Biology of Reproduction最新文献

Oligoasthenoteratospermia (OAT) describes male infertility due to a combination of low sperm count, reduced sperm motility, and abnormal sperm morphology. A common course of action to overcome infertility for males with this condition is intracytoplasmic sperm injection (ICSI). Here we used the Arrdc5 knockout mouse model of OAT to examine the ramifications of bypassing natural barriers preventing fertilization by defective sperm via ICSI on the viability of embryos and health of offspring. ARRDC5 is expressed specifically in the male germline where it has an essential role in sperm morphogenesis and is required for normal embryogenesis. Outcomes of ICSI trials with sperm from Arrdc5-/- males and wild-type oocytes revealed that the efficacy of both 2-cell and blastocyst stage embryo generation is significantly compromised. In addition, forcing increased embryo development by inclusion of artificial oocyte activation enabled the generation of a viable pregnancy from ICSI with Arrdc5-/- sperm, however, the live Arrdc5+/- offspring that was generated had organ wet weights outside of the range of Arrdc5+/+ mice generated by ICSI with sperm from Arrdc5+/+ males. Moreover, evidence of DNA damage transmission to paternal pronuclei following ICSI with sperm from Arrdc5-/- mice was uncovered, though this DNA damage may resolve by the 2-cell stage of embryo development. Collectively, these findings demonstrate that both oocyte activation and post-cleavage preimplantation embryo development are impaired following ICSI with sperm generated by mice with an OAT pathology.

The remarkable advances in cancer therapies significantly enhance the survival rates and longevity of cancer patients. Among childhood, adolescent, and young adult female cancer survivors, however, anti-cancer agents frequently cause primary ovarian insufficiency, early menopause, and infertility, primarily due to the depletion of the ovarian reserve. Oocytes, the female germ cells, exhibit a notable susceptibility to DNA damage, given that they remain in meiotic arrest at prophase I for prolonged durations, from months to years, which increases the risks of accumulating DNA damage overtime. To counteract this, a tightly controlled DNA damage response signaling ensures that only oocytes with an intact genome progress to ovulation, fertilization, and next generations. Chemotherapeutic anti-cancer agents, including doxorubicin, cisplatin, cyclophosphamide, along with irradiation, elicit DNA damage via various mechanisms, including DNA crosslinking, single- and double-strand DNA breaks, and oxidative stress. The genotoxic insults activate DDR in the oocytes, which detect and repair DNA damage or initiate apoptosis to eliminate impaired oocytes. Although several protein molecules such as DNA damage-sensing kinases, checkpoint kinases, p53 family transcription factors, and pro-apoptotic molecules have been discovered, the precise mechanisms of DDR in determining the fate of oocytes, particularly how they differ from those in somatic cells and cancer cells, remain poorly understood. From an oncofertility perspective, the current review analyzes the molecular mechanisms of anti-cancer agent-induced DDR in oocytes and discusses knowledge gaps and urgent future research directions for preserving the ovarian reserve, fertility, and endocrine functions of young female cancer patients.

