Reproductive biology最新文献_第9页

Mitigating testicular dysfunction: Metformin’s role in combating valproic acid-induced damage in rats 减轻睾丸功能障碍：二甲双胍在对抗丙戊酸引起的大鼠损伤中的作用。

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-27 DOI: 10.1016/j.repbio.2025.101082

Alzahraa Ahmed Elhemiely , Wessam H. Elesawy , Hayat A. Abd El Aal , Ali S. Abdelhameed , Giorgio Ivan Russo , Eman S.G. Hassan

The male reproductive system is significantly affected by valproic acid (VPA), an anti-epileptic medication recognized for its detrimental effects on testicular function. This study evaluates the protective role of metformin, a hypoglycemic agent, against VPA-induced testicular dysfunction in rats. Male Sprague-Dawley rats were randomly assigned into four groups (6 rats per group): a control group, a metformin group (50 mg/kg/day), a VPA group (500 mg/kg/day), and a co-treatment group receiving both VPA and metformin. The treatments were administered for 42 days. Parameters evaluated included sperm characteristics, hormone levels, oxidative stress markers, inflammatory mediators, and apoptotic indicators. VPA exposure led to a pronounced decline in sperm motility and count, coupled with increased sperm abnormalities and decreased testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels. Additionally, VPA induced oxidative stress, evidenced by elevated malondialdehyde (MDA) and diminished reduced glutathione, alongside the suppression of Nrf2, HO-1, and NQO1 expressions. The inflammatory response was marked by heightened expression of IL-1β, TNF-α, and TGF-β proteins. VPA also upregulated Caspase-3 and downregulated PCNA, signalling increased apoptosis. Metformin co-administration effectively counteracted these alterations, restoring oxidative balance, mitigating inflammation, and reducing apoptosis to near-normal levels. Metformin significantly alleviates VPA-induced testicular damage by enhancing antioxidant defences via the Nrf2/HO-1/NQO-1 pathway and suppressing inflammatory and apoptotic cascades (TGF-β/TNF-α/IL-1β and Caspase-3/PCNA).

男性生殖系统受到丙戊酸（VPA）的显著影响，丙戊酸是一种抗癫痫药物，因其对睾丸功能的有害影响而被公认。本研究评估了降糖药二甲双胍对vpa诱导的大鼠睾丸功能障碍的保护作用。雄性sd - dawley大鼠随机分为4组（每组6只）：对照组、二甲双胍组（50 mg/kg/day）、VPA组（500 mg/kg/day）、VPA和二甲双胍联合治疗组。治疗持续42天。评估的参数包括精子特征、激素水平、氧化应激标志物、炎症介质和凋亡指标。VPA暴露导致精子活力和数量明显下降，加上精子异常增加，睾丸激素、促卵泡激素（FSH）和黄体生成素（LH）水平下降。此外，VPA诱导氧化应激，丙二醛（MDA）升高，还原性谷胱甘肽减少，Nrf2、HO-1和NQO1表达抑制。炎症反应的标志是IL-1β、TNF-α和TGF-β蛋白的表达升高。VPA还上调Caspase-3，下调PCNA，表明细胞凋亡增加。二甲双胍联合给药有效地抵消了这些改变，恢复氧化平衡，减轻炎症，并将细胞凋亡减少到接近正常水平。二甲双胍通过Nrf2/HO-1/NQO-1通路增强抗氧化防御，抑制炎症和凋亡级联反应（TGF-β/TNF-α/IL-1β和Caspase-3/PCNA），显著减轻vpa诱导的睾丸损伤。

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引用次数: 0

Inducible differentiation of buffalo (Bubalus bubalis) embryonic stem cells towards male and female germ cell-like lineages under ex vivo BMP4-mediated stimulation 在体外bmp4介导的刺激下，水牛胚胎干细胞诱导分化为雄性和雌性生殖细胞样谱系

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-26 DOI: 10.1016/j.repbio.2025.101084

