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Min Chen Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China

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Jia-Lu Shi Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China

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Zi-Meng Zheng Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China

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Zhi Lin Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China

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Ming-Qing Li Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China
NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Jun Shao Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China
Department of Obstetrics, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China

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In brief

Autophagy is important for trophoblast cells at the maternal–fetal interface during early pregnancy. This study suggests that trophoblast cells can promote the autophagy under a regulation of the LPA/LPAR 1–NHE1 axis.

Abstract

The autophagy of trophoblasts is necessary for developing and maintaining a healthy pregnancy. Autophagy dysfunction in trophoblast cells is linked to recurrent spontaneous abortion (RSA). However, the mechanism underlying trophoblast autophagy is unknown. In this study, we investigated the expression of autophagy-related genes in both normal and RSA villi. We also examined the production of LPA and LPAR1 in trophoblast cells during early pregnancy. We found that the activation of the LPA–LPAR1 axis triggered the autophagy of trophoblast cells and increased the expression of NHE1. Inhibition of NHE1 suppressed the autophagy in trophoblast cells and we confirmed that NHE1 regulates LPA production in trophoblast cells. Additionally, we found decreased expression of autophagy-related genes and LPAR1 in villi from RSA patients. These observations indicate that the LPA/LPAR1–NHE1 axis regulates the autophagy of trophoblast cells during pregnancy. Insufficient autophagy and poor expression of LPAR1 in trophoblast cells may result in the dysfunction of the trophoblasts and an increased risk of spontaneous abortion. Overall, our research elucidated that a positive LPA/LPAR1–NHE1 axis can promote the autophagy of trophoblast cells and the abnormal axis leads to the autophagy deficiency of trophoblast cells in recurrent spontaneous abortion.

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Wang Han-zheng
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Lu Shu-hua
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Shen Wei-xiong
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Sun Zhi-da
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Zhou Wei
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Wu Yu-fen
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Zhou Mei-rong
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Summary. Cell suspensions were prepared from human corpora lutea obtained during the mid-luteal phase. Progesterone production was assessed after short-term incubation of luteal cell suspensions. Luteal cells were very sensitive to hCG, the concentration required for 50% maximum response being 0·01 i.u./ml, and the response was 5 times higher than the basal production.

Oestradiol (1–100 μm) induced a significant dose-related decrease in both basal and hCG-stimulated progesterone production. The A-nor steroidal compounds anordrin and AF-45 reduced hCG-stimulated progesterone production only at the high concentration of 100 μm. The ED50 values were approximately 3 μm, 75 μm and 100 μm for oestradiol, AF-45 and anordrin respectively. Anordrin showed no significant effects on basal progesterone production. In addition, oestradiol markedly inhibited the activity of 3β-hydroxysteroid dehydrogenase in luteal cells, expressed by the conversion of pregnenolone to progesterone, but the inhibitory effects of anordrin and AF-45 were negligible or relatively low.

The effects of anordrin and AF-45 were different from those of oestradiol on progesterone production by human luteal cells in vitro, indicating that neither substance is likely to be a useful luteolytic agent in women.

Keywords: A-nor steroid; oestradiol; luteal cells; progesterone; 3β-hydroxysteroid dehydrogenase; man

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Xiaoxu Chen College of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong, China
Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China

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Qian Sun Chengdu Xinan Women’s Hospital, Jinjiang District, Chengdu, China

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Yi Zheng Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China

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Zidong Liu Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China

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Xiangqian Meng Chengdu Xinan Women’s Hospital, Jinjiang District, Chengdu, China

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Wenxian Zeng Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China

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Hongzhao Lu College of Biological Science and Engineering, Shaanxi University of Technology, Hanzhong, China

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Infertility caused by male factors is routinely diagnosed by assessing traditional semen parameters. Growing evidence has indicated that the tsRNAs carried in sperm act as epigenetic factors and potential biomarkers for the assessment of sperm quality. We recently demonstrated that tRNAGln-TTG derived small RNAs played notable roles in the first cleavage of a porcine embryo. However, the function of human sperm tRNAGln-TTG derived small RNAs as a diagnostic biomarker and its role in early embryo development remains unclear. In this study, we found that human sperm tRNAGln-TTG derived small RNAs were highly associated with sperm quality. By microinjecting the antisense sequence into human tripronuclear (3PN) zygotes followed by single-cell RNA-sequencing, we found that human sperm tRNAGln-TTG derived small RNAs participated in the development of a human embryo. Furthermore, Gln-TTGs might influence embryonic genome activation by modulating noncoding RNA processing. These findings demonstrated that human sperm tRNAGln-TTG derived small RNAs could be potential diagnostic biomarkers and could be used as a clinical target for male infertility.

