249. Award Talk: From Nutrition to Elongation: Uterine Histotroph Programs Early Conceptus Development in Ungulates.

Abstract Early pregnancy loss during the peri-implantation period remains a major biological and economic constraint in livestock species, with 20-40% of embryos failing to establish pregnancy. In pigs and ruminants, successful pregnancy establishment requires rapid conceptus elongation, a process that depends on precise coordination between the conceptus and the uterine microenvironment. Central to this coordination is uterine histotroph, the complex mixture of nutrients and signaling molecules secreted by the endometrium. We demonstrate that conceptus elongation is closely associated with dynamic, pregnancy-specific changes in uterine histotroph composition during the peri-implantation window. Metabolomic profiling of uterine luminal fluid reveals enrichment of key nutrients, particularly amino acids, in pregnant compared with cyclic females. Among these, arginine emerges as a dominant and tightly regulated component coinciding with rapid trophoblast growth and elongation. Functional studies establish arginine as an active signaling molecule rather than a passive nutrient. In porcine and ovine trophectoderm cells, arginine activates MTORC1- and MTORC2-dependent pathways that coordinate cell proliferation, migration, cytoskeletal remodeling, and elongation. Comparative transcriptomic analyses further identify both conserved and species-specific arginine-responsive gene programs, reflecting shared nutrient-sensing mechanisms alongside divergence consistent with species-specific implantation strategies. Extending beyond amino acids, we identify adrenomedullin (ADM) as an evolutionarily conserved, nutritionally responsive peptide component of uterine histotroph. ADM promotes trophectoderm proliferation, migration, and adhesion via MTOR activation in vitro, while in vivo disruption of ADM signaling in pigs compromises conceptus development, highlighting its physiological importance during early pregnancy. Finally, we establish porcine endometrial epithelial organoids as a translational platform to model uterine secretory function and nutrient-conceptus interactions ex vivo. Collectively, these integrated studies define uterine histotroph as an active, nutrition-responsive regulator of conceptus elongation and provide mechanistic insight into how maternal nutrition programs early pregnancy success, with implications for improving reproductive efficiency and sustainability in livestock production systems.