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Institute for Life Sciences Pregnancy Induced Changes in the Mouse Liver Transcriptome Leonie R. Grenfell, Samuel P. Hoile, Mark A. Hanson, Karen A. Lillycrop and Graham C. Burdge. Background During pregnancy, dramatic metabolic changes occur in response to the growing fetus. These changes have been particularly documented in the rat liver which shows an increase in size during pregnancy (Poo et al., 1939) in response to sex hormones (Griffiths et al., 1941). Despite this, there has been very little further research in to how these alterations are initiated and regulated by the transcriptome. The aim of this study was to characterize changes in gene expression in the liver in relation to the changing metabolic phenotype of the mother. Leptin levels were significantly increased at d14 (p=0.005). Plasma levels of glucose were found to decrease at d7 before increasing at d18 (p=0.021). No significant differences were found in plasma β-Hb levels. Figure 3. Proportion of genes showing altered gene expression Altered Gene Expression in Liver Down-regulated 3902 Methods Molecules Associated with Altered Gene Expression in Relation to Function 4000 Gastrointestinal disease 3000 2000 Developmental Disorder 1000 b c Energy Intake(KJ) /10g body weight 30 20 10 a b a a 30 Leptin concentration throughout pregnancy Day of Pregnancy un ct io n og i Small Molecule Biochemistry 712 18 a 100 Embryonic Development 577 Total molecules altered within most significant systems = 3254 Substantial alteration in the gene expression profile was found at d18 of pregnancy in the liver when compared to non pregnant controls. 43% of the genes found on the array had more than a 2fold increase or decrease in expression and are associated with fundamental functions across cell proliferation, metabolism and fetal development. Conclusions These results show that pregnancy induces substantial changes in the regulation of the hepatic transcriptome. Further work will test the hypothesis that such transcriptional changes involve altered epigentic regulation of specific genes References Pr eg D 18 Pr eg D 14 Pr eg 0 D 7 Pr eg D 18 Pr eg Pr eg D 7 D 14 N on Pr eg 0 ab Organismal Survival 1363 Griffiths, M., Marks, H. P., & Young, F. G. (1941). Influence of (Œstrogens and Androgens on Glycogen Storage in the Fasting Rat. Nature, 147 (3725), 359–359. Poo, L. J., Lew, W., & Addis, T. (1939). Protein Ananbolism of Organs and Tissues During Pregnancy and Lactation. j. Biol. Chem, 128, 69–77. eg 500 b 200 Pr 1000 ab on 1500 300 N 2000 Concentration of Glucose mg/dl a Glucose concentration throughout pregnancy Digestive System Function Organ Morphology Total molecules altered within most significant systems = 3170 Figure 2. Plasma leptin and glucose concentration during pregnancy. a Cell Death and Survival 1088 D ay 14 D ay 7 D ay ay 0 18 14 D ay 7 D ay 0 ay D D ay Day of Pregnancy Most Significant Systems Altered in Physiological Function Hepatic System Function Lipid Metabolism As expected, significant weight gain was observed between d7 and d14 (p<0.001), which was sustained until d18 (p<0.001). Food intake also increased at d14 compared to pre-conception (p=0.007), reaching a plateau between d14 and d18. Energy intake increased between conception and d7 (p=0.032) before returning to non-pregnant levels in late gestation. a ca lF un ct io n Ph ys nd ul ar a 10 0 2500 io l s se ea Molecular Transport Day of Pregnancy Concentration of Leptin pg/ml Most Significant Systems Altered in Molecular and Cellular Function 20 0 b Total molecules altered within most significant systems = 2251 Cell Morphology D Weight/g 40 a C el lu la rF is D d 40 a Cancer 605 0 an 50 Organismal injury 613 M ol ec D Energy intake during pregnancy is Weight gain during pregnancy Most Significant Systems Altered in Disease and Disorder Hepatic System Disease or de r Figure 1. Weight gain and energy intake throughout pregnancy Figure 4. Molecular pathways associated with expression changes s Results No alteration 10288 Total genes represented on array = 18098 Number of associated molecules 90 day old (n=>6), C57/Blk6 virgin mice maintained on standard chow were mated and weight gain and 24 hour food intake were measured weekly. Age matched virgin female mice were used as non-pregnant controls. Mice were culled at days 7, 14 and 18 of gestation (d7, d14 and d18) and organs collected. Serum levels of βhydroxybutyrate (β-Hb), leptin and glucose were measured using colorimetric or ELISA assays. RNA was extracted from liver and transcriptome analysis carried out on the Illumina MouseRef-8 v2.0 Expression BeadChip. Up-regulated 3908 Day of Pregnancy www.southampton.ac.uk/ifls Acknowledgements