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L-arginine (Arg), a conditionally essential amino acid enriched in uterine histotroph during early pregnancy, plays a key role in conceptus development; however, its genomic effects on the trophectoderm are poorly defined. Therefore, we investigated Arg-responsive transcriptomic changes in porcine (pTr2) and ovine (oTr1) trophectoderm cells using RNA-seq and integrative pathway analyses. Arg significantly stimulated proliferation in both cell types in a non-linear, dose-dependent manner, with maximal effects at 0.2\u00a0mM, consistent with physiological levels. Transcriptomic profiling identified 2723 and 5369 differentially expressed genes in pTr2 and oTr1 cells, respectively, encompassing genes involved in cell proliferation, metabolism, cytoskeletal remodeling, and implantation. Canonical pathway and upstream regulator analyses revealed both conserved and species-specific responses to Arg, including shared activation of actin cytoskeleton and adrenomedullin signaling and suppression of p53 signaling. Species-specific enrichment of cholesterol biosynthesis (pigs) and interferon signaling (sheep) further highlighted divergent strategies for pregnancy recognition. Comparative analyses identified 615 commonly regulated differentially expressed genes and highlighted O-linked N-acetylglucosamine transferase as a conserved upstream regulator, implicating nutrient-responsive O-GlcNAcylation in trophectoderm function. Arg promoted gene programs supporting mitosis, oxidative phosphorylation, and extracellular matrix remodeling while repressing pathways related to apoptosis and pluripotency. These results advance understanding of how Arg activates conserved transcriptional networks to support trophectoderm proliferation and differentiation, while also fine-tuning species-specific pathways aligned with pregnancy recognition and implantation of conceptuses in sheep and pigs.<\/jats:p>","DOI":"10.1093\/biolre\/ioaf226","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T14:35:46Z","timestamp":1759847746000},"page":"1475-1489","source":"Crossref","is-referenced-by-count":4,"title":["Uterine histotroph and conceptus development. V. Comparative analyses of arginine-mediated transcriptomic reprogramming in conceptus trophectoderm of pigs and sheep"],"prefix":"10.1093","volume":"113","author":[{"given":"Sudikshya","family":"Paudel","sequence":"first","affiliation":[{"name":"Department of Animal Science, North Carolina State University , Raleigh, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiukun","family":"Wang","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Biology Laboratory , National Institute of Environmental Health Sciences, Research Triangle Park, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyao","family":"Yu","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Biology Laboratory , National Institute of Environmental Health Sciences, Research Triangle Park, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3970-0771","authenticated-orcid":false,"given":"Tianyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park , NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0117-3582","authenticated-orcid":false,"given":"Xinxia","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Molecular Biomedical Sciences and Bioinformatics Research Center, North Carolina State University , Raleigh, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5823-5086","authenticated-orcid":false,"given":"Fuller W","family":"Bazer","sequence":"additional","affiliation":[{"name":"Department of Animal Science , Texas A&M University, College Station, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1021-8444","authenticated-orcid":false,"given":"Robert C","family":"Burghardt","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences , Texas A&M University, College Station, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Hu","sequence":"additional","affiliation":[{"name":"Epigenetics and Stem Cell Biology Laboratory , National Institute of Environmental Health Sciences, Research Triangle Park, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9660-528X","authenticated-orcid":false,"given":"Xiaoqiu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Animal Science, North Carolina State University , Raleigh, NC ,","place":["USA"]},{"name":"The Comparative 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