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Nature Genetics Oct 2023Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria...
Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy. However, the causative mechanisms of paternal mtDNA elimination have not been defined. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.
Topics: Humans; Male; DNA, Mitochondrial; Maternal Inheritance; Semen; Mitochondria; Spermatozoa; Mitochondrial Proteins
PubMed: 37723262
DOI: 10.1038/s41588-023-01505-9 -
Genes Oct 2023Unlike genetic changes, epigenetics modulates gene expression without stable modification of the genome. Even though all cells, including sperm and egg, have an... (Review)
Review
Unlike genetic changes, epigenetics modulates gene expression without stable modification of the genome. Even though all cells, including sperm and egg, have an epigenome pattern, most of these modifications occur during lifetime and interestingly, some of them, are reversible. Lifestyle and especially nutrients as well as diet regimens are presently gaining importance due to their ability to affect the epigenome. On the other hand, since the epigenome profoundly affects gene expression profile it can be speculated that the epigenome could modulate individual response to nutrients. Recent years have thus seen growing interest on nutrients, macronutrients ratio and diet regimens capable to affect the epigenetic pattern. In fact, while genetic alterations are mostly detrimental at the individual level, reshaping the epigenome may be a feasible strategy to positively counteract the detrimental effect of aging. Here, I review nutrient consumption and diet regimens as a possible strategy to counteract aging-driven epigenome derangement.
Topics: Male; Humans; Semen; Epigenesis, Genetic; Epigenome; Diet; Nutrients
PubMed: 38002940
DOI: 10.3390/genes14111997 -
Advanced Science (Weinheim,... Sep 2023Sperm-induced Ca rise is critical for driving oocyte activation and subsequent embryonic development, but little is known about how lasting Ca oscillations are...
Sperm-induced Ca rise is critical for driving oocyte activation and subsequent embryonic development, but little is known about how lasting Ca oscillations are regulated. Here it is shown that NLRP14, a maternal effect factor, is essential for keeping Ca oscillations and early embryonic development. Few embryos lacking maternal NLRP14 can develop beyond the 2-cell stage. The impaired developmental potential of Nlrp14-deficient oocytes is mainly caused by disrupted cytoplasmic function and calcium homeostasis due to altered mitochondrial distribution, morphology, and activity since the calcium oscillations and development of Nlrp14-deficient oocytes can be rescued by substitution of whole cytoplasm by spindle transfer. Proteomics analysis reveal that cytoplasmic UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is significantly decreased in Nlrp14-deficient oocytes, and Uhrf1-deficient oocytes also show disrupted calcium homeostasis and developmental arrest. Strikingly, it is found that the mitochondrial Na /Ca exchanger (NCLX) encoded by Slc8b1 is significantly decreased in the Nlrp14 oocyte. Mechanistically, NLRP14 interacts with the NCLX intrinsically disordered regions (IDRs) domain and maintain its stability by regulating the K27-linked ubiquitination. Thus, the study reveals NLRP14 as a crucial player in calcium homeostasis that is important for early embryonic development.
Topics: Humans; Male; Calcium; Homeostasis; Oocytes; Semen; Sodium-Calcium Exchanger; Ubiquitination; Animals; Mice; Nucleoside-Triphosphatase
PubMed: 37493331
DOI: 10.1002/advs.202301940 -
ELife Aug 2023New evidence in mice suggests that cells expressing the transcription factor FOXC2 may form a reservoir of quiescent stem cells that contributes to sperm formation.
New evidence in mice suggests that cells expressing the transcription factor FOXC2 may form a reservoir of quiescent stem cells that contributes to sperm formation.
Topics: Mice; Male; Animals; Testis; Spermatogonia; Spermatogenesis; Semen; Spermatozoa
PubMed: 37561114
DOI: 10.7554/eLife.90747 -
Biomolecules Jun 2023Gametogenesis, the process of producing gametes, differs significantly between oocytes and sperm. Most oocytes have chromosomal aneuploidies, indicating that chromosomal... (Review)
Review
Gametogenesis, the process of producing gametes, differs significantly between oocytes and sperm. Most oocytes have chromosomal aneuploidies, indicating that chromosomal aberrations in miscarried and newborn infants are of oocyte origin. Conversely, most structural anomalies are of sperm origin. A prolonged meiotic period caused by increasing female age is responsible for an increased number of chromosomal aberrations. Sperm chromosomes are difficult to analyze because they cannot be evaluated using somatic cell chromosome analysis methods. Nevertheless, researchers have developed methods for chromosome analysis of sperm using the fluorescence in situ hybridization method, hamster eggs, and mouse eggs, allowing for the cytogenetic evaluation of individual sperm. Reproductive medicine has allowed men with severe spermatogenic defects or chromosomal abnormalities to have children. However, using these techniques to achieve successful pregnancies results in higher rates of miscarriages and embryos with chromosomal abnormalities. This raises questions regarding which cases should undergo sperm chromosome analysis and how the results should be interpreted. Here, we reviewed clinical trials that have been reported on oocyte and sperm chromosome analyses. Examination of chromosomal abnormalities in gametes is critical in assisted reproductive technology. Therefore, it is necessary to continue to study the mechanism underlying gametic chromosomal abnormalities.
