{"title":"Correction to: The pathogenesis of endometriosis and adenomyosis: insights from single-cell RNA sequencing.","authors":"","doi":"10.1093/biolre/ioae184","DOIUrl":"https://doi.org/10.1093/biolre/ioae184","url":null,"abstract":"","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oxidation of thiol groups in membrane proteins inhibits the fertilization ability and motility of sperm by suppressing calcium influx.","authors":"Satohiro Nakao, Kazuki Shirakado, Kana Tamura, Reiri Koga, Mayumi Ikeda-Imafuku, Yu Ishima, Naomi Nakagata, Toru Takeo","doi":"10.1093/biolre/ioae183","DOIUrl":"https://doi.org/10.1093/biolre/ioae183","url":null,"abstract":"<p><p>The redox state of thiol groups derived from cysteine residues in proteins regulates cellular functions. Changes in the redox state of thiol groups in the epididymis are involved in sperm maturation. Furthermore, the redox state of thiol groups in proteins changes during the process of sperm capacitation. However, the effect of the redox state of thiol groups in sperm membrane proteins on the fertilization ability of sperm has not been studied. Therefore, in this study, we oxidized thiol groups in sperm membrane proteins using 5,5-dithiobis-(2-nitrobenzoic acid) (DTNB), which is a thiol-selective oxidizing agent, and examined the effect of oxidation of these thiol groups on the fertilization ability of sperm. Oocytes and sperm were obtained from C57BL/6 J mice, and Jcl:ICR mice were used as recipients for embryo transfer. Oxidation of the thiol groups by DTNB decreased the in vitro fertilization rate, and removal of the zona pellucida recovered the fertilization rate. DTNB treatment decreased the amplitude of the lateral head, which is an indicator of hyperactivation, and suppressed an increase in the intracellular calcium ion concentration, which is essential for hyperactivation. These findings suggest that oxidation of thiol groups in sperm membrane proteins can decrease the fertility of sperm by suppressing calcium ion influx and hyperactivation.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Syed Ata Ur Rahman Shah, Bin Tang, Dekui He, Yujiang Hao, Ghulam Nabi, Chaoqun Wang, Zhangbing Kou, Kexiong Wang
{"title":"Physiological function of gut microbiota and metabolome on successful pregnancy and lactation in the captive Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis)†.","authors":"Syed Ata Ur Rahman Shah, Bin Tang, Dekui He, Yujiang Hao, Ghulam Nabi, Chaoqun Wang, Zhangbing Kou, Kexiong Wang","doi":"10.1093/biolre/ioae123","DOIUrl":"10.1093/biolre/ioae123","url":null,"abstract":"<p><p>Gestation period in captive Yangtze finless porpoise (YFP) is a well-coordinated and dynamic process, involving both systemic and local alterations. The gut microbiota and its connection to fecal metabolites are crucial in supporting fetal development and ensuring maternal health during reproductive stages. This study evaluates changes in the gut microbiota and their correlation with fecal metabolites in captive YFPs during different reproductive stages. The results reveal that microbial community structure changed significantly during reproductive stages, while gut microbial diversity remained stable. The genus unclassified Peptostrptococcaceae, Corynebacterium, and norank KD4-96 were significantly greater in non-pregnancy (NP), Terrisporobacter was significantly greater in lactating (LL), and Clostridium was significantly higher in early-pregnancy (EP) compared to the other groups. The host fecal metabolome exhibited significant alterations during the reproductive stages. Indoxyl sulfate, octadecatrienoic acid, and methionyl-methionine were significantly higher in the NP; galactosylglycerol, chondroitin 6-sulfate, and lumichrome were significantly higher in the EP and mid-pregnancy (MP); and valylleucine and butyryl-l-carnitine were significantly higher in the LL. The altered metabolites were mostly concentrated in pathways associated with arachidonic acid metabolism (significantly altered in NP), leucine, valine, and isoleucine biosynthesis (significantly altered in EP and MP), and glycerophospholipid metabolism (significantly altered in LL compared to others stages). Additionally, we found a strong link between variations in the host metabolism and alterations in the fecal bacteria of captive YFP. In conclusion, this study provides detailed insights into host metabolic and fecal bacterial changes in captive YFP during reproduction stages, providing important knowledge for improving the reproductive management in the captive YFP.