Perfluorooctanesulfonic acid (PFOS), a persistent environmental pollutant, is elevated in the plasma of preeclamptic women and may contribute to gestational hypertension. However, its direct effects on placental vascular function remain unclear. This study investigated PFOS' impact on vascular reactivity in human placental chorionic plate arteries (CPAs) and evaluated the therapeutic potential of the mitochondrial-targeted antioxidant mitoquinone (MitoQ). CPAs from normotensive pregnancies were treated with PFOS (10 μM) or vehicle for 24 h. Wire myography assessed contractile responses to KCl and endothelin-1 (ET-1), as well as cyclic adenosine monophosphate (cAMP)-mediated (isoproterenol, forskolin) and cyclic guanosine monophosphate (cGMP)-mediated (sodium nitroprusside, SNP) vasodilation. Adenosine triphosphate (ATP), cAMP, and cGMP levels were quantified, and MitoQ (100 nM) co-treatment was tested for rescue effects. PFOS-exposed CPAs exhibited enhanced maximal contraction to KCl (9.73 ± 0.96 vs. 5.60 ± 0.41 mN) and ET-1 (9.84 ± 1.05 vs. 5.77 ± 0.49 mN). cAMP-dependent relaxation was impaired (isoproterenol: 31.16 ± 4.55% vs. 65.27 ± 6.08%; forskolin: 65.59 ± 2.72% vs. 87.55 ± 1.89%), while SNP-induced cGMP-mediated relaxation remained unaffected. PFOS reduced ATP by 58% (30.43 ± 2.89 vs. 73.71 ± 9.15 μmol/mg) and cAMP by 57% (46.15 ± 9.54 vs. 109.1 ± 8.88 nmol/mg) but did not affect cGMP levels. MitoQ restored ATP/cAMP levels and normalized vascular function, reversing PFOS-induced hypercontractility and cAMP pathway suppression. These findings demonstrate that PFOS directly impairs placental vascular homeostasis via mitochondrial dysfunction and cAMP signaling disruption, implicating it as a mediator of gestational hypertension. Mitochondrial-targeted interventions like MitoQ may mitigate PFOS-associated vascular dysfunction, highlighting therapeutic avenues for high-exposure pregnancies.

Endometrial fibrosis leads to subfertility when periglandular fibrosis impairs endometrial gland function. Identifying distinct protein expressions in mares suffering from this condition is essential for understanding the pathogenesis and developing treatments to delay fibrotic progression. To gain a better understanding of protein dynamics underlying this condition, Data-Independent Acquisition Mass Spectrometry was utilized to comprehensively characterize and compare the equine endometrial and plasma proteome from mares with different severities of endometrial fibrosis. Mares in diestrus were selected as controls (n = 9), moderate endometrial fibrosis (n = 9), and severe endometrial fibrosis (n = 9), based on examination of tissue sections stained with hematoxylin and eosin and immunohistochemically marked for alpha-smooth muscle actin. Approximately 10,000 proteins were identified in endometrial tissue and 500 in plasma. Between moderate fibrosis and controls, 310 and 75 differed in endometrial tissue and plasma, respectively, and between severe fibrosis and controls, 585 and 71 differed, respectively. Extracellular matrix-related pathways were over-represented among upregulated proteins in endometrial tissue from mares with moderate and severe fibrosis. Several of the proteins involved appear to promote development or progression of fibrosis. Immune-related pathways were over-represented among downregulated proteins in mares with moderate fibrosis, and among upregulated proteins in mares with severe fibrosis. Several of the proteins highlighted by our analysis have both immunologic and fibrotic properties. We anticipate that the extensive profiling of endometrial and plasma proteome paves the way for identification of potential diagnostic biomarkers and targets for therapeutic use in equine endometrial fibrosis.

Ovarian endometrioma (OMA), the most prevalent and clinically consequential subtype of endometriosis, represents a chronic inflammatory disorder characterized by ectopic endometrial-like lesions. This condition manifests as progressive dysmenorrhea, ovarian reserve depletion, and subfertility, imposing substantial physical and psychosocial burdens. Current diagnostic modalities remain constrained by the absence of reliable biomarkers, while surgical interventions often yield suboptimal outcomes marked by incomplete lesion resolution and elevated recurrence rates. Despite growing recognition of endometriosis as a systemic disease, the distinct pathogenic mechanisms underlying OMA formation-particularly the interplay between immune dysregulation, steroid hormone hypersensitivity, and microenvironmental reprogramming-remain insufficiently characterized. Emerging evidence implicates multifaceted pathophysiological cascades involving chronic peritoneal inflammation, T-cell polarization anomalies, vascular endothelial growth factor-mediated neoangiogenesis, progesterone resistance, and reactive oxygen species accumulation. Notably, microbiome-derived metabolites and multi-omics integration have redefined paradigms of disease progression by elucidating mechanisms sustaining lesion viability. This review consolidates recent advances in OMA pathogenesis, dissecting molecular drivers of cellular survival, adhesive interactions, and inflammatory cascades within the ovarian microenvironment.

