Placental Responses to Changes in the Maternal Environment Determine Fetal Growth

Placental responses to maternal perturbations are complex and remain poorly understood. Altered maternal environment during pregnancy such as hypoxia, stress, obesity, diabetes, toxins, altered nutrition, inflammation, and reduced utero-placental blood flow may influence fetal development, which can predispose to diseases later in life. The placenta being a metabolically active tissue responds to these perturbations by regulating the fetal supply of nutrients and oxygen and secretion of hormones into the maternal and fetal circulation. We have proposed that placental nutrient sensing integrates maternal and fetal nutritional cues with information from intrinsic nutrient sensing signaling pathways to balance fetal demand with the ability of the mother to support pregnancy by regulating maternal physiology, placental growth, and placental nutrient transport. Emerging evidence suggests that the nutrient-sensing signaling pathway mechanistic target of rapamycin (mTOR) plays a central role in this process. Thus, placental nutrient sensing plays a critical role in modulating maternal–fetal resource allocation, thereby affecting fetal growth and the life-long health of the fetus.

[1]  Y. Kanai,et al.  Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2. , 2016, Clinical science.

[2]  F. Rosario,et al.  Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth , 2015, Proceedings of the National Academy of Sciences.

[3]  Madhulika B. Gupta,et al.  Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR , 2015, Clinical science.

[4]  M. Nijland,et al.  Reduced placental amino acid transport in response to maternal nutrient restriction in the baboon. , 2015, American journal of physiology. Regulatory, integrative and comparative physiology.

[5]  S. Ozanne,et al.  The effect of maternal Inflammation on foetal programming of metabolic disease , 2015, Acta physiologica.

[6]  T. Powell,et al.  Inflammation in maternal obesity and gestational diabetes mellitus. , 2015, Placenta.

[7]  Y. Kanai,et al.  Increased placental nutrient transport in a novel mouse model of maternal obesity with fetal overgrowth , 2015, Obesity.

[8]  G. Burton,et al.  Review: Endocrine regulation of placental phenotype. , 2015, Placenta.

[9]  G. KeswaniSundeep,et al.  Intraplacental gene therapy with Ad-IGF-1 corrects naturally occurring rabbit model of intrauterine growth restriction. , 2015 .

[10]  T. Crombleholme,et al.  Intraplacental gene therapy with Ad-IGF-1 corrects naturally occurring rabbit model of intrauterine growth restriction. , 2015, Human gene therapy.

[11]  R. Sager,et al.  Regulation of Human Trophoblast GLUT1 Glucose Transporter by Insulin-Like Growth Factor I (IGF-I) , 2014, PloS one.

[12]  T. Powell,et al.  The Role of Placental Nutrient Sensing in Maternal-Fetal Resource Allocation1 , 2014, Biology of reproduction.

[13]  Thomas Jansson,et al.  Increasing Maternal Body Mass Index Is Associated with Systemic Inflammation in the Mother and the Activation of Distinct Placental Inflammatory Pathways1 , 2014, Biology of reproduction.

[14]  J. Glazier,et al.  Insight into the pathogenesis of fetal growth restriction in placental malaria: decreased placental glucose transporter isoform 1 expression. , 2014, The Journal of infectious diseases.

[15]  S. Ozanne,et al.  Effects of pregnancy on obesity-induced inflammation in a mouse model of fetal programming , 2014, International Journal of Obesity.

[16]  Guoyao Wu,et al.  Down‐regulation of placental mTOR, insulin/IGF‐I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  S. Weintraub,et al.  Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis. , 2014, Molecular endocrinology.

[18]  Catherine Q Nie,et al.  The role of chemokines in severe malaria: more than meets the eye , 2013, Parasitology.

[19]  T. Powell,et al.  Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts , 2013, Molecular and Cellular Endocrinology.

[20]  T. Crombleholme,et al.  Adenoviral-Mediated Placental Gene Transfer of IGF-1 Corrects Placental Insufficiency via Enhanced Placental Glucose Transport Mechanisms , 2013, PloS one.

[21]  T. Powell,et al.  Role of Placental Nutrient Sensing in Developmental Programming , 2013, Clinical obstetrics and gynecology.