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Ru Zheng State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China
University of Chinese Academy of Sciences, Beijing, People’s Republic of China

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Yue Li Peking University Third Hospital, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Beijing, People’s Republic of China

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Huiying Sun Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, CAS Center for Excellence in Molecular Cell Science, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People’s Republic of China
University of Chinese Academy of Sciences, Beijing, People’s Republic of China

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Xiaoyin Lu State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China
University of Chinese Academy of Sciences, Beijing, People’s Republic of China

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Bao-Fa Sun Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, CAS Center for Excellence in Molecular Cell Science, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People’s Republic of China

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Rui Wang State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China
University of Chinese Academy of Sciences, Beijing, People’s Republic of China

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Lina Cui State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China
University of Chinese Academy of Sciences, Beijing, People’s Republic of China

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Cheng Zhu State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China

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Hai-Yan Lin State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China

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Hongmei Wang State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China

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The syncytiotrophoblast (STB) plays a key role in maintaining the function of the placenta during human pregnancy. However, the molecular network that orchestrates STB development remains elusive. The aim of this study was to obtain broad and deep insight into human STB formation via transcriptomics. We adopted RNA sequencing (RNA-Seq) to investigate genes and isoforms involved in forskolin (FSK)-induced fusion of BeWo cells. BeWo cells were treated with 50 μM FSK or dimethyl sulfoxide (DMSO) as a vehicle control for 24 and 48 h, and the mRNAs at 0, 24 and 48 h were sequenced. We detected 28,633 expressed genes and identified 1902 differentially expressed genes (DEGs) after FSK treatment for 24 and 48 h. Among the 1902 DEGs, 461 were increased and 395 were decreased at 24 h, whereas 879 were upregulated and 763 were downregulated at 48 h. When the 856 DEGs identified at 24 h were traced individually at 48 h, they separated into 6 dynamic patterns via a K-means algorithm, and most were enriched in down–even and up–even patterns. Moreover, the gene ontology (GO) terms syncytium formation, cell junction assembly, cell fate commitment, calcium ion transport, regulation of epithelial cell differentiation and cell morphogenesis involved in differentiation were clustered, and the MAPK pathway was most significantly regulated. Analyses of alternative splicing isoforms detected 123,200 isoforms, of which 1376 were differentially expressed. The present deep analysis of the RNA-Seq data of BeWo cell fusion provides important clues for understanding the mechanisms underlying human STB formation.

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Yue Li Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China
Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Ru Zheng Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China
Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Rui Wang Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China
Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Xiaoyin Lu Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China
Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Cheng Zhu Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Hai-Yan Lin Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Hongmei Wang Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Xiaoguang Yu Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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Jiejun Fu Department of Biochemistry and Molecular Biology, State Key Laboratory of Reproductive Biology, University of Chinese Academy of Sciences, Key Laboratory of Longevity and Ageing-related Diseases, College of Basic Medical Science, Harbin Medical University, Harbin 150081, People's Republic of China

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The placenta has numerous functions, such as transporting oxygen and nutrients and building the immune tolerance of the fetus. Cell fusion is an essential process for placental development and maturation. In human placental development, mononucleated cytotrophoblast (CTB) cells can fuse to form a multinucleated syncytiotrophoblast (STB), which is the outermost layer of the placenta. Nephrin is a transmembrane protein that belongs to the Ig superfamily. Previous studies have shown that nephrin contributes to the fusion of myoblasts into myotubes in zebrafish and mice, presenting a functional conservation with its Drosophila ortholog sticks and stones. However, whether nephrin is involved in trophoblast syncytialization remains unclear. In this study, we report that nephrin was localized predominantly in the CTB cells and STB of human placenta villi from first trimester to term pregnancy. Using a spontaneous fusion model of primary CTB cells, the expression of nephrin was found to be increased during trophoblast cell fusion. Moreover, the spontaneous syncytialization and the expression of syncytin 2, connexin 43, and human chorionic gonadotropin beta were significantly inhibited by nephrin-specific siRNAs. The above results demonstrate that nephrin plays an important role in trophoblast syncytialization.

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Chuwei Li C Li, Medical School, Nanjing University, Nanjing, China

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Zhang Qian Z Qian, Medical School, Nanjing University, Nanjing, China

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Hong Zhang H Zhang, Medical School, Nanjing University, Nanjing, China

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Xie Ge X Ge, Medical School, Nanjing University, Nanjing, China

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Li Chen L Chen, Department of Reproductive Medicine, Nanjing Jinling Hospital, Nanjing, China

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Ting Tang T Tang, Medical School, Nanjing University, Nanjing, China

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Mengqi Xue M Xue, Medical School, Nanjing University, Nanjing, China

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Zhaowanyue He Z He, Medical School, Nanjing University, Nanjing, China

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Lu Zheng L Zheng, Medical School, Nanjing University, Nanjing, China

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Chun Cao C Cao, Department of Reproductive Medicine, Southern Medical University, Guangzhou, China

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Kemei Zhang K Zhang, Department of Reproductive Medicine, Nanjing Medical University, Nanjing, China

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Rujun Ma R Ma, Medical School, Nanjing University, Nanjing, China

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Bing Yao B Yao, Medical School, Nanjing University, Nanjing, China

