Biology of Reproduction最新文献

Follicle-stimulating hormone (FSH) and its receptor (FSHR) constitute one of the cores signaling axes that regulate the reproductive process of mammals. Studies have shown that the glycosylation pattern of FSH and the polymorphism of receptor genes can affect the ligand-receptor binding efficiency and downstream signal intensity, and are related to the susceptibility and phenotype of diseases such as polycystic ovary syndrome (PCOS) and primary ovarian insufficiency (POI). FSH/FSHR not only regulates normal reproductive function by activating multiple pathways such as cAMP/PKA, PI3K/Akt, β-arrestin, and MEK/ERK, but also promotes the progression of malignant tumors such as ovarian cancer (OC) and prostate cancer through mechanisms like activation of cancer stem cells, metabolic reprogramming, and angiogenesis. Therefore, targeting the FSH/FSHR axis has become a highly promising therapeutic strategy. This review summarizes the latest research advances of FSH/FSHR axis in reproductive system diseases and tumors, especially the therapeutic value of FSH/FSHR signaling axis.

Our previous research highlighted the importance of hormones, free fatty acids, lysophospholipids, and antioxidants in supporting in vitro spermatogenesis in mice through the development of a chemically defined medium. While it was possible to induce round spermatids through the culture of testicular tissue in medium containing these factors, challenges remained with the low efficiency of spermatogenesis and the differentiation into elongating spermatids. This study aimed to further improve the in vitro spermatogenesis system by exploring optimal oxygen concentrations and identifying additional factors necessary for spermiogenesis. In addition to the conventional oxygen concentration of 20%, three hypoxic environments (15%, 10%, and 7%) were tested, and an oxygen concentration of 10% was found to be optimal for the maintenance and differentiation of germ cells in vitro. To address the limited tissue growth observed under low oxygen conditions, we further supplemented the culture medium with glucose and insulin, which led to a significant increase in tissue size. However, this enhancement in growth did not translate into improved spermatogenic differentiation. Following this, we explored factors involved in the induction of elongating spermatids. The addition of glycosphingolipids to the culture medium modestly promoted the formation of elongating spermatids, suggesting a potential role of glycosphingolipids in haploid cell differentiation. This study offers new insights into the environmental conditions and factors that influence spermatogenesis in mice.

Exposure to testosterone (T) in pregnant ewes resulted in placental dysfunction and fetal growth restriction (FGR). However, the impact of T on gut microbiota and its contribution to exacerbating intestinal and placental pathologies remains uncharacterized. Pregnant sheep received intramuscular injections of 100 mg T propionate or a control vehicle. To examine the gut microbiota' s role in T-induced FGR, gut microbiota transplantation (GMT) was conducted from T-exposed and control ewes into antibiotic-treated pregnant mice. The findings demonstrated that T exposure exacerbated mitochondrial impairment, autophagy, and ferroptosis in placental and intestinal tissues, alongside inducing gut microbial dysbiosis. GMT further revealed that pathological alterations were mechanistically linked to gut microbiota imbalance. The findings demonstrated that gut-placental axis play a central role in mediating T-induced mitochondrial dysfunction, autophagy, and ferroptosis in maternal intestinal and placental tissues. These results underscore novel therapeutic opportunities, which operate via the gut-placental axis to mitigate FGR.

Maternal stress caused by the environmental factors varied in intrauterine and extrauterine during pregnancy may significantly affect placental and fetal development, as well as offspring health in adulthood. Epigenetic mechanisms are frequently invoked to elucidate these effects. RNA N6-methyladenosine (m6A) modification, one of the most prevalent and abundant post-transcriptional epigenetic modifications in eukaryotic mRNA, has recently garnered widespread attention in life sciences. RNA m6A modification plays critical roles in RNA splicing, translation, localization, stability, and has been implicated in various biological processes, including embryonic development, sex determination, and disease pathogenesis. In studies of placental developmental abnormalities induced by maternal stress during pregnancy, m6A modification has emerged as a key mechanism. This article initially introduces the impact of RNA m6A methylation modification on placental development, subsequently elaborates on recent advances in understanding how maternal stress induces placental abnormalities via m6A modification, and finally summarizes unresolved key questions in this field. This review aims to propose strategies for preventing and treating placental developmental abnormalities caused by maternal stress.

