{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:28:42Z","timestamp":1793111322118,"version":"4.5.0"},"reference-count":108,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":117,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01 HD108166-01A1"],"award-info":[{"award-number":["R01 HD108166-01A1"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>How different is the global proteomic and metabolic profile of mouse blastocysts generated by IVF, cultured in optimal (5% O2) or stressful (20% O2) conditions, compared to in vivo generated blastocysts?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>We found that in IVF-generated embryos: (i) the proteome was more sensitive to high oxygen levels than the global metabolomic profile; (ii) enzymes involved in splicing and the spliceosome are altered; (iii) numerous metabolic pathways, particularly amino acids metabolism, are altered (iv) there is activation of the integrated stress response (ISR) and downregulation of mTOR pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>IVF culture conditions are known to affect the gene expression of embryos. However, comprehensive data on the global metabolic and proteomic changes that occur in IVF-generated embryos are unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>Mouse embryos were generated by natural mating (in vivo control or flushed blastocyst-FB-group) or by IVF using KSOM medium and two distinct oxygen concentrations: 5% O2 (optimal) and 20% O2 (stressful). Proteomic and metabolomic analyses were performed using state-of-the-art mass spectrometry techniques in triplicate (n\u2009=\u2009100 blastocysts per replicate), allowing for detailed profiling of protein and metabolite alterations in each group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>Mouse blastocysts were collected from CD-1 and B6D2F1 strains as specified above. High-resolution liquid chromatography-tandem mass spectrometry (LC-MS\/MS) was used for proteomics, while high-performance liquid chromatography coupled with mass spectrometry (HILIC-MS) was used for metabolomics. In addition, Immunofluorescence was used to assess the activation of stress response pathways, including the ISR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>Proteomic analysis revealed significant changes in protein expression in embryos cultured under 20% O2 compared to 5% O2 and in vivo embryos. Compared to in vivo embryos, IVF embryos cultured under 20% O2 exhibited 599 differentially expressed proteins, with an increase in proteins involved in oxidative stress responses, aminoacyl-tRNA synthesis, and spliceosome pathways. In contrast, IVF embryos cultured under 5% O2 showed fewer changes, with 426 differentially expressed proteins, though still reflecting significant alterations compared to in vivo embryos. These results indicate that embryos in stressful conditions (20% O2) exhibit a stronger stress response and alterations in critical pathways for protein synthesis and DNA repair. Metabolomic analysis revealed that embryos cultured under 20% O2 showed changes in branch-chained amino acid levels, and decreased levels of key metabolites of the TCA cycle and pentose phosphate pathway. Embryos cultured under 5% O2 had increased pyruvate levels, suggesting altered glycolysis. Immunofluorescence confirmed that oxidative stress markers such as GCN2, EIF2\u03b1, and ATF4 were upregulated in IVF embryos, indicating ISR activation. Overall, IVF and embryo culture have a direct impact on embryo proteomes and metabolomes affecting amino acid metabolism and stress-related pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LARGE SCALE DATA<\/jats:title>\n                    <jats:p>N\/A.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>Results in a murine model should be extrapolated with caution to human embryos.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>These findings offer valuable insights into how different IVF culture conditions, specifically oxygen levels, impact the global metabolic and proteomic profiles of embryos. These findings provide critical insights into the profound impact of IVF culture conditions, particularly oxygen levels, on the global metabolic and proteomic landscapes of embryos. By identifying key metabolic pathways disrupted by oxidative stress, we highlight the potential clinical importance of proteomic and metabolomic analyses in understanding embryo quality, improving ART, and ultimately enhancing pregnancy outcomes. The integration of metabolomic and proteomic data offers a comprehensive understanding of how oxidative stress influences cellular function. These insights have direct clinical relevance, providing a foundation for optimizing ART protocols to mitigate oxidative stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This work was supported by grant R01 HD108166-01A1 from the National Institute of Child Health and Human Development (NICHD) to P.F.R. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hropen\/hoaf022","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T07:42:23Z","timestamp":1745566943000},"source":"Crossref","is-referenced-by-count":10,"title":["Proteomic and metabolomic insights into oxidative stress response activation in mouse embryos generated by\n                    <i>in vitro<\/i>\n                    fertilization"],"prefix":"10.1093","volume":"2025","author":[{"given":"Seok Hee","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Center for Reproductive Sciences, University of California San Francisco , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa\u00fal","family":"Lira-Albarr\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Center for Reproductive Sciences, University of California San Francisco , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6528-6009","authenticated-orcid":false,"given":"Paolo F","family":"Rinaudo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Center for Reproductive Sciences, University of California San Francisco , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"2025052408462073700_hoaf022-B1","doi-asserted-by":"crossref","first-page":"101726","DOI":"10.1016\/j.molmet.2023.101726","article-title":"C\/EBPbeta-LIP mediated activation of the malate-aspartate shuttle sensitizes cells to glycolysis inhibition","volume":"72","author":"Ackermann","year":"2023","journal-title":"Mol Metab"},{"key":"2025052408462073700_hoaf022-B2","doi-asserted-by":"crossref","first-page":"5155","DOI":"10.1038\/s41598-018-23408-0","article-title":"Modeling the effects of lipid peroxidation during ferroptosis on membrane properties","volume":"8","author":"Agmon","year":"2018","journal-title":"Sci Rep"},{"key":"2025052408462073700_hoaf022-B3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"2025052408462073700_hoaf022-B4","doi-asserted-by":"crossref","first-page":"3457","DOI":"10.1210\/en.2011-1921","article-title":"Impaired placental nutrient transport in mice generated by in vitro fertilization","volume":"153","author":"Bloise","year":"2012","journal-title":"Endocrinology"},{"key":"2025052408462073700_hoaf022-B5","doi-asserted-by":"crossref","first-page":"11165","DOI":"10.1038\/ncomms11165","article-title":"Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential","volume":"7","author":"Bolton","year":"2016","journal-title":"Nat Commun"},{"key":"2025052408462073700_hoaf022-B6","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1530\/rep.1.00727","article-title":"Amino acid depletion and appearance during porcine preimplantation embryo development in vitro","volume":"130","author":"Booth","year":"2005","journal-title":"Reproduction"},{"key":"2025052408462073700_hoaf022-B7","doi-asserted-by":"crossref","first-page":"F15","DOI":"10.1530\/REP-22-0424","article-title":"DOHaD: a menagerie of adaptations and perspectives: the interplay between early embryo metabolism and mitoepigenetic programming of development","volume":"166","author":"Bruna de Lima","year":"2023","journal-title":"Reproduction"},{"key":"2025052408462073700_hoaf022-B8","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1016\/j.bbamcr.2014.04.006","article-title":"Keeping the eIF2 alpha kinase Gcn2 in check","volume":"1843","author":"Castilho","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"2025052408462073700_hoaf022-B9","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1093\/humrep\/dep273","article-title":"Growth during infancy and early childhood in relation to blood pressure and body fat measures at age 8-18 years of IVF children and spontaneously conceived controls born to subfertile parents","volume":"24","author":"Ceelen","year":"2009","journal-title":"Hum Reprod"},{"key":"2025052408462073700_hoaf022-B10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.placenta.2023.05.018","article-title":"Stress regulation of WFS1 and PERK-p-eIF2alpha-ATF4 signaling pathway in placental tissue cells of intrahepatic cholestasis of pregnancy","volume":"139","author":"Chen","year":"2023","journal-title":"Placenta"},{"key":"2025052408462073700_hoaf022-B11","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1186\/s13046-019-1413-7","article-title":"Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK\/ATF4\/HSPA5 pathway in glioma cells","volume":"38","author":"Chen","year":"2019","journal-title":"J Exp Clin Cancer Res"},{"key":"2025052408462073700_hoaf022-B12","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1093\/bioinformatics\/btu305","article-title":"MSstats: an R package for statistical analysis of quantitative mass spectrometry-based proteomic experiments","volume":"30","author":"Choi","year":"2014","journal-title":"Bioinformatics"},{"key":"2025052408462073700_hoaf022-B13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/humupd\/dmu040","article-title":"IVF