Topics: Pregnancy; Cricetinae; Male; Female; Animals; Mice; In Situ Hybridization, Fluorescence; Semen; Chromosome Aberrations; Oocytes; Spermatozoa
PubMed: 37371589
DOI: 10.3390/biom13061010 -
Microbiome Sep 2023Aging-related fertility decline is a prevalent concern globally. Male reproductive system aging is mainly characterized by a decrease in sperm quality and fertility....
BACKGROUND
Aging-related fertility decline is a prevalent concern globally. Male reproductive system aging is mainly characterized by a decrease in sperm quality and fertility. While it is known that intestinal physiology changes with age and that microbiota is shaped by physiology, the underlying mechanism of how the microbiota affects male reproductive aging is still largely unexplored.
RESULTS
Here, we utilized fecal microbiota transplantation (FMT) to exchange the fecal microbiota between young and old mice. Cecal shotgun metagenomics and metabolomics were used to identify differences in gut microbiota composition and metabolic regulation during aging. Our results demonstrated that FMT from young to old mice alleviated aging-associated spermatogenic dysfunction through an unexpected mechanism mediated by a gut bacteria-derived metabolite, 3-hydroxyphenylacetic acid (3-HPAA). 3-HPAA treatment resulted in an improvement of spermatogenesis in old mice. RNA sequencing analysis, qRT-PCR and Western blot revealed that 3-HPAA induced an upregulation of GPX4, thereby restraining ferroptosis and restoring spermatogenesis. These findings were further confirmed by in vitro induction of ferroptosis and inhibition of GPX4 expression.
CONCLUSIONS
Our results demonstrate that the microbiome-derived metabolite, 3-HPAA, facilitates spermatogenesis of old mice through a ferroptosis-mediated mechanism. Overall, these findings provide a novel mechanism of dysregulated spermatogenesis of old mice, and suggest that 3-HPAA could be a potential therapy for fertility decline of aging males in clinical practice. Video Abstract.
Topics: Mice; Male; Animals; Ferroptosis; Semen; Gastrointestinal Microbiome; Fecal Microbiota Transplantation; Spermatogenesis
PubMed: 37752615
DOI: 10.1186/s40168-023-01659-y -
Ugeskrift For Laeger Oct 2023This review describes the current evidence regarding the putative indications of letrozole (LTZ) in fertility treatment. Prior to intrauterine insemination, LTZ is... (Review)
Review
This review describes the current evidence regarding the putative indications of letrozole (LTZ) in fertility treatment. Prior to intrauterine insemination, LTZ is recommended in women with normogonadotrophic oligo-anovulation. In ovulatory women, LTZ is equal to clomiphene and may be used instead of exogenous gonadotrophin. LTZ may be used as co-treatment in poor responders prior to in vitro fertilization/intracytoplasmic sperm injection. In addition, LTZ prior to frozen-thawed embryo transfer is increasingly used in women with normogonadotrophic oligo-anovulation.
Topics: Male; Female; Humans; Letrozole; Anovulation; Fertility Agents, Female; Semen; Clomiphene
PubMed: 37873987
DOI: No ID Found -
International Journal of Gynaecology... Dec 2023Fertility preservation is a growing field in reproductive medicine that may raise ethical questions. Preservation of fertility must be discussed with the patient if...
Fertility preservation is a growing field in reproductive medicine that may raise ethical questions. Preservation of fertility must be discussed with the patient if gonadotoxic treatment is required, whether in the case of benign or malignant pathology, or in the management of transgender identity. As a result, surgery or chemotherapy that has fewer adverse impacts on fertility should be proposed if this does not alter the prognosis of the disease. If the risk of infertility persists, then fertility cryopreservation should be proposed for children and adults of reproductive age. Sperm, oocytes, and gonadal tissue can be cryopreserved for many years. FIGO wishes to emphasize the importance of fertility preservation in the medical and surgical management of patients, and the importance of a specialized, multidisciplinary approach.
