{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:16:21Z","timestamp":1790774181534,"version":"4.1.0"},"reference-count":107,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,13]],"date-time":"2021-11-13T00:00:00Z","timestamp":1636761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In this review we discuss the beneficial effects of amino acid transport and metabolism on pre- and peri-implantation embryo development, and we consider how disturbances in these processes lead to undesirable health outcomes in adults. Proline, glutamine, glycine, and methionine transport each foster cleavage-stage development, whereas leucine uptake by blastocysts via transport system B0,+ promotes the development of trophoblast motility and the penetration of the uterine epithelium in mammalian species exhibiting invasive implantation. (Amino acid transport systems and transporters, such as B0,+, are often oddly named. The reader is urged to focus on the transporters\u2019 functions, not their names.) B0,+ also accumulates leucine and other amino acids in oocytes of species with noninvasive implantation, thus helping them to produce proteins to support later development. This difference in the timing of the expression of system B0,+ is termed heterochrony\u2014a process employed in evolution. Disturbances in leucine uptake via system B0,+ in blastocysts appear to alter the subsequent development of embryos, fetuses, and placentae, with undesirable consequences for offspring. These consequences may include greater adiposity, cardiovascular dysfunction, hypertension, neural abnormalities, and altered bone growth in adults. Similarly, alterations in amino acid transport and metabolism in pluripotent cells in the blastocyst inner cell mass likely lead to epigenetic DNA and histone modifications that produce unwanted transgenerational health outcomes. Such outcomes might be avoided if we learn more about the mechanisms of these effects.<\/jats:p>","DOI":"10.3390\/cells10113154","type":"journal-article","created":{"date-parts":[[2021,11,14]],"date-time":"2021-11-14T20:48:36Z","timestamp":1636922916000},"page":"3154","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Amino Acid Transport and Metabolism Regulate Early Embryo Development: Species Differences, Clinical Significance, and Evolutionary Implications"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2223-0419","authenticated-orcid":false,"given":"Lon J.","family":"Van Winkle","sequence":"first","affiliation":[{"name":"Department of Medical Humanities, Rocky Vista University, 8401 S. Chambers Road, Parker, CO 80134, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"300","DOI":"10.3389\/fcell.2019.00300","article-title":"One-carbon metabolism regulates embryonic stem cell fate through epigenetic DNA and histone modifications: Implications for transgenerational metabolic disorders in adults","volume":"7","author":"Ryznar","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3389\/fphys.2020.00140","article-title":"Selected amino acids promote mouse pre-implantation embryo development in a growth factor-like manner","volume":"11","author":"Morris","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_3","first-page":"1706","article-title":"Perspective: One-cell and cleavage-stage mouse embryos thrive in hyperosmotic oviductal fluid through expression of a glycine neurotransmitter transporter and a glycine-gated chloride channel: Clinical and transgenerational implications","volume":"11","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7117","DOI":"10.1002\/jcp.30352","article-title":"Initiation of cell volume regulation and unique cell volume regulatory mechanisms in mammalian oocytes and embryos","volume":"236","author":"Tscherner","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1530\/REP-19-0312","article-title":"Glycine receptor \u03b14 subunit facilitates the early embryonic development in mice","volume":"159","author":"Nishizono","year":"2020","journal-title":"Reproduction"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.ydbio.2011.10.021","article-title":"Leucine and arginine regulate trophoblast motility through mTOR-dependent and independent pathways in the preimplantation mouse embryo","volume":"361","author":"Martin","year":"2012","journal-title":"Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1095\/biolreprod.103.018010","article-title":"Amino acid transport regulates blastocyst implantation","volume":"69","author":"Martin","year":"2003","journal-title":"Biol. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/humupd\/dmi044","article-title":"System B0,+ amino acid transport regulates the penetration stage of blastocyst implantation with possible long-term developmental consequences through adulthood","volume":"12","author":"Tesch","year":"2006","journal-title":"Hum. Reprod. Update"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1515\/bmc-2018-0017","article-title":"Can uterine secretion of modified histones alter blastocyst implantation, embryo nutrition, and transgenerational phenotype?","volume":"9","author":"Ryznar","year":"2018","journal-title":"Biomol. Concepts"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0304-4157(88)90024-X","article-title":"Amino acid transport in developing animal oocytes and early conceptuses","volume":"947","year":"1988","journal-title":"Biochim. Biophys. Acta (BBA)-Rev. Biomembr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/mrd.1080340304","article-title":"Alanine and leucine transport in unfertilized pig oocytes and early blastocysts","volume":"34","author":"Prather","year":"1993","journal-title":"Mol. Reprod. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sahoo, D.P., Van Winkle, L.J., D\u00edaz de la Garza, R.I., and Dubrovsky, J.G. (2021). Interkingdom comparison of threonine metabolism for stem cell maintenance in plants and animals. Front. Cell Dev. Biol. Stem Cell Res., in press.","DOI":"10.3389\/fcell.2021.672545"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Treleaven, T., Hardy, M.L., Guttman-Jones, M., Morris, M.B., and Day, M.L. (2021). In Vitro Fertilization of Mouse Oocytes in L-Proline and L-Pipecolic Acid Improves Subsequent Development. Cells, 10.","DOI":"10.3390\/cells10061352"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0005-2736(88)90185-X","article-title":"Glycine transport in mouse eggs ad preimplantation conceptuses","volume":"941","author":"Haghighat","year":"1988","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/jez.1402530211","article-title":"Glycine protects preimplantation mouse conceptuses from a detrimental effect on development of the inorganic ions in oviductal fluid","volume":"253","author":"Haghighat","year":"1990","journal-title":"J. Exp. Zool."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1093\/biolre\/ioy194","article-title":"Methionine adenosyltransferase 2A regulates mouse zygotic genome activation and morula to blastocyst transition","volume":"100","author":"Sun","year":"2019","journal-title":"Biol. Reprod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0005-2736(90)90387-4","article-title":"Changes in the activities of amino acid transport systems b0,+ and L during development of preimplantation mouse conceptuses","volume":"1021","author":"Campione","year":"1990","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0005-2736(90)90151-D","article-title":"Functional changes in cation-preferring amino acid transport during development of preimplantation mouse conceptuses","volume":"1028","author":"Campione","year":"1990","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Van Winkle, L.J., and Ryznar, R. (2019). Amino acid transporters: Roles for nutrition, signaling and epigenetic modifications in embryonic stem cells and their progenitors. eLS, 1\u201313.","DOI":"10.1002\/9780470015902.a0000011.pub4"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3389\/fcell.2016.00017","article-title":"At least three transporters likely mediate threonine uptake needed for mouse embryonic stem cell proliferation","volume":"4","author":"Formisano","year":"2016","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1126\/science.1173288","article-title":"Dependence of mouse embryonic stem cells on threonine catabolism","volume":"325","author":"Wang","year":"2009","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23667","DOI":"10.1074\/jbc.M110.216283","article-title":"L-threonine regulates G1\/S phase transition of mouse embryonic stem cells via PI3K\/Akt, MAPKs, and mTORC pathways","volume":"286","author":"Ryu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_23","first-page":"18","article-title":"Threonine appears to be essential for proliferation of human as well as mouse embryonic stem cells","volume":"2","author":"Galat","year":"2014","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Van Winkle, L.J., Galat, V., and Iannaccone, P.M. (2020). Lysine Deprivation during Maternal Consumption of Low-Protein Diets Could Adversely Affect Early Embryo Development and Health in Adulthood. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17155462"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cmet.2014.03.017","article-title":"Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells","volume":"19","author":"Shiraki","year":"2014","journal-title":"Cell Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1530\/jrf.0.0860679","article-title":"An improved culture medium supports development of random-bred 1-cell mouse embryos in vitro","volume":"86","author":"Chatot","year":"1989","journal-title":"Reproduction"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1095\/biolreprod50.5.1027","article-title":"Differential growth of the mouse preimplantation embryo in chemically defined media","volume":"50","author":"Erbach","year":"1994","journal-title":"Biol. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1007\/BF02766148","article-title":"Nonessential amino acids and glutamine decrease the time of the first three cleavage divisions and increase compaction of mouse zygotes in vitro","volume":"14","author":"Lane","year":"1997","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.devcel.2019.12.018","article-title":"Metabolic control over mTOR-dependent diapause-like state","volume":"52","author":"Hussein","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"708318","DOI":"10.3389\/fcell.2021.708318","article-title":"Molecular Regulation of Paused Pluripotency in Early Mammalian Embryos and Stem Cells","volume":"9","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1023\/A:1016657228171","article-title":"Animal experimentation: Effect of essential amino acids on mouse embryo viability and ammonium production","volume":"18","author":"Lane","year":"2001","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S1472-6483(10)62111-6","article-title":"Enhanced effect of glycyl-L-glutamine on mouse preimplantation embryos in vitro","volume":"9","author":"Biggers","year":"2004","journal-title":"Reprod. Biomed. Online"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1530\/jrf.0.0460431","article-title":"Electron probe microanalysis of the elemental microenvironment of oviducal cleavage stages of the mouse","volume":"46","author":"Roblero","year":"1976","journal-title":"J. Reprod. Fert."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1095\/biolreprod16.2.147","article-title":"The elemental composition of the environments of the gametes and preimplantation embryo during the initiation of pregnancy","volume":"16","author":"Borland","year":"1977","journal-title":"Biol. Reprod."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Leese, H.J., McKeegan, P., and Sturmey, R.G. (2021). Amino acids and the early mammalian embryo: Origin, fate, function and life-long legacy. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18189874"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod64.1.1","article-title":"Amino acid transport regulation and early embryo development","volume":"64","year":"2001","journal-title":"Biol. Reprod."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Capra, E., and Lange-Consiglio, A. (2020). The Biological Function of Extracellular Vesicles during Fertilization, Early Embryo\u2014Maternal Crosstalk and Their Involvement in Reproduction: Review and Overview. Biomolecules, 10.","DOI":"10.3390\/biom10111510"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12118","DOI":"10.1016\/S0021-9258(17)38994-9","article-title":"Na+-dependent transport of basic, zwitterionic, and bicyclic amino acids by a broad-scope system in mouse blastocysts","volume":"260","author":"Christensen","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100","DOI":"10.3389\/fcell.2017.00100","article-title":"Uterine histone secretion likely fosters early embryo development so efforts to mitigate histone cytotoxicity should be cautious","volume":"5","year":"2017","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.yexcr.2014.08.037","article-title":"Fetuin-A associates with histones intracellularly and shuttles them to exosomes to promote focal adhesion assembly resulting in rapid adhesion and spreading in breast carcinoma cells","volume":"328","author":"Nangami","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1126\/science.281.5380.1191","article-title":"Prevention of allogeneic fetal rejection by tryptophan catabolism","volume":"281","author":"Munn","year":"1998","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jri.2003.11.003","article-title":"Indoleamine 2, 3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific","volume":"61","author":"Baban","year":"2004","journal-title":"J. Reprod. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"To, C.Y., Freeman, M., and Van Winkle, L.J. (2020). Consumption of a Branched-Chain Amino Acid (BCAA) during Days 2\u201310 of Pregnancy Causes Abnormal Fetal and Placental Growth: Implications for BCAA Supplementation in Humans. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17072445"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Caetano, L., Eckert, J., Johnston, D., Chatelet, D., Tumbarello, D., Smyth, N., Ingamells, S., Price, A., and Fleming, T. (2021). Blastocyst trophectoderm endocytic activation, a marker of adverse developmental programming. Reproduction, in press.","DOI":"10.1530\/REP-21-0234"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Eckert, J.J., Porter, R., Watkins, A.J., Burt, E., Brooks, S., Leese, H.J., Humpherson, P.G., Cameron, I.T., and Fleming, T.P. (2012). Metabolic induction and early responses of mouse blastocyst developmental programming following maternal low protein diet affecting life-long health. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052791"},{"key":"ref_46","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":"ref_47","doi-asserted-by":"crossref","unstructured":"Fleming, T.P., Sun, C., Denisenko, O., Caetano, L., Aljahdali, A., Gould, J.M., and Khurana, P. (2021). Environmental Exposures around Conception: Developmental Pathways Leading to Lifetime Disease Risk. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18179380"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1080\/15384101.2017.1295178","article-title":"Regulation of 4E-BP1 activity in the mammalian oocyte","volume":"16","author":"Jansova","year":"2017","journal-title":"Cell Cycle"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1016\/S0021-9258(18)69048-9","article-title":"Na+-independent transport of basic and zwitterionic amino acids in mouse blastocysts by a shared system and by processes which distinguish between these substrates","volume":"263","author":"Campione","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1093\/hmg\/ddg228","article-title":"Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis","volume":"12","author":"Visa","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1071\/RD14293","article-title":"Arginine increases development of in vitro-produced porcine embryos and affects the protein arginine methyltransferase\u2013dimethylarginine dimethylaminohydrolase\u2013nitric oxide axis","volume":"27","author":"Redel","year":"2015","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4443","DOI":"10.1016\/S0021-9258(18)34742-2","article-title":"Cationic amino acid transport into cultured animal cells. I. Influx into cultured human fibroblasts","volume":"257","author":"White","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4450","DOI":"10.1016\/S0021-9258(18)34743-4","article-title":"Cationic amino acid transport into cultured animal cells. II. Transport system barely perceptible in ordinary hepatocytes, but active in hepatoma cell lines","volume":"257","author":"White","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1242\/jeb.196.1.109","article-title":"y+-type cationic amino acid transport: Expression and regulation of the mCAT genes","volume":"196","author":"MacLeod","year":"1994","journal-title":"J. Exp. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Terstappen, F., Tol, A.J., Gremmels, H., Wever, K.E., Paauw, N.D., Joles, J.A., van der Beek, E.M., and Lely, A.T. (2020). Prenatal amino acid supplementation to improve fetal growth: A systematic review and meta-analysis. Nutrients, 12.","DOI":"10.3390\/nu12092535"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"586979","DOI":"10.3389\/fphar.2020.586979","article-title":"Role of Dietary Amino Acids and Nutrient Sensing System in Pregnancy Associated Disorders","volume":"11","author":"Hussain","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1093\/jn\/138.8.1421","article-title":"Dietary arginine supplementation during early pregnancy enhances embryonic survival in rats","volume":"138","author":"Zeng","year":"2008","journal-title":"J. Nutr."},{"key":"ref_58","unstructured":"(2021, November 05). Sprague Dawley\u00ae SD\u00ae Outbred Rats. Available online: envigo.com."},{"key":"ref_59","first-page":"231","article-title":"The effect of maternal dietary lysine and methionine levels on pregnancy and lactation in the rat","volume":"21","author":"Stapleton","year":"1980","journal-title":"Nutr. Rep. Int."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S0271-5317(05)80012-0","article-title":"Impact of supplemental lysine or tryptophan on pregnancy course and outcome in rats","volume":"11","author":"Funk","year":"1991","journal-title":"Nutr. Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Najafzadeh, V., Henderson, H., Martinus, R.D., and Oback, B. (2018). Bovine blastocyst development depends on threonine catabolism. bioRxiv.","DOI":"10.1101\/397562"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/stem.1335","article-title":"Regulation of l-threonine dehydrogenase in somatic cell reprogramming","volume":"31","author":"Han","year":"2013","journal-title":"Stem Cells"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1126\/science.1226603","article-title":"Influence of threonine metabolism on S-adenosylmethionine and histone methylation","volume":"339","author":"Locasale","year":"2013","journal-title":"Science"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e201900413","DOI":"10.26508\/lsa.201900413","article-title":"Glycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications","volume":"2","author":"Tian","year":"2019","journal-title":"Life Sci. Alliance"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/humrep\/15.3.694","article-title":"Flow of cells from polar to mural trophectoderm is polarized in the mouse blastocyst","volume":"15","author":"Gardner","year":"2000","journal-title":"Hum. Reprod."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1095\/biolreprod52.1.96","article-title":"Differences in amino acid content of preimplantation mouse embryos that develop in vitro versus in vivo: In vitro effects of five amino acids that are abundant in oviductal secretions","volume":"52","author":"Dickinson","year":"1995","journal-title":"Biol. Reprod."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1242\/dev.103952","article-title":"Mouse early extra-embryonic lineages activate compensatory endocytosis in response to poor maternal nutrition","volume":"141","author":"Sun","year":"2014","journal-title":"Development"},{"key":"ref_68","unstructured":"Najafzadeh, V. (2018). The Role of Amino Acids and the Threonine-SAM Pathway in the Development of Bovine Inner Cell Mass and Pluripotency. [Ph.D. Dissertation, The University of Waikato]."