Unexplained recurrent pregnancy loss (URPL) is complex and has unknown etiologies, simultaneously endangering the patient's physical and mental health. Despite significant advancements in shifting from conventional treatments to cell therapy, clinical research and application in cell therapy have been constrained by its immunogenic properties and biosafety. As a new cell-cell communication pathway, extracellular vesicles (EVs) can transfer their bioactive cargos to other cells by endocytosis, ligand-receptor engagement, or direct fusion, thereby executing diverse biological functions both in proximity and across great distances. It is noteworthy that the role of EVs as a cell-free therapy in the form of a drug transporter has garnered increased attention, and some studies have demonstrated EVs involvement in the key pathology of URPL. This review methodically summarizes the functions of EVs from various sources in URPL, including mesenchymal stem cells, placenta, and other sources of EVs. Furthermore, we discuss the significance of EVs as possible diagnostic biomarkers and therapeutic strategies for URPL and the key questions that need to be addressed in future research.

As a member of the G protein-coupled receptor (GPCR) family, the follicle-stimulating hormone receptor (FSHR) plays a central role in the regulation of female reproduction. By specifically binding to follicle-stimulating hormone (FSH), FSHR regulates the proliferation and differentiation of granulosa cells, follicular development and estradiol (E2) synthesis. In this article, we summarized 37 clinically relevant mutations of the FSHR gene. These mutations are classified according to their functional impacts as follows: (1) Inactivating mutations are primarily located in the extracellular domain (ECD; e.g., p.Ala189Val) and the transmembrane domain (TMD; e.g., p.Asp224Val). These mutations cause receptor expression defects or signaling impairment, clinically manifesting as resistant ovary syndrome (ROS), premature ovarian failure (POF), or related disorders . These conditions are typically characterized by a preserved primordial follicle reserve but an arrested antral follicle development; (2) Activating mutations are concentrated in the TMD (e.g., p.Asp567Gly) and intracellular loops (ICLs; e.g., p.Val514Ala). They exhibit relaxed ligand specificity and result in ligand-independent constitutive activation. This leads to pregnancy-associated spontaneous ovarian hyperstimulation syndrome (sOHSS), characterized by enlarged ovaries containing multiple follicles and supraphysiologically elevated E2 levels. The review highlights the clinical utility of in vitro maturation (IVM) technology in assisted reproduction for patients with FSHR mutations. Clinical evidence demonstrates that mature oocytes are successfully obtained by circumventing FSH stimulation. Through a "molecular pathology → mutation classification → clinical phenotypes → therapeutic strategies" framework, this review establishes a theoretical foundation for precise classification and individualized management of FSHR mutation-related reproductive disorders.

Purpose: Identifying potential gut biomarkers linked to endometriosis for diagnosis and treatment.

Methods: The recruitment of this case-control study was done through the Endometriosis Health Profile-5 questionnaire, validated for endometriosis assessment. A total of 243 women completed the questionnaire and 73 women met the eligibility criteria of the study. Stool samples from the control group (n = 43) and patients with a positive diagnosis of endometriosis (n = 30) were collected and subjected to 16S rRNA gene sequencing using the V3-V4 regions. Various multivariate analysis approaches were used to assess diversity, composition and abundance of intestinal microbiota.

Results: Among the 18 significantly different taxa (p < 0.05) between healthy controls and EMs patients, 3 families, 3 genera and 12 species were identified. Endometriosis patients exhibited slightly higher diversity at the family and genus levels compared to controls (p > 0.05). This could indicate endometriosis is characterized by dominance of few species across diverse families and genera, associated with inflammation and estrogen signaling. Finally, several significant correlations (p < 0.05) were found between questionnaire variables related to "pain" and "infertility" items and certain families, genus and species found in the endometriosis group.

Conclusion: The differential presence of estrobolome-presenting gut taxa between endometriosis patients and controls endorses the possible role of the gut microbiome in female reproductive health, offering potential microbial markers for endometriosis diagnosis, monitoring and treatment. Identified taxa may serve as future prognostic, diagnostic, and therapeutic targets for diagnosis and personalized, preventive or palliative/curative treatment of endometriosis.