culture media: past, present and future","volume":"21","author":"Chronopoulou","year":"2015","journal-title":"Hum Reprod Update"},{"key":"2025052408462073700_hoaf022-B14","doi-asserted-by":"crossref","first-page":"e2132602","DOI":"10.1001\/jamanetworkopen.2021.32602","article-title":"Assessment of cardiovascular health of children ages 6 to 10 years conceived by assisted reproductive technology","volume":"4","author":"Cui","year":"2021","journal-title":"JAMA Netw Open"},{"key":"2025052408462073700_hoaf022-B15","doi-asserted-by":"crossref","first-page":"15672","DOI":"10.1038\/s41598-020-72221-1","article-title":"The dynamics between in vitro culture and metabolism: embryonic adaptation to environmental changes","volume":"10","author":"de Lima","year":"2020","journal-title":"Sci Rep"},{"key":"2025052408462073700_hoaf022-B16","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1095\/biolreprod.113.113134","article-title":"In vitro fertilization affects growth and glucose metabolism in a sex-specific manner in an outbred mouse model","volume":"90","author":"Donjacour","year":"2014","journal-title":"Biol Reprod"},{"key":"2025052408462073700_hoaf022-B17","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1073\/pnas.0306846101","article-title":"Long-term effects of culture of preimplantation mouse embryos on behavior","volume":"101","author":"Ecker","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025052408462073700_hoaf022-B18","doi-asserted-by":"crossref","first-page":"e1007473","DOI":"10.1371\/journal.pgen.1007473","article-title":"RES complex is associated with intron definition and required for zebrafish early embryogenesis","volume":"14","author":"Fernandez","year":"2018","journal-title":"PLoS Genet"},{"key":"2025052408462073700_hoaf022-B19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1530\/REP-16-0473","article-title":"Common and specific transcriptional signatures in mouse embryos and adult tissues induced by in vitro procedures","volume":"153","author":"Feuer","year":"2016","journal-title":"Reproduction"},{"key":"2025052408462073700_hoaf022-B20","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1016\/S0140-6736(18)30312-X","article-title":"Origins of lifetime health around the time of conception: causes and consequences","volume":"391","author":"Fleming","year":"2018","journal-title":"Lancet"},{"key":"2025052408462073700_hoaf022-B21","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1071\/RD14421","article-title":"Blastocyst metabolism","volume":"27","author":"Gardner","year":"2015","journal-title":"Reprod Fertil Dev"},{"key":"2025052408462073700_hoaf022-B22","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1071\/RD04103","article-title":"Ex vivo early embryo development and effects on gene expression and imprinting","volume":"17","author":"Gardner","year":"2005","journal-title":"Reprod Fertil Dev"},{"key":"2025052408462073700_hoaf022-B23","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1530\/jrf.0.0880361","article-title":"Concentrations of nutrients in mouse oviduct fluid and their effects on embryo development and metabolism in vitro","volume":"88","author":"Gardner","year":"1990","journal-title":"J Reprod Fertil"},{"key":"2025052408462073700_hoaf022-B24","doi-asserted-by":"crossref","first-page":"iyad031","DOI":"10.1093\/genetics\/iyad031","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"Gene Ontology Consortium","year":"2023","journal-title":"Genetics"},{"key":"2025052408462073700_hoaf022-B25","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1093\/humrep\/deq266","article-title":"Effect of ICSI on gene expression and development of mouse preimplantation embryos","volume":"25","author":"Giritharan","year":"2010","journal-title":"Hum Reprod"},{"key":"2025052408462073700_hoaf022-B26","first-page":"G290","article-title":"Mechanism of arginine protection against ammonia intoxication in the rat","volume":"247","author":"Goodman","year":"1984","journal-title":"Am J Physiol"},{"key":"2025052408462073700_hoaf022-B27","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.fertnstert.2016.12.007","article-title":"Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis","volume":"107","author":"Guo","year":"2017","journal-title":"Fertil Steril"},{"key":"2025052408462073700_hoaf022-B28","doi-asserted-by":"crossref","first-page":"e23219","DOI":"10.1096\/fj.202202024RR","article-title":"Aminoacyl-tRNA synthetase\u2014a molecular multitasker","volume":"37","author":"Gupta","year":"2023","journal-title":"FASEB J"},{"key":"2025052408462073700_hoaf022-B29","doi-asserted-by":"crossref","first-page":"e08501","DOI":"10.1016\/j.heliyon.2021.e08501","article-title":"Changes in TCA cycle and TCA cycle-related metabolites in plasma upon citric acid administration in