Epididymal epithelial degeneration and lipid metabolism impairment account for male infertility in occludin knockout mice
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ABSTRACT:
PROVIDER: PRJNA699449 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13627864_1.fastq.gz | Fastqsanger.gz | |||
| SRR13627864_2.fastq.gz | Fastqsanger.gz | |||
| SRR13627865_1.fastq.gz | Fastqsanger.gz | |||
| SRR13627865_2.fastq.gz | Fastqsanger.gz | |||
| SRR13627866_1.fastq.gz | Fastqsanger.gz |
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Project description:Occludin (OCLN) is a tight junction protein and Ocln deletion mutation causes male infertility in mice. However, the role of OCLN in male reproductive system remains unknown. In this study, we found defective proximal epididymis in Ocln-null mice with impaired sperm motility and fertilization, but no defects in testicular spermatogenesis. Integrative omics analysis revealed the downregulation of gene clusters enriched in acid secretion and fatty acid metabolism in the Ocln-null epididymis, especially the enzymes related to the unsaturated arachidonic acid pathway. The number of proton-pump V-ATPase-expression clear cells, a key player of luminal acidification in the epididymis, declined drastically from prepubertal age before sperm arrival but not in the early postnatal-age. This was accompanied by clear cell apoptosis and increase in pH in the epididymal fluid of OCLN-deficient mice. The lipidomics results showed significantly increased levels of specific DAGs conjugated to unsaturated fatty acids in the Ocln-mutant. Immunofluorescent labeling showed that the arachidonic acid converting enzyme PTGDS and phospholipase PLA2g12a were prominently altered in the principal cells and luminal contents of the Ocln-mutant epididymis. Whereas the carboxylate ester lipase CES1, originally enriched in the WT basal cells, was found upregulated in the Ocln-mutant principal cells. Overall, this study demonstrates that OCLN is essential for maintaining the survival of acid-secreting clear cells and unsaturated fatty acid catabolism in the mouse epididymis, as well as ensuring sperm maturation and male fertility.
2022-11-07 | GSE166141 | GEO
Project description:Occludin (OCLN) is a tight junction protein and Ocln deletion mutation causes male infertility in mice. However, the role of OCLN in male reproductive system remains unknown. In this study, we found defective proximal epididymis in Ocln-null mice with impaired sperm mobility and fertilization, but no defects in testicular spermatogenesis. Integrative omics analysis revealed the downregulation of gene clusters enriched in acid secretion and fatty acid metabolism in the Ocln-null epididymis, especially the enzymes related to the unsaturated arachidonic acid pathway. The number of proton-pump V-ATPase-expression clear cells, a key player of luminal acidification in the epididymis, declined drastically from prepubertal age before sperm arrival but not in the early postnatal-age. This was accompanied by clear cell apoptosis and increase in pH in the epididymal fluid of OCLN-deficient mice. The lipidomics results showed significantly increased levels of specific DAGs conjugated to unsaturated fatty acids in the Ocln-mutant. Immunofluorescent labeling showed that the arachidonic acid converting enzyme PTGDS and phospholipase PLA2g12a were prominently altered in the principal cells and luminal contents of the Ocln-mutant epididymis. Whereas the carboxylate ester lipase CES1, originally enriched in the WT basal cells, was found upregulated in the Ocln-mutant principal cells. Overall, this study demonstrates that OCLN is essential for maintaining the survival of acid-secreting clear cells and unsaturated fatty acid catabolism in the mouse epididymis, as well as ensuring sperm maturation and male fertility.