[22]  T. Powell,et al.  Review: Adiponectin--the missing link between maternal adiposity, placental transport and fetal growth? , 2013, Placenta.

[23]  Y. Kanai,et al.  Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells , 2013, The Journal of physiology.

[24]  M. Molyneux,et al.  Plasmodium falciparum Malaria Elicits Inflammatory Responses that Dysregulate Placental Amino Acid Transport , 2013, PLoS pathogens.

[25]  F. Rosario,et al.  Activation of placental mTOR signaling and amino acid transporters in obese women giving birth to large babies. , 2013, The Journal of clinical endocrinology and metabolism.

[26]  D. Goberdhan,et al.  The emerging role of mTORC1 signaling in placental nutrient-sensing. , 2012, Placenta.

[27]  A. Fowden,et al.  Maternal corticosterone regulates nutrient allocation to fetal growth in mice , 2012, The Journal of physiology.

[28]  T. Powell,et al.  Placental transport in response to altered maternal nutrition , 2012, Journal of Developmental Origins of Health and Disease.

[29]  S. Devaskar,et al.  Placental glucose and amino acid transport in calorie-restricted wild-type and Glut3 null heterozygous mice. , 2012, Endocrinology.

[30]  Jean X. Jiang,et al.  Chronic maternal infusion of full‐length adiponectin in pregnant mice down‐regulates placental amino acid transporter activity and expression and decreases fetal growth , 2012, The Journal of physiology.

[31]  V. Hietakangas Nutrient sensing. , 2012, Seminars in cell & developmental biology.

[32]  U. Krishna,et al.  Placental Insufficiency and Fetal Growth Restriction , 2011, Journal of obstetrics and gynaecology of India.

[33]  C. Sibley,et al.  Antenatal dexamethasone treatment in midgestation reduces system A-mediated transport in the late-gestation murine placenta. , 2011, Endocrinology.

[34]  G. Burton,et al.  Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice. , 2011, Endocrinology.

[35]  J. Glazier,et al.  Placental malaria-associated inflammation disturbs the insulin-like growth factor axis of fetal growth regulation. , 2011, The Journal of infectious diseases.

[36]  Y. Kanai,et al.  Maternal Protein Restriction in the Rat Inhibits Placental Insulin, mTOR, and STAT3 Signaling and Down-Regulates Placental Amino Acid Transporters , 2011, Endocrinology.

[37]  C. Roberts,et al.  The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth , 2010, The Journal of physiology.

[38]  G. Burton The influence of the intrauterine environment on human placental development , 2010 .

[39]  T. Powell,et al.  Full-Length Adiponectin Attenuates Insulin Signaling and Inhibits Insulin-Stimulated Amino Acid Transport in Human Primary Trophoblast Cells , 2010, Diabetes.

[40]  D. Charnock-Jones,et al.  The influence of the intrauterine environment on human placental development. , 2010, The International journal of developmental biology.

[41]  T. Powell,et al.  IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2. , 2009, American journal of physiology. Cell physiology.

[42]  G. Luo,et al.  Levels of insulin-like growth factors and their receptors in placenta in relation to macrosomia. , 2009, Asia Pacific journal of clinical nutrition.

[43]  R. Powers,et al.  Leptin affects system A amino acid transport activity in the human placenta: evidence for STAT3 dependent mechanisms. , 2009, Placenta.

[44]  T. Powell,et al.  High‐fat diet before and during pregnancy causes marked up‐regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  Mitsuru Nenoi,et al.  Regulation of , 2004 .

[46]  Y. Kanai,et al.  Regulation of placental amino acid transporter activity by mammalian target of rapamycin. , 2009, American journal of physiology. Cell physiology.

[47]  F. Bloomfield,et al.  Treatment of intrauterine growth restriction with maternal growth hormone supplementation in sheep. , 2008, American journal of obstetrics and gynecology.

[48]  D. Charnock-Jones,et al.  Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. , 2008, The American journal of pathology.

[49]  T. Powell,et al.  Maternal hormones linking maternal body mass index and dietary intake to birth weight. , 2008, The American journal of clinical nutrition.