Syed Mohmad Shah , Manmohan Singh Chauhan

Bone Morphogenetic Proteins have been reported to play important roles in developmental biology across the species. The present study investigates the role of BMP4 in inducing germ lineage development. For this purpose, buffalo ES cells were subjected to in vitro differentiation under suspension as well as adherent cultures, at different BMP4 doses and time periods. ES cell colonies were differentiated as EBs as well as adherent monolayers under different BMP4 concentrations (20, 50 and 100 ngml⁻¹) for different time intervals (4, 8 and 14 days). The differentiated cultures were subjected to transcriptional profiling for germ lineage associated genes. qPCR data analysis revealed that BMP4 at a concentration of 50–100 ngml⁻¹ and for a period of 14 days led to maximum induction of such germ lineage associated genes like DAZL, VASA, PLZF (PGC-specific); SYCP3, MLH1, TNP1/2 and PRM2 (Meiotic genes); BOULE and TEKT1 (Spermatocyte markers); and GDF9, ZP2 and 3 (Oocyte markers). Immunocytochemical analysis of the differentiated cultures revealed positive expression of PGC-markers (c-KIT, DAZL and VASA), Meiotic-markers (SYCP3, MLH1 and PROTAMINE1), Spermatocyte-markers (ACROSIN and HAPRIN) and Oocyte-markers (GDF9 and ZP4), marking thereby the differentiation towards germ lineage cells. Oocyte-like structures (OLS) obtained in monolayer differentiated cultures harbored a big nucleus covered with a ZP4 coat, so typical of an oocyte. These OLS, in extended cultures, showed embryonic development and progressed through different embryonic-like structures. Global DNA methylation analysis of the optimally differentiated cultures showed significantly (p < 0.05) decreased levels of 5-methyl-2-deoxycytidine, a mimic of the methylation erasure process typical of gametogenesis. Expression of PGC markers, methylation erasure, and meiotic markers together with expression of spermatocyte and oocyte markers is suggestive of post-meiotic progression into spermatogenesis and oogenesis, respectively- thus reflecting onset of in vitro gametogenesis.

据报道，骨形态发生蛋白在整个物种的发育生物学中起着重要作用。本研究探讨了BMP4在诱导生殖系发育中的作用。为此，在不同BMP4剂量和时间下，水牛胚胎干细胞在悬浮和贴壁培养下进行体外分化。在不同的BMP4浓度（20、50和100 ngml−1）下，不同的时间间隔（4、8和14天），ES细胞菌落分化为EBs和贴壁单层。分化后的培养物进行了生殖谱系相关基因的转录谱分析。qPCR数据分析显示，BMP4浓度为50-100 ngml−1，作用时间为14天，可最大限度地诱导DAZL、VASA、PLZF （pgc特异性）等生殖谱系相关基因；SYCP3、MLH1、TNP1/2和PRM2（减数分裂基因）；BOULE和TEKT1（精母细胞标志物）；GDF9、ZP2和3（卵母细胞标记物）。免疫细胞化学分析显示pgc标记物（c-KIT、DAZL和VASA）、减数分裂标记物（SYCP3、MLH1和PROTAMINE1）、精母细胞标记物（ACROSIN和HAPRIN）和卵母细胞标记物（GDF9和ZP4）的阳性表达，表明分化为生殖系细胞。在单层分化培养中获得的卵母细胞样结构（OLS）含有一个覆盖着ZP4外壳的大细胞核，这是卵母细胞的典型特征。这些OLS在扩展培养中表现出胚胎发育，并通过不同的胚胎样结构发展。优化分化培养的整体DNA甲基化分析显示，5-甲基-2-脱氧胞苷水平显著降低（p <； 0.05），这是配子体发生典型的甲基化消除过程的模拟物。PGC标记、甲基化消除和减数分裂标记的表达与精母细胞和卵母细胞标记的表达分别提示减数分裂后进入精子发生和卵发生，从而反映了体外配子体发生的开始。

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引用次数: 0

Ganoderma lucidum mitigates oxidative stress and apoptosis in chlorpyrifos‑induced testicular toxicity in male rats 灵芝可减轻毒死蜱诱导的雄性大鼠睾丸毒性中的氧化应激和细胞凋亡

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-26 DOI: 10.1016/j.repbio.2025.101086

Afshin Talebinasab , Farrokh Modarresi , Ebrahim Salimi-Sabour , Mojtaba Sepandi , Maryam Ghorbani , Gholam Reza Kaka , Javad Raouf Sarshoori