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With an increase in the mean age at parturition worldwide, female reproductive aging has become a key health problem. Advanced maternal age is reflected by decreased oocyte quality; however, the molecular mechanisms of oocyte aging are uncharacterized. O-linked N-acetylglucosamine (O-GlcNAc), a dynamic posttranslational modification, plays a critical role in the development of many age-related diseases, yet it remains unclear whether and how O-GlcNAc participates in oocyte aging. Here, we found that global O-GlcNAc was elevated in normal biological aging mice oocytes (32-34 weeks) which were characterized by meiotic maturation failure and impaired mitochondrial function. Specifically, O-GlcNAc targeted the mitochondrial fission protein dynamic-related protein 1 (DRP1) to meditate mitochondrial distribution in the process of aging. Using the O-GlcNAcase (OGA) pharmacological inhibitor Thiamet-G and OGA knockdown (OGA-KD) to mimic the age-related high O-GlcNAc in young oocytes from 6-8 week-old mice mimicked the phenotype of oocyte aging. Moreover, reducing O-GlcNAc levels in aging oocytes restored spindle organization to improve oocyte quality. Our results demonstrate that O-GlcNAc is a key regulator of meiotic maturation that participates in the progression of oocyte aging.

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Hui-Hui Shen Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Cheng-Jie Wang Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Xin-Yan Zhang Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Yan-Ran Sheng Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Shao-Liang Yang Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Zi-Meng Zheng Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Jia-Lu Shi Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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Xue-Min Qiu Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China
Clinical Research Center, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China

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Feng Xie Medical Center of Diagnosis and Treatment for Cervical and Intrauterine Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China

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Ming-Qing Li Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China
Department of Obstetrics and Gynecology, Maternal and Child Health Hospital of Longgang District, Shenzhen, Guangdong Province, People’s Republic of China

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Heme oxygenase 1 (HO-1, encoded by the HMOX1 gene) is the rate-limiting enzyme that catalyzes heme degradation, and it has been reported to exert antioxidative effects. Recently, decidualization has been reported to confer resistance to environmental stress signals, protecting against oxidative stress. However, the effects and regulatory mechanism of HO-1 in decidual stromal cells (DSCs) during early pregnancy remain unknown. Here, we verified that the levels of HO-1 and heme in DSCs are increased compared with those in endometrial stromal cells. Additionally, the upregulation of HIF1A expression led to increased HMOX1 expression in DSCs possibly via nuclear factor erythroid 2-related factor (encoded by the NFE2L2 gene). However, addition of the competitive HO-1 inhibitor zinc protoporphyrin IX resulted in an increase in HIF1A expression. Hydrogen peroxide (H2O2) induced the production of reactive oxygen species (ROS), decreased the cell viability of DSCs in vitro, and upregulated the level of heme. As an HO-1 inducer, cobalt protoporphyrin IX decreased ROS production and significantly reversed the inhibitory effect of H2O2 on cell viability. More importantly, patients with unexplained spontaneous abortion had low levels of HO-1 that were insufficient to protect against oxidative stress. This study suggests that the upregulation of HO-1 expression via HIF1A protects DSCs against excessive heme-mediated oxidative stress. Furthermore, the excessive oxidative stress injury and impaired viability of DSCs associated with decreased HO-1 expression should be associated with the occurrence and/or development of spontaneous abortion.

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Wen Zheng Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China
Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, PR China

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Liang Zhang Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Kailai Cai Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Kongju Wu Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Ge Liang Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, PR China

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Lu Zhang Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, PR China

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Lihui Liao Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Fujun Shen Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Wenping Zhang Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Li Wang Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Yan Li Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Ye Wang Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Jie Kou Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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Yi Zhong Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, PR China

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Xin Li Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China

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Jingqiu Cheng Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China

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Meng Gong Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, PR China

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Rong Hou Chengdu Research Base of Giant Panda Breeding, Chengdu, PR China

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In brief

The metabolic processes of the gestation period in pandas remain poorly understood. Our study comprehensively characterizes the metabolism of giant pandas during gestation and proposes arginine and histidine as potential novel biomarkers for detecting the pregnancy state of giant pandas.

Abstract

There has been remarkable progress in the conservation and reproduction of giant pandas. However, the physiology of the gestation period in pandas remains poorly understood. The metabolic processes from estrus to pregnancy are dynamic and precisely regulated, playing a crucial role in pregnancy and related dysfunctions. In this study, we conducted a metabolomic analysis of 37 blood samples collected from pandas in estrus, acyclic, and potential pregnant states, employing rigorous screening to minimize the influence of diet. Our findings suggest that a reduced appetite can serve as an indicator for evaluating implantation time, representing a characteristic response to pregnancy and aiding in the prediction of delivery time in pregnant pandas. Metabolomic results indicate great metabolism variation from estrus to pregnancy, highlighting the association between amino acid metabolism and pregnancy outcomes. Compared to other pandas, individuals who successfully bred exhibit significantly elevated levels of arginine and histidine, even 2 months before experiencing a reduced appetite. Furthermore, the lipid profile undergoes distinct dynamic changes only in estrus samples. In summary, our study comprehensively characterizes the metabolism of giant pandas during gestation and proposes arginine and histidine as potential novel biomarkers for detecting the pregnancy state of giant pandas.

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