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1249-1261"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xing Wu, Jiayan Shen, Jinjin Liu, Nannan Kang, Mingshun Zhang, Xinyu Cai, Xin Zhen, Guijun Yan, Yang Liu, Haixiang Sun
{"title":"Increased EHD1 in trophoblasts causes RSM by activating TGFβ signaling†.","authors":"Xing Wu, Jiayan Shen, Jinjin Liu, Nannan Kang, Mingshun Zhang, Xinyu Cai, Xin Zhen, Guijun Yan, Yang Liu, Haixiang Sun","doi":"10.1093/biolre/ioae110","DOIUrl":"10.1093/biolre/ioae110","url":null,"abstract":"<p><strong>Background: </strong>Recurrent spontaneous miscarriage is one of the complications during pregnancy. However, the pathogenesis of recurrent spontaneous miscarriage is far from fully elucidated.</p><p><strong>Objective: </strong>Since the endocytic pathway is crucial for cellular homeostasis, our study aimed to explore the roles of endocytic recycling, especially EH domain containing 1, a member of the endocytic recycling compartment, in recurrent spontaneous miscarriage.</p><p><strong>Study design: </strong>We first investigated the expression of the endocytic pathway member EH domain containing 1 in villi from the normal and recurrent spontaneous miscarriage groups. Then, we performed ribonucleic acid sequencing and experiments in villi, HTR8 cells and BeWo cells to determine the mechanisms by which EH domain containing 1-induced recurrent spontaneous miscarriage. Finally, placenta-specific EH domain containing 1-overexpressing mice were generated to investigate the recurrent spontaneous miscarriage phenotype in vivo.</p><p><strong>Results: </strong>EH domain containing 1 was expressed in extravillous trophoblasts and syncytiotrophoblast in the villi. Compared with the control group, recurrent spontaneous miscarriage patients expressed higher EH domain containing 1. A high level of EH domain containing 1 decreased proliferation, promoted apoptosis, and reduced the migration and invasion of HTR8 cells by activating the TGFβ receptor 1-SMAD2/3 signaling pathway. The TGFβ receptor 1 antagonist LY3200882 partially reversed the EH domain containing 1 overexpression-induced changes in the cell phenotype. Besides, a high level of EH domain containing 1 also induced abnormal syncytialization, which disturbed maternal-fetal material exchanges. In a mouse model, placenta-specific overexpression of EH domain containing 1 led to the failure of spiral artery remodeling, excessive syncytialization, and miscarriage.</p><p><strong>Conclusions: </strong>Increased expression of EH domain containing 1 impaired the invasion of extravillous trophoblasts mediated by the TGFβ receptor 1-SMAD2/3 signaling pathway and induced abnormal syncytialization of syncytiotrophoblast, which is at least partially responsible for recurrent spontaneous miscarriage.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1235-1248"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pedo L J Monteiro, Milo C Wiltbank, Waneska S Frizzarini, João Paulo N Andrade, Elisa M Cabrera, Sophia G Schoenfeld, Rafael R Domingues, Laura L Hernandez
