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Analysis of the Impact of Pufas on Placental Gene Expression V2.28 Uploadx TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Ernährungsmedizin Analysis of the Impact of Polyunsaturated Fatty Acids (PUFAs) on Placental Gene Expression Eva-Maria Sedlmeier Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. M. Klingenspor Prüfer der Dissertation: 1. Univ.-Prof. Dr. J. J. Hauner 2. Univ.-Prof. Dr. H. Daniel Die Dissertation wurde am 17.10.2013 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 12.12.2013 angenommen. Table of contents Table of contents Table of contents ....................................................................................................... I Summary .................................................................................................................. VI Zusammenfassung ................................................................................................ VIII 1. Introduction ........................................................................................................ 1 1.1. Fetal programming - a strategy to prevent the obesity epidemic? ...........................................1 1.1.1. The obesity epidemic ........................................................................................................1 1.1.2. Fetal programming of obesity ...........................................................................................2 1.1.3. Long chain polyunsaturated fatty acids (LCPUFAs) and fetal / metabolic programming of obesity risk .............................................................................................3 1.2. N-6 and n-3 long chain polyunsaturated fatty acids (LCPUFAs) ..............................................5 1.2.1. Biosynthesis of n-6 and n-3 LCPUFAs .............................................................................5 1.2.2. N-6 and n-3 LCPUFAs as precursors for eicosanoid synthesis .......................................7 1.2.3. The impact of n-6 and n-3 LCPUFAs on gene expression ...............................................8 1.2.4. The relevance of n-6 and n-3 LCPUFAs in pregnancy .....................................................9 1.3. The human placenta .............................................................................................................. 11 1.3.1. Development of the human placenta ............................................................................. 11 1.3.2. Anatomy of human term placenta .................................................................................. 12 1.3.3. Functions of the human placenta .................................................................................. 14 1.3.4. Pathologies of the human placenta ............................................................................... 16 1.3.5. Epigenetic mechanisms in the placenta involved in fetal programming ........................ 16 1.4. Sexual dimorphism ................................................................................................................ 19 1.4.1. Sexual dimorphism in placental physiology ................................................................... 19 1.4.2. Basic mechanisms mediating sexual dimorphism ......................................................... 19 1.4.3. Sexual dimorphisms in the context of obesity, LCPUFAs and fetal programming ........ 20 2. Aim of the study ............................................................................................... 22 3. Subjects and Methods ..................................................................................... 23 3.1. Subjects – the INFAT study population ................................................................................. 23 3.2. Sampling of human term placenta ......................................................................................... 25 3.3. Extraction of total RNA and total RNA containing small RNA ............................................... 27 3.4. DNA microarray analysis ....................................................................................................... 28 3.5. Metabolic pathway analysis ................................................................................................... 29 3.6. Gene expression analysis by RT-qPCR ................................................................................ 30 3.7. Explorative microRNA profiling .............................................................................................. 31 3.8. Analysis of microRNA binding sites within mRNA sequences .............................................. 32 3.9. microRNA expression analysis by RT-qPCR ........................................................................ 33 I Table of contents 3.10. Analysis of protein expression by Western blot analysis....................................................... 34 3.11. Amino acid analysis ............................................................................................................... 35 3.12. Sex steroid analysis in placental tissue and umbilical cord plasma ...................................... 35 3.13. Fatty acid analysis ................................................................................................................. 36 3.14. Statistical analysis ................................................................................................................. 37 4. Results .............................................................................................................. 38 4.1. Overview of applied experimental and analytical strategies ................................................. 38 4.2. Characterization of the INFAT subpopulation selected for molecular analysis of placental tissue ..................................................................................................................................... 41 4.2.1. Analysis groups and statistics ....................................................................................... 41 4.2.2. Maternal baseline characteristics .................................................................................. 41 4.2.3. Compliance of the pregnant women in the INFAT subpopulation ................................. 43 4.2.4. Offspring parameters in the INFAT subpopulation ........................................................ 46 4.2.5. LCPUFA analysis in offspring compartments and placental tissue ............................... 49 4.3. Transcriptome analysis of placental gene expression........................................................... 51 4.3.1. Transcriptome analysis for the impact of the n-3 LCPUFA intervention on placental gene expression ............................................................................................................ 51 4.3.2. Transcriptome analysis for the impact of offspring sex on placental gene expression . 53 4.3.3. Transcriptome analysis for the impact of the n-3 LCPUFA intervention separately in male and female placentas ............................................................................................ 55 4.3.4. Transcriptome dataset investigation for known LCPUFA regulated genes ................... 57 4.3.5. Search for placental pathways to be regulated upon n-3 LCPUFA intervention by metabolic pathway analysis ........................................................................................... 59 4.4. Explorative microRNA profiling for the influence of the n-3 LCPUFA intervention ................ 61 4.5. Combined analysis of data from transcriptome analysis with microRNA profiling data by Diana mirEXTra ..................................................................................................................... 64 4.6. Biological validation of selected target genes and microRNAs by RT-qPCR ....................... 66 4.6.1. Biological validation of selected target genes from pathway analysis on gene expression level ............................................................................................................. 66 4.6.2. Biological validation of mTORC1 pathway and mTORC1 target genes on gene expression level ............................................................................................................. 69 4.6.3. Biological validation of selected microRNAs by RT-qPCR ............................................ 71 4.6.4. Analysis for binding sites of miR-99a within LAT1 and TAUT genes ............................ 73 4.6.5. Validation of LAT1 protein expression by Western blot analysis .................................. 73 4.7. Analysis of amino acid levels in placenta and umbilical cord plasma ................................... 75 4.8. Sex steroid analysis in placenta and umbilical cord plasma ................................................. 79 4.9. Correlation analysis of significantly regulated placental gene, microRNA and protein expression with selected parameters .................................................................................... 81 4.9.1. Correlation analysis between selected placental gene and protein expression as well as related umbilical cord plasma amino acids ........................................................ 81 II Table of contents 4.9.2. Correlation of significantly regulated parameters
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