Amino Acids and Conceptus Development During the Peri-Implantation Period of Pregnancy

Abstract

The dialogue between the mammalian conceptus (embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients, collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of Developmental Origins of Health and Disease (DOHAD). Although mechanisms responsible for differential growth and development of the conceptus resulting in DOHAD phenomena remain unclear, epigenetic events involving methylation of DNA are likely mechanisms. Histotroph includes serine and methionine which can contribute to the one carbon pool, and arginine, lysine and histidine residues which may be targets of methylation. It is also clear that supplementing the diet with arginine enhances fetal-placental development in rodents, swine and humans through mechanisms that remain to be elucidated. However, molecules secreted by conceptuses such as interferon tau in ruminants, estrogens and interferons in pigs and chorionic gonadotrophin, along with progesterone, regulate expression of genes for nutrient transporters. Understanding mechanisms whereby select nutrients regulate expression of genes in cell signaling pathways critical to conceptus development, implantation and placentation is required for improving successful establishment and maintenance of pregnancy in mammals.

The Potential Impact of Animal Science Research on Global Maternal and Child Nutrition and Health: A Landscape Review

“…Some amino acids (e.g., arginine, cysteine, glutamine, and proline) are referred to as conditionally essential because under specific physiologic stages or conditions, such as pregnancy, lactation, and/or upon early weaning, they must also be provided in the diet because rates of use exceed the rate of synthesis. The development of embryos to the blastocyst stage for implantation requires leucine or arginine that initiate cell signaling via the mechanistic target of rapamycin (mTOR) to regulate protein synthesis and catabolism and induce expression of genes for IGF II, NO synthases, and ornithine decarboxylase (39). Physiologic concentrations of leucine, arginine, and glutamine stimulate activities of mTOR and ribosomal protein S6 kinase, as well as proliferation of trophectoderm cells.…”

“…The concentrations of arginine, glutamine, and leucine are greater in uterine fluids than in maternal plasma, and arginine is most stimulatory to proliferation, migration, and gene expression by ovine trophectoderm cells (39, 41). Increases in uterine concentrations of these amino acids between days 10 and 16 of pregnancy coincide with the rapid growth and development of conceptuses during the peri-implantation period.…”

Chronicling the discovery of interferon tau

“…This is because IFNT induces expression of IRF2 in uterine luminal and superficial glandular epithelia in ewes to silence expression of ISGs, but induces expression of many novel genes that support growth and development of the conceptus. Those genes include: wingless-type MMTV integration site family member 7A ( WNT7A ), LGALS15 (galectin 15), HIF2A (hypoxia-inducible factor 2A), CTSL (cathepsin L), CST3 (cystatin C), SLC5A1 (solute carrier family 5, sodium/glucose cotransporter, member 1), GRP (gastrin releasing peptide), HSD11B1 (11 beta hydroxysteroid dehydrogenase type 1), IGFBP1 (insulin-like growth factor binding protein 1) and SLC7A2 (solute carrier family 7, cationic amino acid transporter, y+ system, member 2) (see Bazer et al 2009, Bazer et al 2015a, Bazer et al 2015b). Inhibition of the classical Janus kinase (JAK):STAT cell signaling pathway by IRF2 likely allows expression of the P4-induced and IFNT-stimulated genes to increase in response to both the progestamedins and IFNT via MAPK and PI3K cell signaling in uterine luminal and superficial glandular epithelia.…”

Pregnancy recognition signals in mammals: the roles of interferons and estrogens

“…Arginine is then metabolized to nitric oxide and polyamines that are required for growth and development of the conceptus. Interferon tau, in concert with progesterone, also increases expression of uteroferrin which not only transport iron to the conceptus, but also stimulates erythropoiesis (see Bazer et al, 2009bBazer et al, , 2015.…”

“…Arginine and secreted phosphoprotein 1 (SPP1; also known as osteopontin) activate mechanistic target of rapamycin (MTOR) cell signaling via pathways that converge on AKT1 and MTOR via MTORC1 (cell proliferation and gene expression) and MTORC2 (cell migration, adhesion and cytoskeletal reorganization) to affect oTr cells in conceptuses for transition from spherical to tubular and filamentous forms that can signal pregnancy recognition, as well as undergo implantation and placentation. AKT1, proto-oncogenic protein kinase 1; FAK, focal adhesion kinase; PDK1, phosphoinositide-dependent protein kinase 1; MTOR, mechanistic target of rapamycin; RAPTOR, regulatoryassociated protein of MTOR; RICTOR, rapamycin-insensitive companion of MTOR; IGF2, insulin-like growth factor 2; type I IGF2, type I insulin-like growth factor receptor; ILK, integrin-linked kinases; IRS1, insulin receptor substrate 1; PKC, protein kinase C; SGK, serum/glucocorticoid-regulated kinase; MLST8, mammalian lethal with SEC13 protein 8; PRAS40, proline-rich Akt/PKB substrate 40 kDa; DEPTOR, DEP domain-containing MTORinteracting protein; MSIN1, mammalian stress-activated MAP kinase interacting protein 1; PROTOR, protein observed with RICTOR; NCK2, non-catalytic region of tyrosine kinase, beta; NO, nitric oxide; NOS3, nitric oxide synthase 3; ODC1, ornithine decarboxylase; PI3K, phosphatidylinositol 3-kinase; LIMS1, LIM and senescent cell antigen-like domains 1; S6K, S6 kinase; SPP1, secreted phosphoprotein 1 (see Bazer et al, 2015;Wang et al 2016). …”