{"title":"Hormonal profiles and biomarkers leading to parturition in cattle†.","authors":"Pedo L J Monteiro, Milo C Wiltbank, Waneska S Frizzarini, João Paulo N Andrade, Elisa M Cabrera, Sophia G Schoenfeld, Rafael R Domingues, Laura L Hernandez","doi":"10.1093/biolre/ioae133","DOIUrl":"10.1093/biolre/ioae133","url":null,"abstract":"<p><p>This study aimed to understand the physiological mechanisms regulating parturition and to identify potential biomarkers to predict onset of birth. Additionally, we compared hormone profiles between cows with shorter and longer gestation lengths. Twenty-eight days before due date until 3d postpartum, cows (n = 18) were blood-sampled daily. Circulating concentrations were measured for progesterone and estradiol by RIA, testosterone, prostaglandin F2α metabolite, cortisol, pregnancy-specific protein B by enzyme-linked immunosorbent assay, and lactate concentrations by colorimetric assay. At end of gestation, progesterone decreased from d-14 to d-4 (from 3.6 to 1.4 ng/mL), most likely from rapid loss of placental progesterone production (64% of decline in 24 h). A second rapid decrease in progesterone to undetectable concentrations was observed from d-2 to parturition (from 1.4 to 0.1 ng/ml; most likely luteal origin) corresponding to increase in prostaglandin F2α metabolite from d-2 to parturition (249.7 to 2868.4 pg/mL). E2 and pregnancy-specific protein B increased ~8-fold from ~13d before parturition with acute rise in E2 but not pregnancy-specific protein B (45% vs. 13% in first 24 h). Testosterone decreased slightly during the same period. Cortisol and lactate increased only at calving. Comparison of cows with shorter vs. longer gestation, when data were normalized to parturition day, a difference was detected in circulating E2 and prostaglandin F2α metabolite patterns, but not progesterone and pregnancy-specific protein B. Thus, the first significant hormonal changes associated with parturition begin at d-14 with E2 and pregnancy-specific protein B as two clear biomarkers of impending parturition. Cows with shorter and longer gestation had hormonal differences indicative of identifiable earlier placental maturation.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1282-1296"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Luis Aguila, Rafael V Sampaio, Jacinthe Therrien, Ricardo P Nociti, Remi Labrecque, Amelie Tremblay, Gabrielle Marras, Patrick Blondin, Lawrence C Smith
{"title":"Replacing sperm with genotyped haploid androgenetic blastomeres to generate cattle with predetermined paternal genomes†.","authors":"Luis Aguila, Rafael V Sampaio, Jacinthe Therrien, Ricardo P Nociti, Remi Labrecque, Amelie Tremblay, Gabrielle Marras, Patrick Blondin, Lawrence C Smith","doi":"10.1093/biolre/ioae135","DOIUrl":"10.1093/biolre/ioae135","url":null,"abstract":"<p><p>Although meiosis plays an essential role for the survival of species in natural selection, the genetic diversity resulting from sexual reproduction impedes human-driven strategies to transmit the most suitable genomes for genetic improvement, forcing breeders to select diploid genomes generated after fertilization, that is, after the encounter of sperm and oocytes carrying unknown genomes. To determine whether genomic assessment could be used before fertilization, some androgenetic haploid morula-stage bovine embryos derived from individual sperm were biopsied for genomic evaluation and others used to reconstruct \"semi-cloned\" (SC) diploid zygotes by the intracytoplasmic injection into parthenogenetically activated oocytes, and the resulting embryos were transferred to surrogate females to obtain gestations. Compared to controls, in vitro development to the blastocyst stage was lower and fewer surrogates became pregnant from the transfer of SC embryos. However, fetometric measurements of organs and placental membranes of all SC conceptuses were similar to controls, suggesting a normal post-implantation development. Moreover, transcript amounts of imprinted genes IGF2, IGF2R, PHLDA2, SNRPN, and KCNQ1OT1 and methylation pattern of the KCNQ1 DMR were unaltered in SC conceptuses. Overall, this study shows that sperm can be replaced by genotyped haploid embryonic-derived cells to produce bovine embryos carrying a predetermined paternal genome and viable first trimester fetuses after transfer to female recipients.</p><p><strong>Summary sentence: </strong>Haploid morula-stage embryonic cells derived from a single sperm can be genotyped and injected into activated oocytes to reconstruct diploid zygotes that develop both in vitro into blastocysts and in vivo into viable post-implantation bovine conceptuses with predetermined paternal genomes.