Transcriptional ontogeny of the developing liver
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE21224 | GEO | 2010/10/01
SECONDARY ACCESSION(S): PRJNA126485
REPOSITORIES: GEO
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Project description:We characterized gene expression changes in the developing mouse liver at gestational days (GD) 11.5, 12.5, 13.5, 14.5, 16.5, and 19.5 and in the neonate (postnatal day (PND) 7 and 30) using full-genome microarrays and compared these changes to that in the adult liver. The fetal liver, and to a lesser extent the neonatal liver, exhibited dramatic differences in gene expression compared to adults. Canonical pathway analysis of the fetal liver signature demonstrated increases in functions important in cell replication and DNA fidelity whereas most metabolic pathways of intermediary metabolism were suppressed. Comparison of the dataset to a number of previously published datasets revealed 1) a striking similarity between the fetal liver and that of the pancreas in both mice and humans, 2) a nucleated erythrocyte signature in the fetus and 3) suppression of most xenobiotic metabolism genes throughout development, except a number of transporters associated with expression in hematopoietic cells. Keywords: gene expression/microarray We characterized gene expression changes in the developing mouse liver at gestational days (GD) 19 and in the neonate (postnatal day (PND) 7 and 30) using full-genome microarrays and compared these changes to that in the adult liver. Total RNA was isolated from liver samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 16 samples, with four mice in each of the four age groups, were analyzed.
2010-10-01 | E-GEOD-21224 | biostudies-arrayexpress
Project description:The Göttingen Minipig is gaining ground as nonrodent species in safety testing of drugs for pediatric indications. Due to developmental changes in pharmacokinetics (PK) and pharmacodynamics (PD), physiologically-based pharmacokinetic (PBPK) models are built to better predict drug exposure in children and to aid species selection for nonclinical safety studies. These PBPK models require high quality physiological and PK/PD data such as protein abundance of drug metabolizing enzymes. These data are available for man and rat, but scarce for the Göttingen Minipig. The aim of this study was to assess hepatic cytochrome P450 (CYP) protein abundance in the developing Göttingen Minipig by using mass spectrometry. In addition, sex-related differences in CYP protein abundance and correlation of CYP enzyme activity with CYP protein abundance were assessed. The following age groups were included: gestational day (GD) 84 - 86 (n = 8), GD 108 (n = 6), postnatal day (PND) 1 (n = 8), PND 3 (n = 8), PND 7 (n = 8), PND 28 (n = 8) and adult (n = 8). Liver microsomes were extracted and protein abundance was compared to that in adult animals. Next, the CYP protein abundance was correlated to CYP enzyme activity in the same biological samples. In general, CYP protein abundance gradually increased during development. However, we observed a stable protein expression over time for CYP4A24 and CYP20A1 and for CYP51A1, a high protein expression during the fetal stages was followed by a decrease during the first month of life and an increase towards adulthood. Sex-related differences were observed for CYP4V2_2a and CYP20A1 at PND 1 with highest expression in females for both isoforms. In the adult samples, sex-related differences were detected for CYP1A1, CYP1A2, CYP2A19, CYP2E1_2, CYP3A22, CYP4V2_2a and CYP4V2_2b with higher values in female compared to male Göttingen Minipigs. The correlation analysis between CYP protein abundance and CYP enzyme activity showed that CYP3A22 protein abundance correlated clearly with the metabolism of midazolam at PND 7. These data are remarkably comparable to human data and provide a valuable step forward in the construction of a neonatal and juvenile Göttingen Minipig PBPK model.
2021-02-26 | PXD024158 | Pride
Project description:Using full-genome arrays, the expression of all XMEs was examined during fetal (gestation day (GD) 19), neonatal (postnatal day (PND) 7), prepubescent (PND30), middle age (12 mon), and old age (18 and 24 mon) in the C57Bl6/J mouse liver and compared to young adults. Fetal and neonatal life stages had a dramatic effect on XME expression compared to the relatively minor effects of old age. At all life stages except PND30 down-regulated genes outnumbered up-regulated genes. The altered XMEs included those in all of the major metabolic phases including phase I (alcohol and aldehyde dehydrogenase and Cyp genes), phase II (aldo-keto reductase, glutathione-S-transferases, sulfotransferases and UDP-glucuronosyl transferases) and phase III (transporters). We have generated a comprehensive catalog of XME hepatic gene changes through the life stages of the mouse that can be used to predict chemicals and chemical classes different life stages are more sensitive to. Some CEL files used in this study have been submitted through GSE21224. Keywords: gene expression/microarray We characterized gene expression changes in the developing mouse liver at gestational days (GD) 19), neonatal (postnatal day (PND) 7), prepubescent (PND30), middle age (12 mon), and old age (18 and 24 mon) in the C57Bl6/J mouse liver using full-genome microarrays and compared these changes to that in the adult liver.. We also compared results to GD19, PND32, and PND67 C3H mice. Total RNA was isolated from liver samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 28 samples, four mice in each of the age groups for C57BL/6 and C3H, were analyzed.