[50]  S. Hauguel-de Mouzon,et al.  Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. , 2008, Placenta.

[51]  A. Mehta,et al.  The hypoxia of high altitude causes restricted fetal growth in chick embryos with the extent of this effect depending on maternal altitudinal status , 2008, Journal of Physiology.

[52]  J. Kurtis,et al.  Maternal peripheral blood level of IL-10 as a marker for inflammatory placental malaria , 2008, Malaria Journal.

[53]  M. Villena,et al.  The role of oxygen in prenatal growth: studies in the chick embryo , 2007, The Journal of physiology.

[54]  T. Powell,et al.  Regulation of placental nutrient transport--a review. , 2007, Placenta.

[55]  T. Powell,et al.  Mammalian target of rapamycin in the human placenta regulates leucine transport and is down‐regulated in restricted fetal growth , 2007, The Journal of physiology.

[56]  F. T. Ter Kuile,et al.  Epidemiology and burden of malaria in pregnancy. , 2007, The Lancet. Infectious diseases.

[57]  L. Hviid,et al.  Malaria in pregnancy: pathogenesis and immunity. , 2007, The Lancet. Infectious diseases.

[58]  I. Cetin,et al.  Intrauterine growth restriction is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition. , 2007, American journal of physiology. Endocrinology and metabolism.

[59]  V. Ganapathy,et al.  Down‐regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet , 2006, The Journal of physiology.

[60]  T. Powell,et al.  IFPA 2005 Award in Placentology Lecture. Human placental transport in altered fetal growth: does the placenta function as a nutrient sensor? -- a review. , 2006, Placenta.

[61]  N. Illsley,et al.  Effects of chronic hypoxia in vivo on the expression of human placental glucose transporters. , 2006, Placenta.

[62]  V. Ganapathy,et al.  Inhibition of Amino Acid Transport System A by Interleukin-1β in Trophoblasts , 2005, The Journal of the Society for Gynecologic Investigation: JSGI.

[63]  R. Giorgino,et al.  Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling. , 2005, Endocrinology.

[64]  L. Gottwald,et al.  [Intrauterine growth restriction]. , 2005, Przeglad lekarski.

[65]  Imran Y. Khan,et al.  Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? , 2004, The Journal of physiology.

[66]  R. Wilkening,et al.  Placental uptake and transport of ACP, a neutral nonmetabolizable amino acid, in an ovine model of fetal growth restriction. , 2004, American journal of physiology. Endocrinology and metabolism.

[67]  E. Hafen,et al.  Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. , 2004, Genes & development.

[68]  R. Snow,et al.  Impact of Malaria during Pregnancy on Low Birth Weight in Sub-Saharan Africa , 2004, Clinical Microbiology Reviews.

[69]  P. Gluckman,et al.  Living with the Past: Evolution, Development, and Patterns of Disease , 2004, Science.

[70]  T. Powell,et al.  Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes. , 2004, The Journal of clinical endocrinology and metabolism.

[71]  P. Kremsner,et al.  Cytokine profiles in peripheral, placental and cord blood in pregnant women from an area endemic for Plasmodium falciparum. , 2004, European cytokine network.

[72]  E. Ferrazzi,et al.  Differences in fat and lean mass proportions in normal and growth-restricted fetuses. , 2003, American journal of obstetrics and gynecology.

[73]  G. Desoye,et al.  Insulin receptors in syncytitrophoblast and fetal endothelium of human placenta. Immunohistochemical evidence for developmental changes in distribution pattern , 1994, Histochemistry.

[74]  K. Inoki,et al.  TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival , 2003, Cell.

[75]  G. Fouda,et al.  Changes in the levels of chemokines and cytokines in the placentas of women with Plasmodium falciparum malaria. , 2003, The Journal of infectious diseases.

[76]  B. Johansson,et al.  Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. , 2003, The Journal of clinical endocrinology and metabolism.

[77]  M. Molyneux,et al.  Host Response to Malaria During Pregnancy: Placental Monocyte Recruitment Is Associated with Elevated β Chemokine Expression1 , 2003, The Journal of Immunology.

