title: Gestational food restriction decreases placental interleukin-10 expression and markers of autophagy and endoplasmic reticulum stress in murine intrauterine growth restriction.
abstract: Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies and often results in short- and long-term sequelae for offspring. The mechanisms underlying IUGR are poorly understood, but it is known that healthy placentation is essential for nutrient provision to fuel fetal growth, and is regulated by immunologic inputs. We hypothesized that in pregnancy, maternal food restriction (FR) resulting in IUGR would decrease the overall immunotolerant milieu in the placenta, leading to increased cellular stress and death. Our specific objectives were to evaluate (1) key cytokines (eg, IL-10) that regulate maternal-fetal tolerance, (2) cellular processes (autophagy and endoplasmic reticulum [ER] stress) that are immunologically mediated and important for cellular survival and functioning, and (3) the resulting IUGR phenotype and placental histopathology in this animal model. After subjecting pregnant mice to mild and moderate FR from gestational day 10 to 19, we collected placentas and embryos at gestational day 19. We examined RNA sequencing data to identify immunologic pathways affected in IUGR-associated placentas and validated messenger RNA expression changes of genes important in cellular integrity. We also evaluated histopathologic changes in vascular and trophoblastic structures as well as protein expression changes in autophagy, ER stress, and apoptosis in the mouse placentas. Several differentially expressed genes were identified in FR compared with control mice, including a considerable subset that regulates immune tolerance, inflammation, and cellular integrity. In summary, maternal FR decreases the anti-inflammatory effect of IL-10 and suppresses placental autophagic and ER stress responses, despite evidence of dysregulated vascular and trophoblast structures leading to IUGR.
authors.affiliation: David Geffen School of Medicine at UCLA, Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center of the UCLA Children's Discovery and Innovation Institute, 10833 Le Conte Avenue, MDCC 22-412, Los Angeles, CA, 90095, USA. Electronic address: alisonchu@mednet.ucla.edu.
authors.forename: Alison
authors.initials: A
authors.lastname: Chu
authors.affiliation: David Geffen School of Medicine at UCLA, Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center of the UCLA Children's Discovery and Innovation Institute, 10833 Le Conte Avenue, MDCC 22-412, Los Angeles, CA, 90095, USA. Electronic address: sthamotharan@mednet.ucla.edu.
authors.forename: Shanthie
authors.initials: S
authors.lastname: Thamotharan
authors.affiliation: David Geffen School of Medicine at UCLA, Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center of the UCLA Children's Discovery and Innovation Institute, 10833 Le Conte Avenue, MDCC 22-412, Los Angeles, CA, 90095, USA. Electronic address: aganguly@ucla.edu.
authors.forename: Amit
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: David Geffen School of Medicine at UCLA, Department of Pathology, 4525 MacDonald Research Laboratories, Los Angeles, CA, 90095, USA. Electronic address: mwadehra@mednet.ucla.edu.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Wadehra
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, 3000 Terasaki Life Sciences Building, 610 Charles Young Drive East, Los Angeles, CA, 90095, USA. Electronic address: matteop@mcdb.ucla.edu.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: David Geffen School of Medicine at UCLA, Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center of the UCLA Children's Discovery and Innovation Institute, 10833 Le Conte Avenue, MDCC 22-412, Los Angeles, CA, 90095, USA. Electronic address: sdevaskar@mednet.ucla.edu.
authors.forename: Sherin U
authors.initials: SU
authors.lastname: Devaskar
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001808:Blood Vessels; D004435:Eating; D059865:Endoplasmic Reticulum Stress; D002149:Energy Intake; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000378:metabolism; D048070:Fetal Nutrition Disorders / Q000209:etiology* / Q000378:metabolism; D007108:Immune Tolerance; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009035:Mothers; D010920:Placenta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena; D012333:RNA, Messenger / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014327:Trophoblasts
chemical_list: D012333:RNA, Messenger; D016753:Interleukin-10
keywords: Autophagy; ER stress; Interleukin 10; Intrauterine growth restriction; Mouse placenta; Vasculature