rats","volume":"7","author":"Hara","year":"2021","journal-title":"Heliyon"},{"key":"2025052408462073700_hoaf022-B30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.fertnstert.2024.08.340","article-title":"Ovarian stimulation protocols: impact on oocyte and endometrial quality and function","volume":"123","author":"Harvey","year":"2025","journal-title":"Fertil Steril"},{"key":"2025052408462073700_hoaf022-B31","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1126\/science.adh0073","article-title":"Assisted reproductive technologies at the nexus of fertility treatment and disease prevention","volume":"380","author":"Herbert","year":"2023","journal-title":"Science"},{"key":"2025052408462073700_hoaf022-B32","doi-asserted-by":"crossref","first-page":"eadf0115","DOI":"10.1126\/sciadv.adf0115","article-title":"Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis","volume":"9","author":"Izzo","year":"2023","journal-title":"Sci Adv"},{"key":"2025052408462073700_hoaf022-B33","doi-asserted-by":"crossref","first-page":"10126","DOI":"10.1073\/pnas.152318699","article-title":"Gene targeting of Gemin2 in mice reveals a correlation between defects in the biogenesis of U snRNPs and motoneuron cell death","volume":"99","author":"Jablonka","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025052408462073700_hoaf022-B34","doi-asserted-by":"crossref","first-page":"112632","DOI":"10.1016\/j.celrep.2023.112632","article-title":"Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic \u201cintegrated stress response\u201d","volume":"42","author":"Jones","year":"2023","journal-title":"Cell Rep"},{"key":"2025052408462073700_hoaf022-B35","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.3390\/molecules26164913","article-title":"The role of taurine in mitochondria health: more than just an antioxidant","volume":"26","author":"Jong","year":"2021","journal-title":"Molecules"},{"key":"2025052408462073700_hoaf022-B36","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2025052408462073700_hoaf022-B37","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1530\/rep.1.00854","article-title":"A proteomic analysis of mammalian preimplantation embryonic development","volume":"130","author":"Katz-Jaffe","year":"2005","journal-title":"Reproduction"},{"key":"2025052408462073700_hoaf022-B38","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1172\/JCI42020","article-title":"Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest","volume":"120","author":"Kawamura","year":"2010","journal-title":"J Clin Invest"},{"key":"2025052408462073700_hoaf022-B39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.rbmo.2019.03.102","article-title":"Individual culture and atmospheric oxygen during culture affect mouse preimplantation embryo metabolism and post-implantation development","volume":"39","author":"Kelley","year":"2019","journal-title":"Reprod Biomed Online"},{"key":"2025052408462073700_hoaf022-B40","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.biortech.2006.12.031","article-title":"Effect of L-glutamic acid on the growth and ammonium removal from ammonium solution and natural wastewater by Chlorella vulgaris NTM06","volume":"99","author":"Khan","year":"2008","journal-title":"Bioresour Technol"},{"key":"2025052408462073700_hoaf022-B41","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.fertnstert.2007.04.049","article-title":"Perinatal outcome, health, growth, and medical care utilization of 5- to 8-year-old intracytoplasmic sperm injection singletons","volume":"89","author":"Knoester","year":"2008","journal-title":"Fertil Steril"},{"key":"2025052408462073700_hoaf022-B42","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Kramer","year":"2014","journal-title":"Bioinformatics"},{"key":"2025052408462073700_hoaf022-B43","doi-asserted-by":"crossref","first-page":"17202","DOI":"10.1074\/jbc.M113.466920","article-title":"A self-defeating anabolic program leads to beta-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux","volume":"288","author":"Krokowski","year":"2013","journal-title":"J Biol Chem"},{"key":"2025052408462073700_hoaf022-B44","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1530\/jrf.0.1020169","article-title":"Uptake of a mixture of amino acids by mouse blastocysts","volume":"102","author":"Lamb","year":"1994","journal-title":"J Reprod Fertil"},{"key":"2025052408462073700_hoaf022-B45","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1093\/humrep\/13.4.991","article-title":"Amino acids and vitamins prevent culture-induced metabolic perturbations and associated loss of viability of mouse blastocysts","volume":"13","author":"Lane","year":"1998","journal-title":"Hum Reprod"},{"key":"2025052408462073700_hoaf022-B46","doi-asserted-by":"crossref","first-page":"e79153","DOI":"10.7554\/eLife.79153","article-title":"Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production","volume":"11","author":"Lee","year":"2022","journal-title":"Elife"},{"key":"2025052408462073700_hoaf022-B47","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1530\/REP-11-0484","article-title":"Metabolism