Effect of preimplantation embryo culture on adult glucose homeostasis

Summary

Principal Investigator: Paolo Rinaudo
Abstract: DESCRIPTION (provided by applicant): Stress in utero or during the early post natal period plays a cardinal role in shaping future health. An initial stressor, occurring when the embryo is exquisitely sensitive to environmental changes, reprograms the developing gene networks, tissue, and organs so that the resulting individual is predisposed to disease. We hold that suboptimal preimplantation conditions predispose adult individuals to altered glucose homeostasis, leading to an increased incidence of insulin resistance. Our preliminary data show that increased stress during in vitro culture results in proportionate deterioration of gene expression in mouse embryos. Most importantly, we have identified thioredoxin-interacting protein (txnip) as a marker of preimplantation stress. Txnip mRNA and protein levels are upregulated in blastocyst after in vitro culture;suboptimal culture conditions (Whitten's medium- WM) results in a more intense txnip upregulation than culture in optimized medium (KSOM with amino acid, KAA). Txnip expression remains elevated in adult animals and adult mice have impaired glucose homeostasis. Significantly, adults animals cultured in WM have a more severe phenotype than animals cultured in KAA indicating that a memory of the preimplantation stress is maintained in the adult animal. The aberrant txnip gene expression is associated with altered expression of several genes that control DNA methylation, suggesting an epigenetic regulation. Txnip is the principal inhibitor of thioredoxin (txn), a key cellular antioxidant. Txnip levels are regulated by cellular contents of glucose, glutamine, adenosine containing compounds;txnip appears therefore to link the cellular nutritional state with redox state and subsequent metabolic regulation. In addition, txnip is involved in the regulation of peripheral glucose metabolism via downregulation of AKT2/PKB2 pathway and is associated with decreased pancreatic beta cell mass. We propose that (1) txnip is a key element of the embryonic metabolic sensing mechanism and that (2) txnip upregulation in the embryo modifies homeostatic mechanisms so that txnip will remain elevated in adult tissues (3) elevation of txnip in adult tissues results in alteration of glucose homeostasis. To test this hypothesis, we will investigate: (1) how the txnip-txn system responds to progressively worsening environment (2) the mechanisms responsible to maintain elevated txnip expression in adult tissues (3) the phenotype of adult mice generated in vitro. This study is important because will offer insight into basic mechanisms utilized by the preimplantation embryo to respond to different environmental conditions. In addition, data derived from this study can be used to monitor children conceived by assisted reproductive technology (ART). As such, this application is responsive to the Program Announcement (PA-08-104): Adverse outcome of Assisted Reproductive Technologies. Indeed, more than 3 million children have been conceived with the help of ART and multiple studies have reported an increased incidence of maternal and fetal complications in this population. PUBLIC HEALTH RELEVANCE: Stress in utero or during the early post natal period plays a cardinal role in shaping future health. An initial stressor, occurring when the embryo is exquisitely sensitive to environmental changes, reprograms the developing cells, tissues and organs so that the resulting individual is predisposed to disease. This research is designed to define how progressively worsening stress during early embryo development affect future health. Knowledge gained from this research may lead to novel understanding of the mechanisms used by the embryo to sense and to adapt to different environments.
Funding Period: 2010-09-01 - 2015-08-31
more information: NIH RePORT

Top Publications

  1. pmc Fetal programming and metabolic syndrome
    Paolo Rinaudo
    Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94115, USA
    Annu Rev Physiol 74:107-30. 2012
  2. pmc ART and health: clinical outcomes and insights on molecular mechanisms from rodent studies
    S K Feuer
    Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94115, USA
    Mol Hum Reprod 19:189-204. 2013
  3. pmc A role for the chemokine receptor CCR6 in mammalian sperm motility and chemotaxis
    Pedro Caballero-Campo
    Unidad de Reproducción Humana, Clínica Tambre, Madrid, Spain Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of California, San Francisco, CA
    J Cell Physiol 229:68-78. 2014
  4. pmc Preimplantation stress and development
    Sky Feuer
    Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Endocrinology and Infertility, University of California, San Francisco, California, 94115
    Birth Defects Res C Embryo Today 96:299-314. 2012
  5. pmc In vitro fertilization affects growth and glucose metabolism in a sex-specific manner in an outbred mouse model
    Annemarie Donjacour
    Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, California
    Biol Reprod 90:80. 2014