Chlorpyrifos (CPS) is an organophosphate pesticide known to induce oxidative stress, apoptosis, and histopathological damage in male reproductive tissues. Ganoderma lucidum (GDL), a medicinal fungus rich in bioactive polysaccharides and triterpenoids, has demonstrated potent antioxidant and antiapoptotic properties in various models. This study aimed to evaluate the protective effects of GDL extract against CPS-induced testicular toxicity in male rats by assessing histological integrity, oxidative stress markers, apoptosis signaling, and hormonal balance. Twenty-four adult male Wistar rats were randomly divided into four groups (n = 6): Cont, CPS (20 mg/kg), GDL (150 mg/kg), and Treat. Treatments were administered orally once daily for 30 days. At the end of the study, the testes were harvested for morphometric and Cosentino histopathological scoring, immunohistochemistry for BAX, BCL2, and Ki67, RTqPCR quantification, biochemical assays of antioxidant enzymes and serum testosterone, LH, and FSH measurements. CPS treatment significantly elevated histopathological damage scores, and disrupted regular cell arrangement. IHC revealed increased BAX and decreased BCL2 and Ki67 expression, corroborated by the upregulation of Bax and Caspase3 transcripts and downregulation of Bcl2. Antioxidant enzymes were suppressed and MDA was elevated in the CPS group. Hormonal assays showed decreased testosterone and LH. Co-administration of GDL partially restored histological architecture, normalized Voronoi patterns, attenuated apoptotic marker alterations, enhanced antioxidant defenses, reduced lipid peroxidation, and recovered hormone levels toward control values. GDL extract confers significant protection against CPS-induced testicular injury by mitigating oxidative stress, modulating apoptotic pathways, and preserving endocrine function, highlighting its therapeutic potential against pesticide-related reproductive toxicity.

毒死蜱（Chlorpyrifos， CPS）是一种有机磷农药，已知会引起雄性生殖组织的氧化应激、细胞凋亡和组织病理学损伤。灵芝（Ganoderma lucidum， GDL）是一种富含生物活性多糖和三萜的药用真菌，在多种模型中显示出有效的抗氧化和抗凋亡特性。本研究旨在通过评估组织完整性、氧化应激标志物、凋亡信号和激素平衡来评估GDL提取物对cps诱导的雄性大鼠睾丸毒性的保护作用。24只成年雄性Wistar大鼠随机分为4组（n = 6）：对照组、CPS（20 mg/kg）组、GDL（150 mg/kg）组和治疗组。治疗方法为每日口服1次，连续30天。在研究结束时，收集睾丸进行形态计量学和Cosentino组织病理学评分，BAX、BCL2和Ki67的免疫组织化学检测，RTqPCR定量检测，抗氧化酶生化检测和血清睾酮、LH和FSH测量。CPS治疗显著提高了组织病理学损伤评分，并扰乱了正常的细胞排列。IHC显示BAX表达升高，BCL2和Ki67表达降低，证实了BAX和Caspase3转录上调和BCL2下调。CPS组抗氧化酶抑制，MDA升高。激素检测显示睾酮和黄体生成素下降。共同给药GDL部分恢复了组织结构，正常化了Voronoi模式，减弱了凋亡标记物的改变，增强了抗氧化防御，减少了脂质过氧化，并将激素水平恢复到控制值。GDL提取物通过减轻氧化应激、调节细胞凋亡途径和保持内分泌功能，对cps诱导的睾丸损伤具有显著的保护作用，突出了其治疗农药相关生殖毒性的潜力。

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引用次数: 0

Metformin-loaded Chitosan nanoparticles alleviate insulin resistance in the polycystic ovarian syndrome rat model through modulation of PI3K/AKT/ GLUT4 in ovarian tissue 二甲双胍负载壳聚糖纳米颗粒通过调节卵巢组织PI3K/AKT/ GLUT4减轻多囊卵巢综合征大鼠模型的胰岛素抵抗

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-26 DOI: 10.1016/j.repbio.2025.101081

Samah Magdy Issa , Eman H. Thabet , Abeer.E. Dief , Walaa Omar , Samar R. Saleh , Marwa M. Essawy , Eman El Eter

Polycystic ovary syndrome (PCOS) is a common disorder in females characterized by insulin resistance (IR), hyperandrogenemia and anovulation. The etiology of PCOS is unknown. However, disrupted phosphatidylinositol 3-kinase (PI3K) and protein kinase B/AKT signaling pathway may be a possible cause of IR in PCOS. Metformin can activate AKT via PI3K and improve IR. However, metformin alone has shown conflicting results. Chitosan nanoparticles (CSNPs) are natural nano-carriers with anti-diabetic effects. Therefore, we aimed to elucidate the therapeutic potential of metformin-loaded CSNPs (CSNPs-Met) in a letrozole-induced PCOS rat model. The study comprised five groups of rats: control, PCOS, PCOS plus metformin, PCOS plus CSNPs, and PCOS plus CSNPs-Met. Letrozole was found to successfully induce PCOS, as evidenced by elevated serum testosterone levels, homeostasis model assessment-insulin resistance (HOMA-IR), an increased number of cystic follicles, fewer corpora lutea and a disturbed estrus cycle. The pAKT and GLUT4 protein levels were significantly lower in ovarian and muscular tissues than in control group (P < 0.001), suggesting impaired insulin signaling and glucose transport that may contribute to both the metabolic and reproductive disturbances. CSNP-Met showed a significant decrease in testosterone, HOMA-IR, cystic follicles with an increase in the number of corpora lutea, as well as the levels of pAKT and GLUT4 in ovarian and muscular tissues (P < 0.001). In addition, the estrus cycle was restored to normal levels. Hence, CSNPs-Met showed superior efficacy in ameliorating PCOS-associated parameters relative to metformin alone. In addition, these results support future translational studies to explore the clinical applicability of CSNPs in PCOS management.