In 2021, Ken McNatty, Danielle Monniaux, and I published a review essay illustrating how ovarian folliculogenesis can sometimes be bizarre, amazing, or even almost incomprehensible. Examples included the mechanisms underlying intra- and inter-species differences in ovulation rates; the possibility of awakening human primordial follicles in vitro, maturing and fertilising them to produce viable offspring; and a model in which inactivation of a single oocyte gene results in sterile mice with follicular growth blocked at the primary stage but normal steroid cyclicity maintained [1]. The aim of this second essay is to present further examples of the extraordinary diversity of ovarian function across animal species and, where possible, to propose hypotheses that may explain them. These concern: the presence of oogonial stem cells in the ovaries of invertebrates and non-mammalian vertebrates, and their very probable absence in mammals;the many and varied strategies of ovarian development and oogenesis in teleosts;the metabolic dialogue between cumulus cells and oocytes across mammalian species;the presence of numerous germline genes, specifically or even exclusively expressed in the mammalian oocyte, whose invalidation has no phenotypic consequence on fertility in the mouse;the unique features of ovarian function in the dog, particularly the frequent presence of polyovular follicles and the distinctive mode of post-ovulatory oocyte maturation; andthe absence of an intra-ovarian dominance factor in mono-ovulating species, disproving an old hypothesis: the selection of a single follicle is instead due to a succession of negative and then positive feedback between follicles and the hypothalamic-pituitary axis. This essay is also a final tribute to Ken McNatty, who liked to say that the ovary could be crazy.

Zinc is essential for the proper functioning of a variety of cells and tissues. Due to the limited understanding of the role of zinc in the bovine ovary, our objective was to investigate the role of zinc in bovine mural granulosa cell (mGC) viability and identify cell signaling pathways regulated by zinc in this cell type. Key indicators of cell behavior were measured after cultured bovine mGCs were incubated with increasing levels of a zinc chelator, TPEN. Cell viability decreased in a dose dependent manner, with a 91% loss of cell viability seen at 10 μM TPEN (p = 1.02 × 10-9), which corresponded to a 49% increase in caspase 3/7 activity (p = 0.006) and an upregulation of p-YAP at Ser127 (p = 0.006). TRULI, a potent LATS1/2 inhibitor, in combination with TPEN treatments, partially rescued the decrease in cell viability seen at 3.5 μM TPEN (p = 2.54 × 10-7) and the increase in caspase 3/7 activity seen at 10 μM TPEN (p = 0.0003). Surprisingly, TPEN treatment for 6 h showed a dose dependent increase in relative fold change in expression of the known YAP gene targets, CCN1 (p = 3.85 × 10-10) and CCN2 (p = 1.95 × 10-7). While the mechanism by which increased Hippo activation mediates TPEN-stimulated apoptosis is still unknown, these results demonstrate that zinc is an essential micronutrient for bovine mGC viability, and that zinc deficiency promotes Hippo signaling leading to increased apoptosis in bovine mGCs.

Selective breeding in laying hens has resulted in a laying rate of approximately one egg per day during their first year. Due to variability within a flock, egg-laying rates decline after the first year, leading producers to cull hens. The aim of this study was to identify physiological and molecular differences between persistent (PL, egg-laying rate = 100%) and non-persistent layers (NPL, egg-laying rate ≤82%) after the first year. Forty laying hens were reared from 16 to 76 weeks of age and a subset was maintained until 96 weeks. Throughout the study, egg-laying data were recorded daily, and plasma samples and body weights were collected once to twice monthly. At 76 weeks, PL (n = 7) and NPL (n = 6) hens were identified. PL hens were heavier than NPL hens starting at 36 weeks and triiodothyronine levels decreased in PL hens from 26 to 76 weeks. At 76 weeks, ovarian tissue was collected from PL (n = 3) and NPL (n = 4) hens for follicle counts, gene expression analysis, and histological analysis. PL hens had significantly more 3-5 and >12 mm follicles, higher anti-Mullerian hormone and bone morphogenic protein 15 mRNA expression, and lower atresia rates in follicles <100 μm, suggesting a larger remaining ovarian reserve than NPL hens. Ovarian RNA-sequencing analysis revealed 279 differentially expressed genes between PL and NPL hens and analysis predicted the estrogen receptor as an upstream regulator. A greater understanding of the physiology and molecular patterns of persistent hens could provide insights into ovarian aging and enhance production efficiency.