[78]  S. Smith,et al.  Hypoxia reduces expression and function of system A amino acid transporters in cultured term human trophoblasts. , 2003, American journal of physiology. Cell physiology.

[79]  M. Molyneux,et al.  Placental Tumor Necrosis Factor Alpha but Not Gamma Interferon Is Associated with Placental Malaria and Low Birth Weight in Malawian Women , 2003, Infection and Immunity.

[80]  S. Hauguel-de Mouzon Polar expression and phosphorylation of human leptin receptor isoforms in paired, syncytial, microvillous and basal membranes from human term placenta. , 2003, Placenta.

[81]  M. Ingec,et al.  Umbilical Cord and Maternal Blood Leptin Concentrations in Intrauterine Growth Retardation , 2002, Clinical chemistry and laboratory medicine.

[82]  S. Kaser,et al.  Polar expression and phosphorylation of human leptin receptor isoforms in paired, syncytial, microvillous and basal membranes from human term placenta. , 2002, Placenta.

[83]  T. Powell,et al.  Alterations in the activity of placental amino acid transporters in pregnancies complicated by diabetes. , 2002, Diabetes.

[84]  T. Powell,et al.  Glucose transport and system A activity in syncytiotrophoblast microvillous and basal plasma membranes in intrauterine growth restriction. , 2002, Placenta.

[85]  A. Zarate,et al.  Insulin‐like growth factor I, epidermal growth factor and transforming growth factor beta expression and their association with intrauterine fetal growth retardation, such as development during human pregnancy , 2001, Diabetes, obesity & metabolism.

[86]  G. Pardi,et al.  Placental transport of leucine, phenylalanine, glycine, and proline in intrauterine growth-restricted pregnancies. , 2001, The Journal of clinical endocrinology and metabolism.

[87]  P. Björntorp,et al.  Prenatal cytokine exposure results in obesity and gender-specific programming. , 2001, American journal of physiology. Endocrinology and metabolism.

[88]  J. Meulen Glucose tolerance in adults after prenatal exposure to famine , 2001, The Lancet.

[89]  P. Gluckman,et al.  Glucose tolerance in adults after prenatal exposure to famine , 2001, The Lancet.

[90]  B. Larsson,et al.  Maternal Endotoxemia Results in Obesity and Insulin Resistance in Adult Male Offspring. , 2001, Endocrinology.

[91]  A. Flyvbjerg,et al.  Macrosomia Associated With Maternal Serum Insulin‐Like Growth Factor‐I and ‐II in Diabetic Pregnancy , 2001, Obstetrics and gynecology.

[92]  D. Barker,et al.  Glucose tolerance in adults after prenatal exposure to famine , 2001, The Lancet.

[93]  C. Menéndez,et al.  The burden of malaria in pregnancy in malaria-endemic areas. , 2001, The American journal of tropical medicine and hygiene.

[94]  S. Zamudio,et al.  Altitude and fetal growth: current knowledge and future directions , 2000, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[95]  R. Lane,et al.  Placental expression of glucose transporter proteins 1 and 3 in growth-restricted fetal rats. , 1999, American journal of obstetrics and gynecology.

[96]  T. Powell,et al.  Placental glucose transport and GLUT 1 expression in insulin-dependent diabetes. , 1999, American journal of obstetrics and gynecology.

[97]  T. Powell,et al.  Placental Transport of Leucine and Lysine Is Reduced in Intrauterine Growth Restriction1 , 1998, Pediatric Research.

[98]  C. Menéndez,et al.  Massive chronic intervillositis of the placenta associated with malaria infection. , 1998, The American journal of surgical pathology.

[99]  T. Powell,et al.  Intrauterine Growth Restriction Is Associated with a Reduced Activity of Placental Taurine Transporters , 1998, Pediatric Research.

[100]  C. Sibley,et al.  Association between the Activity of the System A Amino Acid Transporter in the Microvillous Plasma Membrane of the Human Placenta and Severity of Fetal Compromise in Intrauterine Growth Restriction , 1997, Pediatric Research.