of the preimplantation embryo: 40 years on","volume":"143","author":"Leese","year":"2012","journal-title":"Reproduction"},{"key":"2025052408462073700_hoaf022-B48","doi-asserted-by":"crossref","first-page":"e2215855119","DOI":"10.1073\/pnas.2215855119","article-title":"Alanine synthesized by alanine dehydrogenase enables ammonium-tolerant nitrogen fixation in Paenibacillus sabinae T27","volume":"119","author":"Li","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025052408462073700_hoaf022-B49","doi-asserted-by":"crossref","first-page":"110391","DOI":"10.1016\/j.celrep.2022.110391","article-title":"Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation","volume":"38","author":"Li","year":"2022","journal-title":"Cell Rep"},{"key":"2025052408462073700_hoaf022-B50","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.3390\/cells10113111","article-title":"Comparative analyses of single-cell transcriptomic profiles between in vitro totipotent blastomere-like cells and in vivo early mouse embryonic cells","volume":"10","author":"Lin","year":"2021","journal-title":"Cells"},{"key":"2025052408462073700_hoaf022-B51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2017.02.024","article-title":"Ulipristal acetate administration at mid-cycle changes gene expression profiling of endometrial biopsies taken during the receptive period of the human menstrual cycle","volume":"447","author":"Lira-Albarran","year":"2017","journal-title":"Mol Cell Endocrinol"},{"key":"2025052408462073700_hoaf022-B52","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1017\/S2040174421000313","article-title":"DNA methylation profile of liver of mice conceived by in vitro fertilization","volume":"13","author":"Lira-Albarran","year":"2022","journal-title":"J Dev Orig Health Dis"},{"key":"2025052408462073700_hoaf022-B53","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.mce.2019.02.010","article-title":"Functional genomic analysis of the human receptive endometrium transcriptome upon administration of mifepristone at the time of follicle rupture","volume":"485","author":"Lira-Albarran","year":"2019","journal-title":"Mol Cell Endocrinol"},{"key":"2025052408462073700_hoaf022-B54","first-page":"S148","author":"Liu","year":"2010"},{"key":"2025052408462073700_hoaf022-B55","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1016\/j.bbamcr.2016.01.023","article-title":"Carnitine transport and fatty acid oxidation","volume":"1863","author":"Longo","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2025052408462073700_hoaf022-B56","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1093\/humrep\/dead155","article-title":"Increased serine synthesis in cumulus cells of young infertile women with diminished ovarian reserve","volume":"38","author":"Lu","year":"2023","journal-title":"Hum Reprod"},{"key":"2025052408462073700_hoaf022-B57","doi-asserted-by":"crossref","first-page":"e3194","DOI":"10.1002\/btpr.3194","article-title":"Probing morphological, genetic and metabolomic changes of in vitro embryo development in a microfluidic device","volume":"37","author":"Mancini","year":"2021","journal-title":"Biotechnol Prog"},{"key":"2025052408462073700_hoaf022-B58","doi-asserted-by":"crossref","first-page":"D613","DOI":"10.1093\/nar\/gkaa1024","article-title":"WikiPathways: connecting communities","volume":"49","author":"Martens","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"2025052408462073700_hoaf022-B59","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease","volume":"11","author":"Martinez-Reyes","year":"2020","journal-title":"Nat Commun"},{"key":"2025052408462073700_hoaf022-B60","doi-asserted-by":"crossref","first-page":"D672","DOI":"10.1093\/nar\/gkad1025","article-title":"The Reactome Pathway Knowledgebase 2024","volume":"52","author":"Milacic","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"2025052408462073700_hoaf022-B61","doi-asserted-by":"crossref","first-page":"1136252","DOI":"10.3389\/fcvm.2023.1136252","article-title":"Temporal changes in glucose metabolism reflect polarization in resident and monocyte-derived macrophages after myocardial infarction","volume":"10","author":"Mouton","year":"2023","journal-title":"Front Cardiovasc Med"},{"key":"2025052408462073700_hoaf022-B62","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cell.2018.07.030","article-title":"Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers","volume":"174","author":"Murphy","year":"2018","journal-title":"Cell"},{"key":"2025052408462073700_hoaf022-B63","doi-asserted-by":"crossref","first-page":"5131","DOI":"10.1007\/s00018-020-03574-z","article-title":"L-serine synthesis via the phosphorylated pathway in