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1311-1325"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Single-cell RNA sequencing reveals the important role of Dcaf17 in spermatogenesis of golden hamsters†.","authors":"Rongzhu Ma, Shuang Liang, Wentao Zeng, Jianmin Li, Yana Lai, Xiaoyu Yang, Feiyang Diao","doi":"10.1093/biolre/ioae132","DOIUrl":"10.1093/biolre/ioae132","url":null,"abstract":"<p><p>Dcaf17, also known as DDB1- and CUL4-associated factor 17, is a member of the DCAF family and acts as the receptor for the CRL4 ubiquitin E3 ligase complex. Several previous studies have reported that mutations in Dcaf17 cause Woodhouse-Sakati syndrome, which results in oligoasthenoteratozoospermia and male infertility. As a model to explore the role of Dcaf17 in the male reproductive system, we created Dcaf17-deficient male golden hamsters using CRISPR-Cas9 technology; the results of which demonstrate that deletion of Dcaf17 led to abnormal spermatogenesis and infertility. To uncover the underlying molecular mechanisms involved, we conducted single cell Ribonucleic Acid sequencing analysis to evaluate the effect of Dcaf17 deficiency on transcriptional levels in spermatogenic cells during various stages of spermatogenesis. These data emphasize the significant regulatory role played by Dcaf17 in early spermatogenic cells, with many biological processes being affected, including spermatogenesis and protein degradation. Dysregulation of genes associated with these functions ultimately leads to abnormalities. In summary, our findings highlight the critical function of Dcaf17 in spermatogenesis and clarify the specific stage at which Dcaf17 exerts its effects, while simultaneously providing a novel animal model for the study of Dcaf17.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1326-1340"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sergio Gómez-Olarte, Verena Mailänder, Júlia Castro-Neves, Violeta Stojanovska, Anne Schumacher, Nicole Meyer, Ana C Zenclussen
{"title":"The ENDOMIX perspective: how everyday chemical mixtures impact human health and reproduction by targeting the immune system†.","authors":"Sergio Gómez-Olarte, Verena Mailänder, Júlia Castro-Neves, Violeta Stojanovska, Anne Schumacher, Nicole Meyer, Ana C Zenclussen","doi":"10.1093/biolre/ioae142","DOIUrl":"10.1093/biolre/ioae142","url":null,"abstract":"<p><p>Endocrine-disrupting chemicals are natural and synthetic compounds found ubiquitously in the environment that interfere with the hormonal-immune axis, potentially impacting human health and reproduction. Exposure to endocrine-disrupting chemicals has been associated with numerous health risks, such as neurodevelopmental disorders, metabolic syndrome, thyroid dysfunction, infertility, and cancers. Nevertheless, the current approach to establishing causality between these substances and disease outcomes has limitations. Epidemiological and experimental research on endocrine-disrupting chemicals faces challenges in accurately assessing chemical exposure and interpreting non-monotonic dose response curves. In addition, most studies have focused on single chemicals or simple mixtures, overlooking complex real-life exposures and mechanistic insights, in particular regarding endocrine-disrupting chemicals' impact on the immune system. The ENDOMIX project, funded by the EU's Horizon Health Program, addresses these challenges by integrating epidemiological, risk assessment, and immunotoxicology methodologies. This systemic approach comprises the triangulation of human cohort, in vitro, and in vivo data to determine the combined effects of chemical mixtures. The present review presents and discusses current literature regarding human reproduction in the context of immunotolerance and chemical disruption mode of action. It further underscores the ENDOMIX perspective to elucidate the impact of endocrine-disrupting chemicals on immune-reproductive health.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1170-1187"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arslan Tariq, Zachary K Seekford, John J Bromfield