2022-10-25 | PXD037690 |
Project description:Occludin (OCLN) is a tight junction protein and Ocln deletion mutation causes male infertility in mice. However, the role of OCLN in male reproductive system remains unknown. In this study, we used an interdisciplinary approach to elucidate the underlying mechanism of male infertility in related to OCLN function, including Ocln knockout mice as well as a combined omics analysis and immunofluorescent labelling. Our results showed that the epididymis of Ocln-null mice displayed a phenomenon resembling epididymal sperm granuloma, which occurred especially in the junctional region between caput and corpus epididymidis. Sperm motility and fertilisation capacity were also impaired in these Ocln-null mice, accompanied by enlarged tubules in the proximal regions and degeneration in the distal regions of epididymis. Cellular localization analysis showed that OCLN immunofluorescence was enriched only in the apical junction of epithelial principal cells in the proximal regions of epididymis. Integrative omics analysis revealed the downregulation of gene clusters enriched in acid secretion and fatty acid metabolism in the Ocln-null epididymis, especially the enzymes related to the unsaturated arachidonic acid pathway. The number of proton-pump V-ATPase-expression clear cells, a key player of luminal acidification in the epididymis, declined drastically from prepubertal age before sperm arrival but not in the early postnatal age. This was accompanied by programmed cell death of clear cells and increased pH in the epididymal fluid of OCLN-deficient mice. The lipidomics results showed significantly increased levels of specific DAGs conjugated to unsaturated fatty acids in the Ocln-mutant. Immunofluorescent labelling showed that the arachidonic acid converting enzyme PTGDS and phospholipase PLA2g12a were prominently altered in the principal cells and luminal contents of the Ocln-mutant epididymis. Whereas the carboxylate ester lipase CES1, originally enriched in the WT basal cells, was found upregulated in the Ocln-mutant principal cells. Overall, this study demonstrates that OCLN is essential for maintaining caput-to-corpus epithelial integrity, survival of acid-secreting clear cells, and unsaturated fatty acid catabolism in the mouse epididymis, thereby ensuring sperm maturation and male fertility.
| S-EPMC9742356 | biostudies-literature
Project description:Background. Primary cilia (PC) are solitary antennae present at the cell surface. These non-motile cilia play an important role in organ development and tissue homeostasis through the transduction of the Hedgehog (Hh) signaling pathway. We recently revealed the presence of PC in the epithelium of the developing epididymis, an organ of the male reproductive system whose dysfunction triggers male infertility. Acknowledging that systemic blockade of the Hh pathway trigger epididymal dysfunctions in vivo, our main goals were 1) to portray the epididymal Hh environment, 2) to determine the direct responsiveness of epididymal epithelial cells to Hh, and 3) to define the contribution of PC to the transduction of this pathway. Results. The Hh ligands Indian and Sonic hedgehog (Ihh and Shh) were respectively located in principal and clear cells of the mouse epididymis by immunofluorescent staining. The propensity of epididymal principal cells to respond to Hh signaling was assessed on immortalized epididymal DC2 cells by western-blot, confocal imaging and 3D-reconstruction. Our results indicate that epididymal principal cells secrete Ihh and expose PC that co-localize with the conventional acetylated tubulin/Arl13b ciliary markers, as well as with GLI3 Hh signaling factor. Gene expression microarray profiling indicated that the expression of 43 and 248 genes was respectively and significantly modified following pharmacological treatment of DC2 cells with the Hh agonist SAG (250 nM) or the Hh antagonist cyclopamine (20 µM) compared with the control. Among Hh target genes identified, 6.7 % presented perfect matches for GLI-transcription factor consensus sequences, and the majority belonged to interferon-dependent immune response and lipocalin 2 pathways. Finally, the contribution of epididymal PC to the transduction of canonical Hh pathway was validated by ciliobrevinD treatment, which induced a significant decrease of PC length and the expressional reduction of Hh signalling targets. Conclusions. All together our data indicate that PC from epithelial principal cells regulate gene expression profile through a possible autocrine Hh signaling. This provides new hypotheses regarding the potential contribution of PC and Hh signaling in intercellular cross-talk and immunological regulation of the epididymis.
2020-04-17 | GSE143829 | GEO
Project description:Granulosa cells are essential to the growth, development, and maturation of oocytes and follicles. In patients with EMs-related infertility, follicle maturation disorders, poor oocyte quality may be closely related to GCs in the follicle. However, the molecular biological mechanism of GCs in EMs-related infertility has not been reported. Therefore, we tried to explore the possible causes of EMs-related infertility through the study of ovarian GCs in patients with EMs-related infertility and tubal factor infertility.
2021-03-05 | GSE168214 | GEO
Project description:Transcriptional profiling of human epididymal cell lines FHCE1 and IHCE1 respectively derived from the caput epididymidis of a fertile and an obstructive azoospermic patient. These two cell lines are comprised of homogenous populations of principal cells immortalized with the SV40 Large T antigen. Goal was to determine if cell junctions are impaired in this type of male infertility. Two-condition experiment, FHCE1 vs. IHCE1 cells. Replicates: 3 replicates from each cell line.