多囊卵巢综合征（PCOS）是一种以胰岛素抵抗（IR）、高雄激素血症和无排卵为特征的女性常见疾病。多囊卵巢综合征的病因尚不清楚。然而，磷脂酰肌醇3-激酶（PI3K）和蛋白激酶B/AKT信号通路的中断可能是PCOS中IR的可能原因。二甲双胍可通过PI3K激活AKT，改善IR。然而，单用二甲双胍产生了相互矛盾的结果。壳聚糖纳米颗粒（csnp）是具有抗糖尿病作用的天然纳米载体。因此，我们旨在阐明二甲双胍负载csnp （csnp - met）在来曲唑诱导的PCOS大鼠模型中的治疗潜力。研究分为五组大鼠：对照组、PCOS、PCOS +二甲双胍、PCOS + csnp、PCOS + csnp - met。来曲唑可成功诱导多囊卵巢综合征，表现为血清睾酮水平升高、稳态模型评估-胰岛素抵抗（HOMA-IR）、囊泡数量增加、黄体减少和发情周期紊乱。卵巢和肌肉组织中的pAKT和GLUT4蛋白水平明显低于对照组（P <； 0.001），表明胰岛素信号和葡萄糖转运受损可能导致代谢和生殖障碍。CSNP-Met显著降低睾酮、HOMA-IR、囊泡和黄体数量，以及卵巢和肌肉组织中pAKT和GLUT4的水平（P <； 0.001）。此外，发情周期恢复到正常水平。因此，csnp - met在改善pcos相关参数方面表现出优于单用二甲双胍的疗效。此外，这些结果支持未来的转化研究，以探索csnp在PCOS治疗中的临床适用性。

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引用次数: 0

Toxicological effects of fluazuron on bovine reproductive cells: Implications for fertilization, sperm quality, and oviductal integrity 氟唑龙对牛生殖细胞的毒理学影响：对受精、精子质量和输卵管完整性的影响

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-25 DOI: 10.1016/j.repbio.2025.101087

Anabella Andrea Campagna , Mariana Carolina Fabra , Noelia Nikoloff , Ana Cristina Carranza-Martin

Fluazuron is a veterinary antiparasitic compound widely used as pour-on in cattle. However, little is known about its potential reproductive toxicity. This study aimed to evaluate the effects of fluazuron on sperm quality, bovine oviduct epithelial cells (BOECs), and bovine in vitro fertilization (IVF). Frozen-thawed sperm were exposed to fluazuron (50 µg/mL) for 2 h and evaluated for motility, mitochondrial activity, and membrane integrity, while BOECs were cultured with fluazuron for 24 h and assessed using MTT and comet assays. IVF was performed with gametes exposed to fluazuron for 18 h to evaluate pronuclear formation, and 24 h to study embryo development. Short-term fluazuron did not significantly affect sperm motility, viability, or membrane function. However, it decreased viability and induced DNA damage in BOECs after 24 h of treatment. Following fluazuron exposure during IVF, no differences were observed between the fluazuron-treated group and the control group in terms of pronuclear formation. However, a significantly higher incidence of abnormally condensed chromatin within the pronuclei was detected in the fluazuron-treated group. Furthermore, embryonic development decreased in both blastocyst and hatching rates in fluazuron treatment. These findings suggest that fluazuron may disrupt early reproductive events through multiple mechanisms, including BOEC dysfunction and chromatin damage. Our results highlight the importance of evaluating reproductive risks associated with antiparasitic drug exposure in livestock.

氟唑脲是一种兽药抗寄生虫化合物，广泛用于牛的倾倒。然而，人们对其潜在的生殖毒性知之甚少。本研究旨在评价氟唑龙对精子质量、牛输卵管上皮细胞（BOECs）和牛体外受精（IVF）的影响。将冷冻解冻的精子暴露在氟祖龙（50 µg/mL）中2 小时，并评估其活力、线粒体活性和膜完整性，而boec用氟祖龙培养24 小时，并使用MTT和comet测定法评估。将配子暴露在fluazuron中18 h以评估原核形成，24 h以研究胚胎发育。短期氟唑龙对精子活力、活力或膜功能没有显著影响。然而，在24 h后，它降低了BOECs的活力并诱导DNA损伤。在试管婴儿期间暴露于氟唑龙后，氟唑龙治疗组和对照组在原核形成方面没有观察到差异。然而，在氟唑龙处理组中，检测到原核内异常浓缩染色质的发生率明显更高。此外，在氟唑龙处理下，囊胚发育和孵化率均下降。这些发现表明氟唑龙可能通过多种机制破坏早期生殖事件，包括BOEC功能障碍和染色质损伤。我们的研究结果强调了评估与家畜抗寄生虫药物暴露相关的生殖风险的重要性。

