2022, 23(8), 4110; https://doi.org/10.3390/ijms23084110 - 8 Apr 2022

Cited by 111 | Viewed by 15624

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous and extremely common disease with symptoms that vary with the age of the patient, typically characterized by hyperandrogenism, chronic oligo-anovulation, and/or several metabolic disorders. The syndrome includes various phenotypes, and the pathogenesis is multifactorial, often involving [...] Read more.

Polycystic ovary syndrome (PCOS) is a heterogeneous and extremely common disease with symptoms that vary with the age of the patient, typically characterized by hyperandrogenism, chronic oligo-anovulation, and/or several metabolic disorders. The syndrome includes various phenotypes, and the pathogenesis is multifactorial, often involving insulin resistance. This feature is closely related to ovarian dysfunction, inflammation, hyperandrogenism, and metabolic disorders, which characterize and complicate the syndrome. Therapy currently considers both lifestyle improvements and medications, and must be tailored on a case-by-case basis. To date, the published studies have not arrived at a definition of the most suitable therapy for each individual case and many of the drugs used are still off-label. In this review, we discuss some controversial diagnostic and therapeutic aspects of PCOS, such as the role of insulin resistance, inflammation, and hyperandrogenism. We also evaluated the advantages and disadvantages of contraceptive therapy and antiandrogens. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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Other

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11 pages, 1795 KiB

Open AccessBrief Report

Impaired Blastocyst Formation in Lnx2-Knockdown Mouse Embryos

by Seung-Jae Lee, Jaehwan Kim, Gwidong Han, Seung-Pyo Hong, Dayeon Kim and Chunghee Cho

Int. J. Mol. Sci. 2023, 24(2), 1385; https://doi.org/10.3390/ijms24021385 - 10 Jan 2023

Viewed by 1755

Abstract

Ligand of Numb-protein X 2 (LNX2) is an E3 ubiquitin ligase that is known to regulate Notch signaling by participating in NUMB protein degradation. Notch signaling is important for differentiation and proliferation in mammals, and plays a significant role in blastocyst formation during [...] Read more.

Ligand of Numb-protein X 2 (LNX2) is an E3 ubiquitin ligase that is known to regulate Notch signaling by participating in NUMB protein degradation. Notch signaling is important for differentiation and proliferation in mammals, and plays a significant role in blastocyst formation during early embryonic development. In this study, we investigated Lnx2 in mouse preimplantation embryos. Expression analysis showed that Lnx2 is expressed in oocytes and preimplantation embryos. Lnx2-knockdown embryos normally progress to the morula stage, but the majority of them do not develop into normal blastocysts. Transcript analysis revealed that the expression levels of genes critical for cell lineage specification, including octamer-binding transcription factor 4 (Oct4), are increased in Lnx2 knockdown embryos. Furthermore, the expression levels of Notch and Hippo signaling-related genes are also increased by Lnx2 knockdown. Collectively, our results show that Lnx2 is important for blastocyst formation in mice, suggest that this may act via lineage specification of inner cell mass, and further show that Lnx2 may be involved in transcriptionally regulating various genes implicated in early embryonic development. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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14 pages, 2572 KiB

Open AccessCase Report

Molecular Characterization of a Rare Case of Monozygotic Dichorionic Diamniotic Twin Pregnancy after Single Blastocyst Transfer in Preimplantation Genetic Testing (PGT)

by Sophie Brouillet, Sandie Mereuze, Noémie Ranisavljevic, Claire Chauveau, Samir Hamamah, Julie Cattin, Camille Verebi, Christelle Cabrol, Aliya Ishmukhametova, Anne Girardet, Tal Anahory and Marjolaine Willems

Int. J. Mol. Sci. 2022, 23(18), 10835; https://doi.org/10.3390/ijms231810835 - 16 Sep 2022

Cited by 3 | Viewed by 2351

Abstract

Preimplantation genetic testing (PGT) is widely used to select unaffected embryos, increasing the odds of having a healthy baby. During the last few decades, it was accepted that monozygotic dichorionic diamniotic twin pregnancies occurred from the embryo splitting before Day 3 postfertilization according [...] Read more.

Preimplantation genetic testing (PGT) is widely used to select unaffected embryos, increasing the odds of having a healthy baby. During the last few decades, it was accepted that monozygotic dichorionic diamniotic twin pregnancies occurred from the embryo splitting before Day 3 postfertilization according to Corner’s dogma. Hence, the occurrence of a dichorionic diamniotic twin pregnancy after a single blastocyst transfer was considered a dizygotic pregnancy resulting from blastocyst transfer and concurrent natural fertilization. In our study, we have provided for the first time molecular proof that a single blastocyst transfer can result in a monozygotic dichorionic diamniotic twin pregnancy, invalidating Corner’s dogma. In this case, we recommend systematically assessing the genetic status of dichorionic twins after single blastocyst transfer using prenatal diagnosis to exclude the risk from a potential concurrent spontaneous pregnancy and to ensure that both fetuses are unaffected. To achieve this goal, we have developed here an innovative noninvasive prenatal diagnosis by exclusion of paternal variants with droplet digital PCR, maximizing the reliability of genetic diagnosis. Further multicentric prospective studies using genetic testing are now required to establish the rate of blastocyst splitting leading to dichorionic pregnancy in PGT and to identify the risk factors. Full article

(This article belongs to the Special Issue Advance in Reproductive Biology and Related Diseases)

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