2010-06-08 | E-GEOD-21391 | biostudies-arrayexpress
Project description:Transcriptional profiling of human epididymal cell lines FHCE1 and IHCE1 respectively derived from the caput epididymidis of a fertile and an obstructive azoospermic patient. These two cell lines are comprised of homogenous populations of principal cells immortalized with the SV40 Large T antigen. Goal was to determine if cell junctions are impaired in this type of male infertility.
2010-06-01 | GSE21391 | GEO
Project description:Infertility is a growing global health concern affecting millions of couples worldwide. Both overweight and underweight individuals face reproductive issues, resulting in infertility. Due to small size and short life, mice are not necessarily suitable animal models for human infertility. While, pigs having large size, anatomical and physiological similarities with human are considered as more ideal animal model of human disease. Leptin is a well-known adipokine that serves as an endocrine signal between adiposity and fertility. However, the exact mechanisms underlying leptin's effects on reproductive function remain unclear. To shed light on this, our study focused on pigs genetically engineered to overexpress leptin. These leptin-overexpressing pigs exhibited several reproductive abnormalities, including reduced body weight and size, decreased back fat thickness, and displayed late onset of puberty, and irregular estrous behavior characterized by increased inter-estrous interval and more breeding attempts until pregnancy. This reproductive impairment in leptin pigs was followed by hormonal imbalances and altered steroidogenesis. Bulk RNA sequencing of the ovaries revealed neutrophilic infiltration followed by upregulation of inflammation related genes. To gain a deeper understanding of the cellular levels, we employed single-nucleus RNA sequencing (snRNA-seq), and found that leptin overexpression triggered immune response, suppressed follicle development and luteinization, imposing metabolism dysfunction and hormone imbalance in ovary. Further, trends of phenotypical infertility symptoms and endocrine changes in underweight female patients mirrored the alterations observed in our leptin pigs. These findings suggest that leptin-overexpressing pigs could serve as a valuable animal model for studying infertility and investigating potential therapeutic interventions.
2023-07-17 | GSE237153 | GEO
Project description:To assess the relations of infertility causes and treatment to cancer risk, we will conduct a retrospective cohort study of approximately 12,000 women evaluated for infertility between 1965-1988. These women will be ascertained from several large infertility clinics and private practices in various geographic locations in the United States: Boston, Chicago, Detroit, New York, and Palo Alto. These practices were selected on the basis of their having large number of patients who received ovulation stimulating drugs many years in the distant past. Abstractors reviewed clinic medical records to identify eligible study participants and abstract data needed to classify causes of infertility and document therapies employed. Using a variety of tracing sources (including the National Death Index, credit bureaus, and postmasters), the vital status and location of the study subjects were determined. Subjects who were traced and identified as alive are being sent a detailed questionnaire that requests information on their health status as well as on a number of lifestyle practices. For subjects who report a cancer, medical verification is being sought from the diagnosing physicians and/or facilities. Death certificates are being sought for deceased subjects.
| 2030151 | ecrin-mdr-crc
Project description:Sperm small RNAs have emerged as important non-genetic contributors to embryogenesis and offspring health. A subset of sperm small RNAs are thought to be acquired during epididymal transit. However, the transfer of RNAs from the somatic epididymis to the sperm has been questioned, and the identity of the specific small RNAs transferred remains unclear. Here, we employ Cre/Lox genetics to generate germline- and epididymal-specific Dgcr8 conditional knockout mice to investigate the dynamics of sperm microRNAs and their function in the early embryo. Interestingly, sperm from germline specific Dgcr8 knockout males restored the levels of 58 of the 98 (59%) miRNAs that were lost in testicular sperm during epididymal transit. Conversely, sperm from epididymal Dgcr8 knockouts displayed a 5-fold reduction in 25 miRNAs. This substantial loss of epididymal miRNAs in sperm was accompanied by transcriptomic changes in the embryo which was rescued by microinjection of epididymal miRNAs. These findings ultimately demonstrate the acquisition of miRNAs by sperm during epididymal transit and their regulation of post-fertilization embryonic gene expression.
2024-08-31 | GSE244885 | GEO