Obesity is a rising public health concern in the United States, with significant implications for maternal and fetal health during pregnancy. Maternal obesity is associated with increased risks of miscarriage, reduced implantation and pregnancy rates, fetal anomalies, abnormal fetal growth, stillbirth, preeclampsia, gestational diabetes, hypertensive disorders, labor and wound complications, and maternal depression. Current strategies for managing these risks include pre-pregnancy weight loss, nutritional counseling and weight management during pregnancy, lifestyle modifications, and low-dose aspirin to reduce the risk of preeclampsia. The effects of these interventions remain limited, underscoring the need for novel therapeutic approaches. A growing number of preclinical studies suggest that antioxidants such as coenzyme Q10 and pyrroloquinoline quinone may be promising candidates to mitigate the oxidative stress and mitochondrial dysfunction associated with maternal obesity and its comorbidities. Coenzyme Q10 supports mitochondrial function, ovarian reserve, and placental function while reducing obesity-related complications such as preeclampsia and miscarriage. Pyrroloquinoline quinone enhances mitochondrial biogenesis, regulates fatty acid metabolism, and ameliorates inflammation, with preclinical studies showing improved fertility and pregnancy rates, as well as protective effects against the development of adult metabolic diseases in offspring of pregnancies complicated with obesity. Together, coenzyme Q10 and pyrroloquinoline quinone offer promising nutraceutical strategies to improve fertility and reproductive health, placental function, pregnancy outcomes, and long-term metabolic consequences in offspring. Mechanistic insights gained from the preclinical research may inform future clinical studies to explore the therapeutic potential and synergistic benefits of combined coenzyme Q10 and pyrroloquinoline quinone treatment during human pregnancy complicated by obesity.

The alpha 7 nicotinic acetylcholine (ACh) receptor (CHRNA7) is targeted by ACh, choline, and exogenous chemicals, including nicotine and insecticides. According to database searches, it is expressed by several cell types of the human ovary, including granulosa cells (GCs). This expression site was confirmed by immunohistochemistry in human and nonhuman primate ovaries. Cultured human GCs, derived from in vitro fertilization patients, express functional CHRNA7, indicated among others by acutely elevated intracellular Ca2+ levels upon addition of the selective CHRNA7 agonist PNU 282987. Heterogeneity in this acute response may be due, in part, to the varying expression of the human-specific channel variant CHRFAM7A, which acts as a negative regulator. CHRNA7 activation is reported to dampen inflammatory reactions in non-neuronal cells, and in cultured human GCs, as recently reported, inflammatory responses are induced by hypoxia (1% O2). Studies in GCs exposed to 1% O2 may mirror the physiological situation in the periovulatory human follicle, and we found that PNU 282987 significantly decreased the low O2-induced elevations of IL6, CXCL8, and IL1B. Proteomic studies identified further consequences in human GCs exposed to 1% O2. Thus, PNU 282987 increased abundances of 31 proteins and decreased abundances of six proteins. Of note, several collagens were among the decreased proteins, which might be novel ovarian biomarkers for GC luteinization and oocyte quality. Our results imply roles of endogenous CHRNA7 activators and possibly exogenous chemicals in limiting inflammatory responses and in the regulation of other human GC functions. This influence may depend on the relative abundance of CHRNA7 and translation of CHRFAM7A.