humans","volume":"77","author":"Murtas","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"2025052408462073700_hoaf022-B64","volume-title":"Manipulating the Mouse Embryo. A Laboratory Manual","author":"Nagy","year":"2003","edition":"3rd edn"},{"key":"2025052408462073700_hoaf022-B65","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/S0093-691X(03)00206-1","article-title":"Amino acid metabolism of preimplantation bovine embryos cultured with bovine serum albumin or polyvinyl alcohol","volume":"61","author":"Orsi","year":"2004","journal-title":"Theriogenology"},{"key":"2025052408462073700_hoaf022-B66","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1038\/s41596-022-00710-w","article-title":"Using MetaboAnalyst 5.0 for LC-HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data","volume":"17","author":"Pang","year":"2022","journal-title":"Nat Protoc"},{"key":"2025052408462073700_hoaf022-B67","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1158\/0008-5472.CAN-19-3588","article-title":"An integrative gene expression and mathematical flux balance analysis identifies targetable redox vulnerabilities in melanoma cells","volume":"80","author":"Paudel","year":"2020","journal-title":"Cancer Res"},{"key":"2025052408462073700_hoaf022-B68","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/j.fertnstert.2007.09.062","article-title":"Comparison of the efficacy of two commercially available media for culturing one-cell embryos in the in vitro fertilization mouse model","volume":"90","author":"Perin","year":"2008","journal-title":"Fertil Steril"},{"key":"2025052408462073700_hoaf022-B69","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.cell.2017.12.001","article-title":"Leptin mediates a glucose-fatty acid cycle to maintain glucose homeostasis in starvation","volume":"172","author":"Perry","year":"2018","journal-title":"Cell"},{"key":"2025052408462073700_hoaf022-B70","doi-asserted-by":"crossref","first-page":"e48469","DOI":"10.15252\/embr.201948469","article-title":"Wnt regulates amino acid transporter Slc7a5 and so constrains the integrated stress response in mouse embryos","volume":"21","author":"Poncet","year":"2020","journal-title":"EMBO Rep"},{"key":"2025052408462073700_hoaf022-B71","doi-asserted-by":"crossref","first-page":"e60191","DOI":"10.7554\/eLife.60191","article-title":"MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1","volume":"10","author":"Popay","year":"2021","journal-title":"Elife"},{"key":"2025052408462073700_hoaf022-B72","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkz369","article-title":"g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update)","volume":"47","author":"Raudvere","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2025052408462073700_hoaf022-B73","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1530\/rep.1.00297","article-title":"Effects of embryo culture on global pattern of gene expression in preimplantation mouse embryos","volume":"128","author":"Rinaudo","year":"2004","journal-title":"Reproduction"},{"key":"2025052408462073700_hoaf022-B74","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/j.fertnstert.2006.05.017","article-title":"Effects of oxygen tension on gene expression in preimplantation mouse embryos","volume":"86","author":"Rinaudo","year":"2006","journal-title":"Fertil Steril"},{"key":"2025052408462073700_hoaf022-B75","doi-asserted-by":"crossref","first-page":"107151","DOI":"10.1016\/j.jbc.2024.107151","article-title":"The integrated stress response in metabolic adaptation","volume":"300","author":"Ryoo","year":"2024","journal-title":"J Biol Chem"},{"key":"2025052408462073700_hoaf022-B76","doi-asserted-by":"crossref","first-page":"725043","DOI":"10.3389\/fcimb.2021.725043","article-title":"The role of tricarboxylic acid cycle metabolites in viral infections","volume":"11","author":"Sanchez-Garcia","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"2025052408462073700_hoaf022-B77","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1007\/s13361-016-1469-y","article-title":"Untargeted metabolomics strategies-challenges and emerging directions","volume":"27","author":"Schrimpe-Rutledge","year":"2016","journal-title":"J Am Soc Mass Spectrom"},{"key":"2025052408462073700_hoaf022-B78","doi-asserted-by":"crossref","first-page":"1223312","DOI":"10.3389\/fendo.2023.1223312","article-title":"Metabolism of parathyroid organoids","volume":"14","author":"Sekhar","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025052408462073700_hoaf022-B79","doi-asserted-by":"crossref","first-page":"904701","DOI":"10.3389\/fphar.2022.904701","article-title":"Antidepressants fluoxetine mediates endoplasmic reticulum stress and autophagy of non-small cell lung cancer cells through the ATF4-AKT-mTOR signaling pathway","volume":"13","author":"Shao","year":"2022","journal-title":"Front Pharmacol"},{"key":"2025052408462073700_hoaf022-B80","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1016\/j.devcel.2021.07.020","article-title":"Metabolic