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引用次数: 0

Recurrent pregnancy loss: Crosstalk between immune cells, decidual cells, and cellular autophagy 复发性妊娠丢失：免疫细胞、蜕细胞和细胞自噬之间的串扰。

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-19 DOI: 10.1016/j.repbio.2025.101083

Xingxing Yuan , Chaofan Li , Xiaoyu Zhang , Xiaoling Feng

Recurrent pregnancy loss (RPL), affecting ∼5 % of couples, remains idiopathic in up to 50 % of cases. This review synthesizes the multifactorial pathogenesis of RPL, emphasizing dysregulated molecular pathways, genetic polymorphisms such as NOS2 rs2779249, and environmental triggers such as Toxoplasma gondii infection and pesticide exposure. Immune dysfunction is central, characterized by altered Treg subsets such as reduced CD4⁺ and increased CD8⁺ Tregs, impaired checkpoint expression such as PD-1/PD-L1 and Tim-3, aberrant cytokine profiles such as elevated IL-7, IL-1β, TNF-α and reduced TGF-β, and decidual NK (dNK) cell dysregulation impacting trophoblast invasion via pathways like IGF-2/PEG10. Non-coding RNAs further contribute by promoting trophoblast apoptosis, suppressing migration/invasion, and driving inflammation through MAPK/JNK/NF-κB signaling. Decidualization defects involve metabolic imbalance, unresolved endoplasmic reticulum stress, microRNA dysregulation, TNFα-induced senescence, and disrupted β-catenin/STAT3 crosstalk. Autophagy exhibits dual role: while protective in decidual stromal cells (DSCs) by supporting Treg expansion and immune tolerance, its dysregulation triggers trophoblast apoptosis via MCL-1 degradation and caspase activation. Environmental toxins exacerbate oxidative stress and apoptosis. Therapeutic prospects include immune checkpoint agonists, lncRNA/miRNA antagonists, autophagy flux modulators, growth factor therapies, and LMWH targeting thrombotic and inflammatory pathways. However, clinical translation faces challenges, including pathway duality, pleiotropic effects, targeted delivery limitations, and limited human trial data. Future research should focus on single-cell resolution studies, personalized approaches, and safer nanocarriers for biologics to bridge mechanistic insights into effective RPL interventions.

复发性妊娠丢失（RPL）影响约5 %的夫妇，在高达50% %的病例中仍然是特发性的。本文综述了RPL的多因素发病机制，重点介绍了分子通路失调、基因多态性如NOS2 rs2779249以及弓形虫感染和农药暴露等环境触发因素。免疫功能障碍是核心，其特征是Treg亚群改变，如CD4 +减少和CD8 + Tregs增加，检查点表达受损，如PD-1/PD-L1和Tim-3，细胞因子异常，如IL-7、IL-1β、TNF-α和TGF-β升高，以及通过IGF-2/PEG10等途径影响滋养细胞侵袭的NK细胞失调。非编码rna进一步通过MAPK/JNK/NF-κB信号传导促进滋养细胞凋亡，抑制迁移/侵袭，驱动炎症。去个性化缺陷包括代谢失衡、内质网应激未解决、microRNA失调、tnf α诱导的衰老和β-catenin/STAT3串扰中断。自噬具有双重作用：一方面通过支持Treg扩增和免疫耐受对蜕膜间质细胞（DSCs）具有保护作用，另一方面其失调通过MCL-1降解和caspase激活触发滋养层细胞凋亡。环境毒素加剧氧化应激和细胞凋亡。治疗前景包括免疫检查点激动剂、lncRNA/miRNA拮抗剂、自噬通量调节剂、生长因子疗法和靶向血栓和炎症途径的低分子肝素。然而，临床翻译面临挑战，包括途径双重性、多效性、靶向递送限制和有限的人体试验数据。未来的研究应该集中在单细胞分辨率研究、个性化方法和更安全的生物制剂纳米载体上，以建立有效的RPL干预机制的桥梁。

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引用次数: 0

Decoding ovarian aging in women: Cellular damage, signaling networks, and treatment frontiers 解码女性卵巢老化：细胞损伤、信号网络和治疗前沿。