Detail Information

Publications5

  1. pmc Fetal programming and metabolic syndrome
    Paolo Rinaudo
    Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94115, USA
    Annu Rev Physiol 74:107-30. 2012
    ..Although metabolic syndrome in adulthood is undoubtedly caused by multiple factors, including modifiable behavior, fetal life may provide a critical window in which individuals are predisposed to metabolic syndrome later in life...
  2. pmc ART and health: clinical outcomes and insights on molecular mechanisms from rodent studies
    S K Feuer
    Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94115, USA
    Mol Hum Reprod 19:189-204. 2013
    ....
  3. pmc A role for the chemokine receptor CCR6 in mammalian sperm motility and chemotaxis
    Pedro Caballero-Campo
    Unidad de Reproducción Humana, Clínica Tambre, Madrid, Spain Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of California, San Francisco, CA
    J Cell Physiol 229:68-78. 2014
    ..Therefore, some of the physiological reactions mediated by CCR6 ligands in male reproduction extend beyond a pro-inflammatory response and might find application in clinical reproduction and/or contraception...
  4. pmc Preimplantation stress and development
    Sky Feuer
    Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Endocrinology and Infertility, University of California, San Francisco, California, 94115
    Birth Defects Res C Embryo Today 96:299-314. 2012
    ..Given that animal studies suggest alteration of metabolic pathways following preimplantation stress, it will be of great importance to follow-up ART individuals as they enter later stages of adult life...
  5. pmc In vitro fertilization affects growth and glucose metabolism in a sex-specific manner in an outbred mouse model
    Annemarie Donjacour
    Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, California
    Biol Reprod 90:80. 2014
    ..Future work on the long-term effects of IVF offspring should focus on glucose metabolism and the cardiovascular system. ..

Research Grants30

  1. Developmental Gene-Environment Interactions and Premature Ovarian Failure
    Ulrike Luderer; Fiscal Year: 2013
    ..Understanding these mechanisms is important to developing interventions for the prevention of premature ovarian failure. ..
  2. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  3. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  4. Southern California Children's Enviromental Health Center (SC-CEHC)
    Rob S McConnell; Fiscal Year: 2013
    ....
  5. UC Berkeley/Stanford Children's Enviromental Health Center
    Gary M Shaw; Fiscal Year: 2013
    ..7) To support the data management and QA/QC operations of CHAPS-SJV. 8) To support and implement the data sharing plan. 9) To support the annual CEHC meetings and the travel of CHAPS-SJV investigators to these meetings. ..
  6. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  7. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  8. Hormonal Signals that Regulate Ovarian Diffrentiation
    Kelly E Mayo; Fiscal Year: 2013
    ..It is our expectation that the basic research projects presented in this P01 program proposal will have considerable impact, ultimately leading to improvements in human reproductive health. ..
  9. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
    ..The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research. ..
  10. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..
  11. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  12. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  13. Regulation of Tumorigenesis and therapeutic resistance by Nrf2 in lung cancer
    Shyam Biswal; Fiscal Year: 2013
    ..Successful completion of this project will develop a new therapeutic strategy for lung cancer treatment. ..
  14. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  15. Mechanisms by which Obesity in Pregnancy Leads to Obesity in Offspring
    Rebecca A Simmons; Fiscal Year: 2013
    ..Since the incidence of obesity is rapidly increasing in the United States, these studies will have great impact on health. ..
  16. Functional Analysis of the Embryonic Epigenome in a Non-rodent Model
    Mark E Westhusin; Fiscal Year: 2013
    ....
  17. Role of Brg1 in Embryo Development and Pluripotency
    JASON GLENN KNOTT; Fiscal Year: 2013
    ..Collectively, these studies are highly relevant to the mission of the NICHD. ..
  18. Embryonic Gene Expression During Diabetic Embryopathy
    Mary R Loeken; Fiscal Year: 2013
    ..This proposal is innovative because the concept that early embryonic gene expression is developmentally regulated by signals generated by fuel metabolism that alter chromatin structure has not previously been investigated. ..
  19. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  20. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  21. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  22. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  23. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  24. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..