Topics: Child; Adult; Humans; Male; Fertility Preservation; Semen; Cryopreservation; Oocytes; Infertility; Neoplasms
PubMed: 37807831
DOI: 10.1002/ijgo.15187 -
Human Reproduction Update Nov 2023Mammalian reproduction requires the fusion of two specialized cells: an oocyte and a sperm. In addition to producing gametes, the reproductive system also provides the... (Review)
Review
BACKGROUND
Mammalian reproduction requires the fusion of two specialized cells: an oocyte and a sperm. In addition to producing gametes, the reproductive system also provides the environment for the appropriate development of the embryo. Deciphering the reproductive system requires understanding the functions of each cell type and cell-cell interactions. Recent single-cell omics technologies have provided insights into the gene regulatory network in discrete cellular populations of both the male and female reproductive systems. However, these approaches cannot examine how the cellular states of the gametes or embryos are regulated through their interactions with neighboring somatic cells in the native tissue environment owing to tissue disassociations. Emerging spatial omics technologies address this challenge by preserving the spatial context of the cells to be profiled. These technologies hold the potential to revolutionize our understanding of mammalian reproduction.
OBJECTIVE AND RATIONALE
We aim to review the state-of-the-art spatial transcriptomics (ST) technologies with a focus on highlighting the novel biological insights that they have helped to reveal about the mammalian reproductive systems in the context of gametogenesis, embryogenesis, and reproductive pathologies. We also aim to discuss the current challenges of applying ST technologies in reproductive research and provide a sneak peek at what the field of spatial omics can offer for the reproduction community in the years to come.
SEARCH METHODS
The PubMed database was used in the search for peer-reviewed research articles and reviews using combinations of the following terms: 'spatial omics', 'fertility', 'reproduction', 'gametogenesis', 'embryogenesis', 'reproductive cancer', 'spatial transcriptomics', 'spermatogenesis', 'ovary', 'uterus', 'cervix', 'testis', and other keywords related to the subject area. All relevant publications until April 2023 were critically evaluated and discussed.
OUTCOMES
First, an overview of the ST technologies that have been applied to studying the reproductive systems was provided. The basic design principles and the advantages and limitations of these technologies were discussed and tabulated to serve as a guide for researchers to choose the best-suited technologies for their own research. Second, novel biological insights into mammalian reproduction, especially human reproduction revealed by ST analyses, were comprehensively reviewed. Three major themes were discussed. The first theme focuses on genes with non-random spatial expression patterns with specialized functions in multiple reproductive systems; The second theme centers around functionally interacting cell types which are often found to be spatially clustered in the reproductive tissues; and the thrid theme discusses pathological states in reproductive systems which are often associated with unique cellular microenvironments. Finally, current experimental and computational challenges of applying ST technologies to studying mammalian reproduction were highlighted, and potential solutions to tackle these challenges were provided. Future directions in the development of spatial omics technologies and how they will benefit the field of human reproduction were discussed, including the capture of cellular and tissue dynamics, multi-modal molecular profiling, and spatial characterization of gene perturbations.
WIDER IMPLICATIONS
Like single-cell technologies, spatial omics technologies hold tremendous potential for providing significant and novel insights into mammalian reproduction. Our review summarizes these novel biological insights that ST technologies have provided while shedding light on what is yet to come. Our review provides reproductive biologists and clinicians with a much-needed update on the state of art of ST technologies. It may also facilitate the adoption of cutting-edge spatial technologies in both basic and clinical reproductive research.
Topics: Animals; Humans; Male; Female; Transcriptome; Semen; Reproduction; Oocytes; Fertility; Mammals
PubMed: 37353907
DOI: 10.1093/humupd/dmad017 -
Experimental Gerontology Aug 2023Ageing is a natural process with physiological changes in different body parts and has been associated with decreased reproductive capacity. Factors such as imbalance in... (Review)
Review
Ageing is a natural process with physiological changes in different body parts and has been associated with decreased reproductive capacity. Factors such as imbalance in the antioxidant defence system, vascular diseases, diabetes mellitus, accessory reproductive glands infection, obesity as well as buildup of toxic substances play a role in age-related male reproductive malfunction. Age is inversely proportional to volume of semen, sperm count, sperm progressive motility, sperm viability, normal sperm morphology. The observed negative correlation between ageing and semen indices contributes to male infertility and reproductive decline. Normal levels of ROS, plays crucial role in facilitating sperm function, such as capacitation, hyper-activation, acrosome reaction as well as sperm-oocyte fusion; however, a substantial elevation in the endogenous level of ROS, especially in reproductive tissues, usually instigates destruction of sperm cells and heightened male infertility. Contrarily, antioxidants, such as vitamins C and E, beta-carotene, and micronutrients like zinc and folate, have been found by researchers to facilitate normal semen quality and male reproductive function. Furthermore, the role of hormonal imbalance as a result of the compromised hypothalamic-pituitary-gonadal axis, Sertoli and Leydig cells disorder, and nitric oxide-medicated erectile dysfunction during ageing cannot be undermined.
Topics: Male; Humans; Semen Analysis; Semen; Reactive Oxygen Species; Spermatozoa; Antioxidants; Infertility, Male; Aging; Sperm Motility
PubMed: 37315721
DOI: 10.1016/j.exger.2023.112232