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-17 DOI: 10.1016/j.repbio.2025.101075

Shivani Ingole, Kanchan Khare, Veepin Dwivedi, Brijesh Taksande, Milind Umekar, Shubhada Mangrulkar

Ovarian aging is a significant biological process characterized by the gradual decline of ovarian function and fertility in women as they age. It is a multifaceted process that involves various molecular mechanisms. This review article delves into the complex nature of ovarian aging, marked by reductions in both the quantity and quality of oocytes, hormonal imbalances, and heightened risks of infertility and pregnancy complications. It consolidates current understanding of the physiological, cellular, and molecular mechanisms driving ovarian aging, such as mitochondrial dysfunction, oxidative stress, telomere shortening, DNA (Deoxyribonucleic Acid) damage, inflammation, and apoptosis. This review primarily focuses on human ovarian aging, while also integrating relevant insights from animal models particularly rodent studies that have contributed to our understanding of underlying mechanisms. It explores key signaling pathways involved in aging, including AMPK (AMP-Activated Protein Kinase), mTOR (mammalian target of rapamycin), Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2), SIRT1 (Sirtuin 1), and FOXO3 (Forkhead Box O Transcription Factor) pathways. The review also discusses emerging therapeutic strategies designed to delay or reverse ovarian aging, which include antioxidants, hormone replacement therapy, stem cell-based treatments, CRMs (CR mimetics), gene therapy, and traditional medicines. Additionally, the article examines the potential role of polyamines in ovarian function and aging. By thoroughly analyzing the current research landscape and identifying future research directions, this review offers valuable insights for researchers and clinicians dedicated to improving reproductive health and quality of life for aging women.

卵巢衰老是一个重要的生物学过程，其特征是随着年龄的增长，卵巢功能和生育能力逐渐下降。这是一个涉及多种分子机制的多方面过程。这篇综述文章深入探讨了卵巢衰老的复杂性，其特征是卵母细胞数量和质量的减少，激素失衡，不孕和妊娠并发症的风险增加。它巩固了目前对驱动卵巢衰老的生理、细胞和分子机制的理解，如线粒体功能障碍、氧化应激、端粒缩短、DNA（脱氧核糖核酸）损伤、炎症和凋亡。本综述主要关注人类卵巢衰老，同时也整合了动物模型特别是啮齿动物研究的相关见解，这些见解有助于我们理解潜在的机制。它探索了与衰老相关的关键信号通路，包括AMPK （AMP-Activated Protein Kinase）、mTOR（哺乳动物雷帕霉素靶点）、Nrf2 （Nuclear Factor Erythroid 2- related Factor 2）、SIRT1 （Sirtuin 1）和FOXO3 （Forkhead Box O Transcription Factor）通路。本综述还讨论了旨在延缓或逆转卵巢衰老的新兴治疗策略，包括抗氧化剂、激素替代疗法、干细胞治疗、CRMs （CR模拟物）、基因治疗和传统药物。此外，本文探讨了多胺在卵巢功能和衰老中的潜在作用。通过对当前研究现状的全面分析和未来研究方向的确定，本综述为致力于改善老年妇女生殖健康和生活质量的研究人员和临床医生提供了有价值的见解。

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引用次数: 0

Gonadal morphogenesis and sexual differentiation in rhea (Rhea americana) 美洲rhea （rhea americana）性腺形态发生与性分化

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-15 DOI: 10.1016/j.repbio.2025.101079

Marilú Cristofoli , Flavia Maria Pia Montenegro Donoso , Mayla Magalhães de Oliveira Alcobaça , Fabiana Morse Gosson Jorge , Danielle Cristina Calado de Brito , Moacir Franco de Oliveira , Antônio Chaves de Assis Neto

The rhea (Rhea americana) is a docile and highly adaptable ratite with notable zootechnical potential for the production of meat, eggs, feathers, and leather. Beyond its economic relevance, captive breeding plays an important role in conservation. However, information on its embryonic and gonadal development remains limited—knowledge that is essential for improving reproductive management. This study aimed to characterize gonadal differentiation during artificial incubation, focusing on developmental stages at days 9, 12, 15, 18, 21, and 24. We provide a detailed morphological and cytological description of germ and somatic cells, documenting the appearance of the gonadal crest at day 9, the formation of undifferentiated gonads by day 12, and the onset of sexual differentiation at day 15. Morphometric analyses of cortex thickness and gonad–mesonephros area relationships enabled comparisons between sexes. The gonads were positioned cranioventrally on the mesoneph, and testicular maturation occurred earlier than ovarian differentiation. Transmission electron microscopy revealed greater mitochondrial density in male germ cells than in female germ cells, indicating early functional divergence. These results contribute to the understanding of reproductive development in R. americana and support the development of conservation and breeding strategies for this and related species.

