Genomes and Genes
Effect of preimplantation embryo culture on adult glucose homeostasis
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
- Fetal programming and metabolic syndromePaolo 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...
- ART and health: clinical outcomes and insights on molecular mechanisms from rodent studiesS 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....
- A role for the chemokine receptor CCR6 in mammalian sperm motility and chemotaxisPedro 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...
- Preimplantation stress and developmentSky 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...
- In vitro fertilization affects growth and glucose metabolism in a sex-specific manner in an outbred mouse modelAnnemarie Donjacour
Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, California
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