plasticity drives development during mammalian embryogenesis","volume":"56","author":"Sharpley","year":"2021","journal-title":"Dev Cell"},{"key":"2025052408462073700_hoaf022-B81","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1097\/01.ftd.0000179845.53213.39","article-title":"METLIN: a metabolite mass spectral database","volume":"27","author":"Smith","year":"2005","journal-title":"Ther Drug Monit"},{"key":"2025052408462073700_hoaf022-B82","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/s41586-024-07374-4","article-title":"Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1","volume":"629","author":"Son","year":"2024","journal-title":"Nature"},{"key":"2025052408462073700_hoaf022-B83","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/humrep\/del447","article-title":"Metabolism of human embryos following cryopreservation: implications for the safety and selection of embryos for transfer in clinical IVF","volume":"22","author":"Stokes","year":"2007","journal-title":"Hum Reprod"},{"key":"2025052408462073700_hoaf022-B84","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1161\/CIRCULATIONAHA.121.057623","article-title":"Nuclear receptor NR1D1 regulates abdominal aortic aneurysm development by targeting the mitochondrial tricarboxylic acid cycle enzyme aconitase-2","volume":"146","author":"Sun","year":"2022","journal-title":"Circulation"},{"key":"2025052408462073700_hoaf022-B85","doi-asserted-by":"crossref","first-page":"eabj6877","DOI":"10.1126\/sciadv.abj6877","article-title":"Loss of ATF4 leads to functional aging-like attrition of adult hematopoietic stem cells","volume":"7","author":"Sun","year":"2021","journal-title":"Sci Adv"},{"key":"2025052408462073700_hoaf022-B86","doi-asserted-by":"crossref","first-page":"e21800","DOI":"10.1371\/journal.pone.0021800","article-title":"REVIGO summarizes and visualizes long lists of gene ontology terms","volume":"6","author":"Supek","year":"2011","journal-title":"PLoS One"},{"key":"2025052408462073700_hoaf022-B87","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1091\/mbc.e04-11-1034","article-title":"Human splicing factor SF3a, but not SF1, is essential for pre-mRNA splicing in vivo","volume":"16","author":"Tanackovic","year":"2005","journal-title":"Mol Biol Cell"},{"key":"2025052408462073700_hoaf022-B88","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/ki.1982.166","article-title":"Influence of pyruvate on ammonia metabolism by renal cortical mitochondria","volume":"22","author":"Tannen","year":"1982","journal-title":"Kidney Int"},{"key":"2025052408462073700_hoaf022-B89","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1093\/humrep\/dez102","article-title":"The composition of human preimplantation embryo culture media and their stability during storage and culture","volume":"34","author":"Tarahomi","year":"2019","journal-title":"Hum Reprod"},{"key":"2025052408462073700_hoaf022-B90","doi-asserted-by":"crossref","first-page":"e0028422","DOI":"10.1128\/jb.00284-22","article-title":"Redundancy in citrate and cis-aconitate transport in Pseudomonas aeruginosa","volume":"204","author":"Underhill","year":"2022","journal-title":"J Bacteriol"},{"key":"2025052408462073700_hoaf022-B91","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41387-022-00213-3","article-title":"Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes","volume":"12","author":"Vanweert","year":"2022","journal-title":"Nutr Diabetes"},{"key":"2025052408462073700_hoaf022-B92","doi-asserted-by":"crossref","first-page":"884088","DOI":"10.3389\/fcell.2022.884088","article-title":"Placental abnormalities are associated with specific windows of embryo culture in a mouse model","volume":"10","author":"Vrooman","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"2025052408462073700_hoaf022-B93","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.cell.2009.02.009","article-title":"The spliceosome: design principles of a dynamic RNP machine","volume":"136","author":"Wahl","year":"2009","journal-title":"Cell"},{"key":"2025052408462073700_hoaf022-B94","doi-asserted-by":"crossref","first-page":"24, 1","DOI":"10.1095\/biolreprod.112.100552","article-title":"Oxygen regulates amino acid turnover and carbohydrate uptake during the preimplantation period of mouse embryo development","volume":"87","author":"Wale","year":"2012","journal-title":"Biol Reprod"},{"key":"2025052408462073700_hoaf022-B95","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1095\/biolreprod.113.109256","article-title":"Oxygen affects the ability of mouse blastocysts to regulate ammonium","volume":"89","author":"Wale","year":"2013","journal-title":"Biol Reprod"},{"key":"2025052408462073700_hoaf022-B96","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1038\/s41467-021-21962-2","article-title":"Branched-chain