美洲美洲豹（美洲美洲豹）是一种温顺、适应性强的美洲豹，在生产肉、蛋、羽毛和皮革方面具有显著的动物技术潜力。除了经济意义之外，圈养繁殖在保护中也起着重要作用。然而，关于其胚胎和性腺发育的信息仍然有限，这些知识对改善生殖管理至关重要。本研究旨在表征人工孵化期间的性腺分化，重点关注第9、12、15、18、21和24天的发育阶段。我们对生殖细胞和体细胞进行了详细的形态学和细胞学描述，记录了第9天性腺嵴的出现，第12天未分化性腺的形成，以及第15天性分化的开始。皮质厚度和性腺-中肾区关系的形态计量学分析使两性之间的比较成为可能。性腺位于中卵膜的颅腹侧，睾丸成熟早于卵巢分化。透射电镜显示，男性生殖细胞的线粒体密度高于女性生殖细胞，表明早期功能分化。这些结果有助于了解美洲大蠊的生殖发育，并为美洲大蠊及其近缘种的保护和育种策略的制定提供依据。

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引用次数: 0

Controlled ovarian hyperstimulation reduces mouse embryo implantation capacity through uterine HIF-2α mediated pathway 控制性卵巢过度刺激通过HIF-2α介导的途径降低小鼠胚胎着床能力

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-10 DOI: 10.1016/j.repbio.2025.101074

Zheng Zhi , Haijun Yang , Zhangming Liu , Wei Pan , Yanzhi Hao , Xinming Zhang , Shuancheng Zhang , Huazhou Xu , Huirong Ma , Huilan Du , Cuimiao Song , Qiong Wu

Controlled ovarian hyperstimulation (COH) is a cornerstone of assisted reproductive technologies, yet its effects on endometrial function and embryo implantation remain poorly understood, particularly regarding the role of hypoxia-inducible factor 2α (HIF-2α) signaling. Therefore, the objective of this study was to investigate whether COH-induced endometrial dysfunction impairs mouse embryo implantation through the HIF-2α pathway. A COH mouse model was established using gonadotropin-releasing hormone agonist (GnRH-a)/human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) administration. Embryo implantation status was evaluated on gestational days 5, 6, and 20; endometrial tissues were analyzed for HIF-2α pathway activity via immunohistochemistry (IHC), immunofluorescence (IF), Western blot (WB) and quantitative real-time PCR (qRT-PCR); histological changes were assessed by Jones silver staining and transmission electron microscopy (TEM); serum estradiol (E₂), progesterone (P₄), and prolactin (PRL) levels were measured by radioimmunoassay (RIA). COH mice exhibited reduced total embryo implantation rates (on day 5, 6 and 20), together with decreased serum E₂, P₄, and PRL levels. COH mice exhibited preserved luminal epithelium integrity with increased microvillus density and continuous basement membrane structure. qRT-PCR and WB demonstrated significantly downregulated HIF-2α expression at both mRNA and protein levels, accompanied by reduced downstream RAB27B (member of RAS oncogene family)/matrix metalloproteinase 9 (MMP9) and lysyl oxidase (LOX)/adrenomedullin (ADM) signaling, which associated with impaired luminal epithelium detachment and compromised trophoblast invasion. Together, these findings identify HIF-2α as a potential key mediator of COH-induced endometrial microenvironment alterations, revealing molecular mechanisms underlying implantation failure. Importantly, the HIF-2α-RAB27B/MMP9 and HIF-2α-LOX/ADM axes are highlighted as promising therapeutic targets to optimize assisted reproductive outcomes.