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2156-3-18","article-title":"The human L-threonine 3-dehydrogenase gene is an expressed pseudogene","volume":"3","author":"Edgar","year":"2002","journal-title":"BMC Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ymben.2019.02.003","article-title":"Glycine decarboxylase regulates the maintenance and induction of pluripotency via metabolic control","volume":"53","author":"Kang","year":"2019","journal-title":"Metab. Eng."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.cell.2011.03.003","article-title":"Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network","volume":"145","author":"Ang","year":"2011","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"780S","DOI":"10.3945\/an.115.011031","article-title":"Influence of amino acid metabolism on embryonic stem cell function and differentiation","volume":"7","author":"Kilberg","year":"2016","journal-title":"Adv. Nutr."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.semcancer.2019.01.005","article-title":"A regulatory circuitry locking pluripotent stemness to embryonic stem cell: Interaction between threonine catabolism and histone methylation","volume":"Volume 57","author":"Chen","year":"2019","journal-title":"Seminars in Cancer Biology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"7360121","DOI":"10.1155\/2019\/7360121","article-title":"Metabolism is a key regulator of induced pluripotent stem cell reprogramming","volume":"2019","author":"Spyrou","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4860","DOI":"10.1038\/emboj.2011.401","article-title":"UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells","volume":"30","author":"Zhang","year":"2011","journal-title":"EMBO J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.stem.2021.02.011","article-title":"Mitochondria as signaling organelles control mammalian stem cell fate","volume":"28","author":"Chakrabarty","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1089\/scd.2015.0117","article-title":"Connecting mitochondria, metabolism, and stem cell fate","volume":"24","author":"Wanet","year":"2015","journal-title":"Stem Cells Dev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2874283","DOI":"10.1155\/2017\/2874283","article-title":"Pluripotent stem cell metabolism and mitochondria: Beyond ATP","volume":"2017","author":"Lees","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7068567","DOI":"10.1155\/2017\/7068567","article-title":"Mitochondrial heterogeneity: Evaluating mitochondrial subpopulation dynamics in stem cells","volume":"2017","author":"Woods","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/wsbm.1209","article-title":"Modeling cellular compartmentation in one-carbon metabolism","volume":"5","author":"Scotti","year":"2013","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"R159","DOI":"10.1530\/REP-18-0431","article-title":"Mitochondria in early development: Linking the microenvironment, metabolism and the epigenome","volume":"157","author":"Harvey","year":"2019","journal-title":"Reproduction"},{"key":"ref_82","unstructured":"Alexander, P.B. (2010). Requirement of a High-Flux Metabolic State for Mouse Embryonic Stem Cell Self-Renewal. [Ph.D. Dissertation, The University of Texas Southwestern Medical Center at Dallas]."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"15828","DOI":"10.1073\/pnas.1111312108","article-title":"Targeted killing of a mammalian cell based upon its specialized metabolic state","volume":"108","author":"Alexander","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/nature13544","article-title":"The DNA methylation landscape of human early embryos","volume":"511","author":"Guo","year":"2014","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1017\/S0007114508921747","article-title":"Transmission of raised blood pressure and endothelial dysfunction to the F2 generation induced by maternal protein restriction in the F0, in the absence of dietary challenge in the F1 generation","volume":"100","author":"Torrens","year":"2008","journal-title":"Br. J. Nutr."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4337","DOI":"10.1096\/fj.12-210401","article-title":"Pregnancy in aged rats that were born small: Cardiorenal and metabolic adaptations and second-generation fetal growth","volume":"26","author":"Gallo","year":"2012","journal-title":"FASEB J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1530\/REP-14-0619","article-title":"Low female birth weight and advanced maternal age programme alterations in next-generation blastocyst development","volume":"149","author":"Master","year":"2015","journal-title":"Reproduction"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.cell.2013.09.002","article-title":"Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development","volume":"155","author":"Padmanabhan","year":"2013","journal-title":"Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"10064","DOI":"10.1073\/pnas.1806333115","article-title":"Paternal diet programs offspring health through sperm-and seminal plasma-specific