alpha-ketoacids are preferentially reaminated and activate protein synthesis in the heart","volume":"12","author":"Walejko","year":"2021","journal-title":"Nat Commun"},{"key":"2025052408462073700_hoaf022-B97","doi-asserted-by":"crossref","first-page":"101261","DOI":"10.1016\/j.molmet.2021.101261","article-title":"Insulin action, type 2 diabetes, and branched-chain amino acids: a two-way street","volume":"52","author":"White","year":"2021","journal-title":"Mol Metab"},{"key":"2025052408462073700_hoaf022-B98","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S1472-6483(10)61840-8","article-title":"Embryonic development and pregnancies following sequential culture in human tubal fluid and a modified simplex optimized medium containing amino acids","volume":"5","author":"Wiemer","year":"2002","journal-title":"Reprod Biomed Online"},{"key":"2025052408462073700_hoaf022-B99","doi-asserted-by":"crossref","first-page":"a003707","DOI":"10.1101\/cshperspect.a003707","article-title":"Spliceosome structure and function","volume":"3","author":"Will","year":"2011","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2025052408462073700_hoaf022-B100","doi-asserted-by":"crossref","first-page":"D801","DOI":"10.1093\/nar\/gks1065","article-title":"HMDB 3.0\u2014the Human Metabolome Database in 2013","volume":"41","author":"Wishart","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2025052408462073700_hoaf022-B101","doi-asserted-by":"crossref","first-page":"115757","DOI":"10.1016\/j.ecoenv.2023.115757","article-title":"Ochratoxin A triggers endoplasmic reticulum stress through PERK\/NRF2 signaling and DNA damage during early embryonic developmental competence in pigs","volume":"269","author":"Woo","year":"2024","journal-title":"Ecotoxicol Environ Saf"},{"key":"2025052408462073700_hoaf022-B102","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1093\/plphys\/kiac256","article-title":"An Arabidopsis Retention and Splicing complex regulates root and embryo development through pre-mRNA splicing","volume":"190","author":"Xiong","year":"2022","journal-title":"Plant Physiol"},{"key":"2025052408462073700_hoaf022-B103","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.15252\/embj.201591041","article-title":"SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth","volume":"34","author":"Yang","year":"2015","journal-title":"EMBO J"},{"key":"2025052408462073700_hoaf022-B104","doi-asserted-by":"crossref","first-page":"104352","DOI":"10.1016\/j.phrs.2019.104352","article-title":"Serine and one-carbon metabolism, a bridge that links mTOR signaling and DNA methylation in cancer","volume":"149","author":"Zeng","year":"2019","journal-title":"Pharmacol Res"},{"key":"2025052408462073700_hoaf022-B105","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s11427-022-2209-3","article-title":"Highly efficient generation of blastocyst-like structures from spliceosomes-repressed mouse totipotent blastomere-like cells","volume":"66","author":"Zhang","year":"2023","journal-title":"Sci China Life Sci"},{"key":"2025052408462073700_hoaf022-B106","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40104-016-0139-z","article-title":"Novel metabolic and physiological functions of branched chain amino acids: a review","volume":"8","author":"Zhang","year":"2017","journal-title":"J Anim Sci Biotechnol"},{"key":"2025052408462073700_hoaf022-B107","doi-asserted-by":"crossref","first-page":"101854","DOI":"10.1016\/j.redox.2021.101854","article-title":"Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2\/ATF4\/BNIP3-dependent mitophagy in placental trophoblasts","volume":"40","author":"Zhu","year":"2021","journal-title":"Redox Biol"},{"key":"2025052408462073700_hoaf022-B108","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1128\/MCB.17.2.946","article-title":"Cloning of Caenorhabditis U2AF65: an alternatively spliced RNA containing a novel exon","volume":"17","author":"Zorio","year":"1997","journal-title":"Mol Cell Biol"}],"container-title":["Human Reproduction Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hropen\/advance-article-pdf\/doi\/10.1093\/hropen\/hoaf022\/63017112\/hoaf022.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2025\/2\/hoaf022\/63017112\/hoaf022.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/article-pdf\/2025\/2\/hoaf022\/63017112\/hoaf022.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T08:46:47Z","timestamp":1748076407000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hropen\/article\/doi\/10.1093\/hropen\/hoaf022\/8120735"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025]]},"references-count":108,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,3,7]]}},"URL":"https:\/\/doi.org\/10.1093\/hropen\/hoaf022","relation":{},"ISSN":["2399-3529"],"issn-type":[{"value":"2399-3529","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2025]]},"article-number":"hoaf022"}}