[101]  C. Rodeck,et al.  Fetal and maternal plasma insulin-like growth factors and binding proteins in pregnancies with appropriate or retarded fetal growth. , 1997, Early human development.

[102]  R. Wilkening,et al.  Placental transport of threonine and its utilization in the normal and growth-restricted fetus. , 1997, The American journal of physiology.

[103]  C. H. Smith,et al.  Spatial Polarization of Insulin-Like Growth Factor Receptors on the Human Syncytiotrophoblast , 1997, Pediatric Research.

[104]  C. Sibley,et al.  Effect of Fetal Growth Restriction on System A Amino Acid Transporter Activity in the Maternal Facing Plasma Membrane of Rat Syncytiotrophoblast , 1996, Pediatric Research.

[105]  M. Kilberg,et al.  Effect of low-protein diet-induced intrauterine growth retardation on rat placental amino acid transport. , 1996, The American journal of physiology.

[106]  J. C. Ross,et al.  Placental transport and fetal utilization of leucine in a model of fetal growth retardation. , 1996, The American journal of physiology.

[107]  P. Karl Insulin‐like growth factor‐1 stimulates amino acid uptake by the cultured human placental trophoblast , 1995, Journal of cellular physiology.

[108]  P. Gluckman,et al.  Maternal insulin-like growth factor-I infusion alters feto-placental carbohydrate and protein metabolism in pregnant sheep. , 1994, Endocrinology.

[109]  T. Jansson,et al.  Glucose transporter protein expression in human placenta throughout gestation and in intrauterine growth retardation. , 1993, The Journal of clinical endocrinology and metabolism.

[110]  C. Sibley,et al.  Amino Acid (System A) Transporter Activity in Microvillous Membrane Vesicles from the Placentas of Appropriate and Small for Gestational Age Babies , 1993, Pediatric Research.

[111]  R. Wilkening,et al.  Placental glucose transport in heat-induced fetal growth retardation. , 1992, The American journal of physiology.

[112]  S. Fisher,et al.  Amino acid transport by the cultured human placental trophoblast: effect of insulin on AIB transport. , 1992, The American journal of physiology.

[113]  C Osmond,et al.  Fetal and infant growth and impaired glucose tolerance at age 64. , 1991, BMJ.

[114]  T. Jansson,et al.  Placental Transfer of Glucose and Amino Acids in Intrauterine Growth Retardation: Studies with Substrate Analogs in the Awake Guinea Pig , 1990, Pediatric Research.

[115]  M. Guerre-Millo,et al.  [Glucose transporters]. , 1990, Annales de medecine interne.

[116]  G. Pardi,et al.  Umbilical amino acid concentrations in normal and growth-retarded fetuses sampled in utero by cordocentesis. , 1990, American journal of obstetrics and gynecology.

[117]  K. Nicolaides,et al.  Plasma amino acids in appropriate‐ and small‐for‐gestational‐age fetuses , 1990, American journal of obstetrics and gynecology.

[118]  J Golding,et al.  Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. , 1989, BMJ.

[119]  C. Osmond,et al.  INFANT MORTALITY, CHILDHOOD NUTRITION, AND ISCHAEMIC HEART DISEASE IN ENGLAND AND WALES , 1986, The Lancet.

[120]  J. Schulman,et al.  Placental Transfer of Analogs of Glucose and Amino Acids in Experimental Intrauterine Growth Retardation , 1979, Pediatric Research.

[121]  A. Forsdahl,et al.  Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? , 1977, International journal of rehabilitation research. Internationale Zeitschrift fur Rehabilitationsforschung. Revue internationale de recherches de readaptation.

[122]  J. Štulc [Placental transport]. , 1978, Ceskoslovenska gynekologie.

[123]  P. Rosso Maternal-fetal exchange during protein malnutrition in the rat. Placental transfer of glucose and a nonmetabolizable glucose analog. , 1977, The Journal of nutrition.

[124]  P. Rosso Maternal-fetal exchange during protein malnutrition in the rat. Placental transfer of alpha-amino isobutyric acid. , 1977, The Journal of nutrition.

[125]  M. Culpin,et al.  PREVENTION OF ACCIDENTS , 1938, British medical journal.