pathways in mice","volume":"115","author":"Watkins","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/pros.20089","article-title":"A comprehensive characterization of the peptide and protein constituents of human seminal fluid","volume":"61","author":"Fung","year":"2004","journal-title":"Prostate"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1530\/REP-09-0281","article-title":"Paternal DNA packaging in spermatozoa: More than the sum of its parts? DNA, histones, protamines and epigenetics","volume":"139","author":"Miller","year":"2010","journal-title":"Reproduction"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"s110","DOI":"10.1017\/S1751731118000526","article-title":"The epic journey of sperm through the female reproductive tract","volume":"12","author":"Miller","year":"2018","journal-title":"Animal"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-animal-020518-115206","article-title":"One-carbon metabolism: Linking nutritional biochemistry to epigenetic programming of long-term development","volume":"7","author":"Clare","year":"2019","journal-title":"Annu. Rev. Anim. Biosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11892-019-1163-0","article-title":"Paternal nongenetic intergenerational transmission of metabolic disease risk","volume":"19","author":"Su","year":"2019","journal-title":"Curr. Diabetes Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0014-5793(00)02401-7","article-title":"The essential amino acid lysine acts as precursor of glutamate in the mammalian central nervous system","volume":"488","author":"Papes","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1086\/302919","article-title":"Identification of the \u03b1-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia","volume":"66","author":"Sacksteder","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/jimd.12076","article-title":"New insights into human lysine degradation pathways with relevance to pyridoxine-dependent epilepsy due to antiquitin deficiency","volume":"42","author":"Crowther","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.stemcr.2018.05.018","article-title":"Disruption of GRIN2B impairs differentiation in human neurons","volume":"11","author":"Bell","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1002\/jnr.21444","article-title":"The glutamate-glutamine cycle is not stoichiometric: Fates of glutamate in brain","volume":"85","author":"McKenna","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.neuropharm.2005.05.014","article-title":"Endogenous activation of mGlu5 metabotropic glutamate receptors supports self-renewal of cultured mouse embryonic stem cells","volume":"49","author":"Cappuccio","year":"2005","journal-title":"Neuropharmacology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/j.1471-4159.2006.04038.x","article-title":"Endogenously activated mGlu5 metabotropic glutamate receptors sustain the increase in c-Myc expression induced by leukaemia inhibitory factor in cultured mouse embryonic stem cells","volume":"99","author":"Spinsanti","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1530\/jrf.0.0650367","article-title":"Amino acid transport and exchange in preimplantation mouse embryos","volume":"65","author":"Kaye","year":"1982","journal-title":"Reproduction"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev.arplant.53.091401.110929","article-title":"New insights into the regulation and functional significance of lysine metabolism in plants","volume":"53","author":"Galili","year":"2002","journal-title":"Annu. Rev. Plant Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"C30","DOI":"10.1152\/ajpcell.00385.2020","article-title":"mTORC1\/2 signaling is downregulated by amino acid-free culture of mouse preimplantation embryos and is only partially restored by amino acid readdition","volume":"320","author":"Zamfirescu","year":"2021","journal-title":"Am. J. Physiol. -Cell Physiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nature13981","article-title":"Intracellular \u03b1-ketoglutarate maintains the pluripotency of embryonic stem cells","volume":"518","author":"Carey","year":"2015","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.stemcr.2013.09.001","article-title":"L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation","volume":"1","author":"Comes","year":"2013","journal-title":"Stem Cell Rep."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1530\/rep.0.1260299","article-title":"Metabolic characterization of the bovine blastocyst, inner cell mass, trophectoderm and blastocoel fluid","volume":"126","author":"Gopichandran","year":"2003","journal-title":"Reproduction"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3154\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:29:44Z","timestamp":1760167784000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/3154"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,13]]},"references-count":107,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10113154"],"URL":"https:\/\/doi.org\/10.3390\/cells10113154","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,13]]}}}