控制性卵巢过度刺激（COH）是辅助生殖技术的基础，但其对子宫内膜功能和胚胎着床的影响尚不清楚，特别是关于缺氧诱导因子2α (HIF-2α)信号的作用。因此，本研究的目的是探讨coh诱导的子宫内膜功能障碍是否通过HIF-2α途径损害小鼠胚胎着床。采用促性腺激素释放激素激动剂(GnRH-a)/人绝经期促性腺激素(hMG)/人绒毛膜促性腺激素（hCG）给药建立COH小鼠模型。在妊娠5、6、20天评估胚胎着床状况；采用免疫组化（IHC）、免疫荧光（IF）、免疫印迹（WB）和实时荧光定量PCR （qRT-PCR）检测子宫内膜HIF-2α通路的活性；采用琼斯银染色和透射电镜观察组织学变化；采用放射免疫分析法（RIA）测定血清雌二醇（E2）、孕酮（P4）、催乳素（PRL）水平。COH小鼠的总胚胎着床率降低（第5、6和20天），血清E2、P4和PRL水平降低。COH小鼠保持了腔内上皮的完整性，微绒毛密度增加，基底膜结构连续。qRT-PCR和WB结果显示，HIF-2α mRNA和蛋白水平均显著下调，下游RAB27B （RAS癌基因家族成员）/基质金属蛋白酶9 （MMP9）和赖氨酸氧化酶(LOX)/肾上腺髓质素（ADM）信号传导减少，这与管腔上皮脱离受损和滋养细胞侵袭受损有关。总之，这些发现确定HIF-2α是coh诱导的子宫内膜微环境改变的潜在关键介质，揭示了植入失败的分子机制。重要的是，HIF-2α-RAB27B/MMP9和HIF-2α-LOX/ADM轴被强调为优化辅助生殖结果的有希望的治疗靶点。

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引用次数: 0

Analyzing the toxicological effects of PET-MPs on male infertility: Insights from network toxicology, mendelian randomization, and transcriptomics 分析PET-MPs对男性不育的毒理学影响：来自网络毒理学、孟德尔随机化和转录组学的见解

IF 2.5 3区生物学 Q3 REPRODUCTIVE BIOLOGY

Reproductive biology

Pub Date : 2025-09-09 DOI: 10.1016/j.repbio.2025.101076

Yang Yang , Linfeng Li , Ning Zhang , Zheng Zhang , Zhengyang Wu , Dongmei Ji

Current research indicates that polyethylene terephthalate microplastics (PET-MPs) may significantly impair male reproductive function. This study aimed to investigate the potential molecular mechanisms underlying this impairment. Potential gene targets of PET-MPs were predicted via the SwissTargetPrediction database. GWAS summary statistics for male infertility were obtained from the GWAS Catalog, and eQTL data were acquired from the eQTLGen database. SMR analysis was subsequently performed to identify genes exhibiting significant causal associations with male infertility. The potential targets of PET-MPs contributing to male infertility were ultimately identified by intersecting the two gene sets. Additionally, bulk RNA-seq and scRNA-seq analyses were employed to elucidate the potential molecular mechanisms underlying PET-MPs-induced male infertility. Our findings suggest that CLK4 may serve as a functional target through which PET-MPs contribute to male infertility, with elevated CLK4 expression representing a significant risk factor. Molecular docking and molecular dynamics simulations demonstrated that PET-MPs can form stable binding conformations with the CLK4 protein. We further identified terminally differentiated CD4⁺ T cells as a prominent risk factor for male infertility, revealing a significant positive correlation between CLK4 expression levels and Th1 cell infiltration. Additionally, CLK4 exhibited a biphasic expression pattern during spermatocyte-to-sperm differentiation, initially increasing before subsequent downregulation. These observations indicate that PET-MPs may participate in the pathogenesis of male infertility by targeting CLK4 to modulate Th1 cell infiltration and disrupt normal spermatogenic processes. In conclusion, our study demonstrates that CLK4 may serve as a potential target for PET-MP-induced male infertility, and we further elucidate the underlying molecular mechanisms.

目前的研究表明，聚对苯二甲酸乙二醇酯微塑料（PET-MPs）可能严重损害男性生殖功能。本研究旨在探讨这种损伤的潜在分子机制。通过SwissTargetPrediction数据库预测PET-MPs的潜在基因靶点。男性不育的GWAS汇总统计数据来自GWAS目录，eQTL数据来自eQTLGen数据库。随后进行SMR分析，以确定与男性不育有显著因果关系的基因。PET-MPs导致男性不育的潜在靶标最终通过交叉两个基因集确定。此外，大量RNA-seq和scRNA-seq分析被用于阐明pet - mps诱导男性不育的潜在分子机制。我们的研究结果表明，CLK4可能是PET-MPs导致男性不育的一个功能靶点，CLK4表达升高是一个重要的危险因素。分子对接和分子动力学模拟表明PET-MPs可以与CLK4蛋白形成稳定的结合构象。我们进一步发现终末分化的CD4+ T细胞是男性不育的重要危险因素，揭示了CLK4表达水平与Th1细胞浸润之间的显著正相关。此外，CLK4在精细胞向精子分化过程中表现出双相表达模式，最初升高，随后下调。这些观察结果表明，PET-MPs可能通过靶向CLK4调节Th1细胞浸润和破坏正常的生精过程参与男性不育的发病机制。总之，我们的研究表明CLK4可能是pet - mp诱导的男性不育的潜在靶点，我们进一步阐明了潜在的分子机制。

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引用次数: 0