Kisspeptin knockout (KISS1-/-) pigs exhibit hypogonadotropic hypogonadism. Hormone analogs targeting different levels of the hypothalamic-pituitary-gonad axis were used to characterize the secretion of reproductive hormones (LH, luteinizing hormone; and follicle-stimulating hormone, FSH) and ovarian responses (estradiol and progesterone) in KISS1-/- gilts. Uteri and ovaries were collected from KISS1+/+ and KISS1-/- gilts to confirm ovulatory outcomes. Pulses of LH and FSH were observed in KISS1-/- gilts that differed (P < 0.05) in amplitude and nadir from pulses in wild-type KISS1+/+ and KISS1+/- gilts. A neurokinin B (NKB) agonist stimulated LH but not FSH in wild-type gilts, whereas NKB affected neither LH nor FSH in KISS1-/- gilts. The kisspeptin receptor agonist, C6, stimulated LH secretion in wild-type gilts but not in KISS1-/- gilts (P < 0.05). Secretion of LH in KISS1-/- gilts depends on the dose and frequency of gonadotropin-releasing hormone (GnRH). Priming with estradiol-17β and GnRH before pregnant mare serum gonadotropin and human chorionic gonadotropin treatment resulted in luteal structures on the ovary of KISS1-/- gilts, though ovulation rate was less (P < 0.05) than KISS1+/+ gilts. This is the first report showing NKB regulation of LH secretion in swine. It is confirmed that a single copy of the KISS1 allele in gilts confers normal gonadotropin secretion following stimulation with NKB, kisspeptin, and GnRH analogs. The sustained activation of the kisspeptin receptor by C6 generated long-lasting LH secretion in gilts to induce ovulation. Ovulation in KISS1-/- gilts is possible, but treatments need optimization to maximize ovulation rate.

Accurate diagnosis of diseases of the female reproductive system is essential for achieving optimal health outcomes in women. Optical coherence tomography (OCT) is a novel and pivotal technology in biomedical imaging, providing near-histological resolution and enabling acquisition rates of multiple frames per second. As a critical branch of OCT, endoscopic OCT is capable of in vivo imaging of human physiological lumens, offering unique advantages in the detection of early small lesions within tissues. In recent years, the compelling imaging capabilities and safety features of endoscopic OCT have rendered it highly attractive for uterine cavity imaging and disease diagnosis. This offers valuable technical support for the early and precise diagnosis of reproductive diseases, fertility preservation, and comprehensive reproductive health management. In this review, we summarize the applications of endoscopic OCT in the female reproductive system and mainly elaborate on its value and potential applications in the uterus, fallopian tubes, and ovaries, which aims to provide novel insights and technical support for the early detection and precise diagnosis of diseases in the female reproductive system.

Intrauterine adhesion (IUA) is a leading cause of uterine infertility and often recurs post surgery due to limited treatments. Although estrogen is widely used to prevent recurrence, its efficacy remains unclear. A key characteristic of IUA is the excessive production of extracellular matrix (ECM) by activated myofibroblasts, which disrupts normal endometrial mechanics. Whether estrogen and ECM stiffness synergistically promote fibroblast to myofibroblast transition remains unknown. This study investigates why estrogen shows unsatisfactory efficacy in preventing IUA recurrence. We cultured cells on substrates with different stiffness levels to mimic the mechanical properties of healthy and fibrotic endometrial tissues. We treated immortalized human endometrial stromal fibroblast cell lines, as well as fibroblasts isolated from normal and fibrotic tissues, with varying estrogen concentrations. Additionally, we used transforming growth factor (TGF)-beta 1 to induce fibroblast activation, creating a cellular model of intrauterine adhesion. Our results showed that high-dose estrogen promotes fibroblast-to-myofibroblast transition in normal endometrial tissue but reverses this process in fibrotic tissue. Analysis of human endometrial stromal fibroblast cell lines and TGF-β1-induced human endometrial stromal fibroblast cells further indicated that high-dose estrogen inhibits myofibroblast activation. Notably, the opposing effects of estrogen on fibroblasts from normal versus fibrotic tissues are influenced by tissue stiffness. Furthermore, estrogen receptor alpha partially mediates the response of endometrial stromal cells to high-dose estrogen. These data suggest high-dose estrogen and ECM stiffness collaboratively regulate the fibroblast phenotype. Targeting myofibroblasts with high-dose estrogen in the adhesion region represents a promising antifibrotic strategy.