{"title":"Inflammation during oocyte maturation reduces developmental competence and increases apoptosis in blastocysts.","authors":"Arslan Tariq, Zachary K Seekford, John J Bromfield","doi":"10.1093/biolre/ioae180","DOIUrl":"https://doi.org/10.1093/biolre/ioae180","url":null,"abstract":"<p><p>Uterine infections cause ovarian dysfunction and infertility. The bacterial endotoxin, lipopolysaccharide (LPS), accumulates in the follicular fluid of dominant follicles of cows with uterine infections. Granulosa cells produce an innate inflammatory response to LPS, altering the follicular microenvironment of the oocyte. We hypothesized that developmental competence and embryo quality would be reduced when oocytes are matured in an inflammatory environment. Bovine mural granulosa cells were exposed to either 1 μg/mL of LPS or medium alone for 24 h to produce conditioned medium. Inflammatory responses of mural granulosa cells were confirmed by increased expression of CXCL8, IL1B, IL6 and TNF. Bovine cumulus-oocyte complexes were matured for 22 ± 1 h in medium supplemented with either 1 μg/mL of LPS, 10% v/v conditioned medium of granulosa cells treated with either LPS (LCM) or medium alone (CCM), or no supplementation (CON). In addition, polymyxin B (20 μg/mL) was added to maturation medium to sequester LPS. Following maturation, cumulus-oocyte complexes were fertilized and cultured for 7.5 days with no further treatment. Oocyte maturation using LPS or LCM impaired development to the blastocysts stage, reduced the number of total and CDX2 negative blastomeres and increased TUNEL positive cells in blastocysts. Polymyxin B could rescue these effects in the LPS group but not in the LCM group, indicating factors produced by granulosa cells and not LPS alone compromised oocyte development. These findings suggest that the inflammatory milieu produced by granulosa cells in response to LPS impairs oocyte competence and quality of resultant blastocyst-stage embryos.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lu-Yao Zhang, Ke Zhang, Xi Zhao, Hai-Ping Tao, Gong-Xue Jia, You-Gui Fang, Yun-Peng Hou, Qi-En Yang
{"title":"Fetal hypoxia exposure induces Hif1a activation and autophagy in adult ovarian granulosa cells†.","authors":"Lu-Yao Zhang, Ke Zhang, Xi Zhao, Hai-Ping Tao, Gong-Xue Jia, You-Gui Fang, Yun-Peng Hou, Qi-En Yang","doi":"10.1093/biolre/ioae141","DOIUrl":"10.1093/biolre/ioae141","url":null,"abstract":"<p><p>Environmental hypoxia adversely impacts the reproduction of humans and animals. Previously, we showed that fetal hypoxia exposure led to granulosa cell (GC) autophagic cell death via the Foxo1/Pi3k/Akt pathway. However, the upstream regulatory mechanisms underlying GC dysfunction remain largely unexplored. Here, we tested the hypothesis that fetal hypoxia exposure altered gene expression programs in adult GCs and impaired ovarian function. We established a fetal hypoxia model in which pregnant mice were maintained in a high-plateau hypoxic environment from gestation day (E) 0-16.5 to study the impact of hypoxia exposure on the ovarian development and subsequent fertility of offspring. Compared with the unexposed control, fetal hypoxia impaired fertility by disordering ovarian function. Specifically, fetal hypoxia caused mitochondrial dysfunction, oxidant stress, and autophagy in GCs in the adult ovary. RNA sequencing analysis revealed that 437 genes were differentially expressed in the adult GCs of exposed animals. Western blotting results also revealed that fetal exposure induced high levels of hypoxia-inducible factor 1-alpha (Hif1a) expression in adult GCs. We then treated granulosa cells isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary.</p>","PeriodicalId":8965,"journal":{"name":"Biology of Reproduction","volume":" ","pages":"1220-1234"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}