2010-10-01 | E-GEOD-21716 | biostudies-arrayexpress
Project description:Liver gene transcripts patterns were used to characterize toxicity from exposure to polybrominated diphenyl ethers (PBDEs), flame retardant components. In this study, Wistar Han dams were exposed by gavage to the PBDE mixture (DE71) starting at gestation day 6 (GD 6) and continuing to weaning on postnatal day 21 (PND 21). Offspring from the dams began PBDE direct dosing on PND 12 and were dosed daily through PND 21. After weaning, they were dosed 5 days per week for another 13 weeks. Liver samples were collected at PND 22 and week 13 for liver gene expression analysis and interrogated with the Affymetrix Rat Genome 230 2.0 Array. PBDE treatment induced 1,066 liver gene transcript changes in females and 1,200 transcriptional changes in males at PND 22 (false discovery rate (FDR) < 0.01), but only 263 liver transcriptional changes at 13 weeks in male rats (FDR <0.05). No significant differences in dose response were found between male and female pups.
2011-10-05 | GSE32156 | GEO
Project description:In the present study we investigate the effect of maternal pulmonary exposure to titanium dioxide (UV-Titan designed for use in the paint and lacquer industry) on prenatally exposed offspring. Time-mated mice (C57BL/6BomTac) were exposed by inhalation for 1 h/day to 42 mg UV-titan/m3 aerosolized powder or filtered air during gestation days (GD) 8-18. We evaluated levels of DNA strand breaks using the comet assay in bronchioalveolar lavage (BAL) cells and liver cells of the time-mated mice, and in liver cells of the offspring. In parallel, we analyzed changes in gene expression in the liver tissue of offspring using DNA microarrays. We demonstrate that UV-Titan did not induce DNA strand breaks in the time-mated mice or their offspring. Transcriptional profiling of newborn liver tissue revealed changes in the expression of genes related to the retinoic acid (RA) signalling pathway in the females, while gene expression in male offspring was relatively unaffected by exposure. Time-mated, nulliparous mice (C57BL/6BomTac, Taconic Europe, Ejby, Denmark) were exposed to filtered clean air or approximately 42 mg/m3 UV-Titan on GD 8M-bM-^@M-^S18 for 1 hr/day by a whole-body exposure.Delivery was expected on GD 20, and designated postnatal day (PND) 0. On PND 2, one offspring (M-bM-^@M-^\newbornM-bM-^@M-^]) per litter was killed by decapitation, to yield litters with at least 5 offspring per exposure group. The newborn offspring were collected two days after birth. On PND 23-24 (M-bM-^@M-^\at weaningM-bM-^@M-^]) one male and one female per litter were killed. Organs were dissected, weighed, placed in NUNC cryotubes, snap frozen in liquid N2 and stored at -80M-BM-0C until analysis. Exposed dams were killed on PND 24-25 (26-27 days after last exposure). DNA strad break detection was carried out in bronchoalveolar lavage fluid in dams by COMET assay. Total RNA was extracted from offspring livers and gene expression profiling was carried out on whole liver tissues from offspring. 9 UV-Titan treated and 7 controls mice consisting of 8 males and 8 females mRNA, hepatic, developmental, Toxicogenomics, nano-titanium dioxide
2012-03-19 | E-GEOD-29067 | biostudies-arrayexpress
Project description:Liver gene transcripts patterns were used to characterize toxicity from exposure to polybrominated diphenyl ethers (PBDEs), flame retardant components. In this study, Wistar Han dams were exposed by gavage to the PBDE mixture (DE71) starting at gestation day 6 (GD 6) and continuing to weaning on postnatal day 21 (PND 21). Offspring from the dams began PBDE direct dosing on PND 12 and were dosed daily through PND 21. After weaning, they were dosed 5 days per week for another 13 weeks. Liver samples were collected at PND 22 and week 13 for liver gene expression analysis and interrogated with the Affymetrix Rat Genome 230 2.0 Array. PBDE treatment induced 1,066 liver gene transcript changes in females and 1,200 transcriptional changes in males at PND 22 (false discovery rate (FDR) < 0.01), but only 263 liver transcriptional changes at 13 weeks in male rats (FDR <0.05). No significant differences in dose response were found between male and female pups. There were a total of 6 groups and 5x replication for each group, for 30 total samples that were analyzed. The groups were (1) pup-male-CTL, (2) pup-female-CTL, (3) pup-male-PBDE, (4) pup-female-PBDE, (5) rat-male-CTL, (6) rat-male-PBDE. We generated the following pairwise comparisons using R/maanova: malePups(PBDE vs CTL), femalePups(PBDE vs CTL), maleRats(PBDE vs CTL), CTLpups(male vs female), PBDEpups(male vs female). We also performed ANOVA test for SEX-by-DOSE (pups) and AGE-by-DOSE (males). For pups, genes with an FDR≤1% were selected; for rats, genes with FDR < 5% were selected.
2011-10-04 | E-GEOD-32156 | biostudies-arrayexpress
Project description:Background: Interindividual differences in liver functions such as protein synthesis, lipid and carbohydrate metabolism and drug metabolism are influenced by epigenetic factors. The role of the epigenetic machinery in such processes has, however, been barely investigated. 5-hydroxymethylcytosine (5hmC) is a recently re-discovered epigenetic DNA modification that plays an important role in the control of gene expression. Results: In this study, we investigate 5hmC occurrence and genomic distribution in 8 fetal and 7 adult human liver samples in relation to ontogeny and function. LC-MS analysis shows that in the adult liver samples 5hmc comprises up to 1% of the total cytosine content, whereas in all fetal livers it is below 0.125%. Immunohistostaining of liver sections with a polyclonal anti-5hmC antibody shows that 5hmC is detected in most of the hepatocytes. Genome-wide mapping of the distribution of 5hmC in human liver samples by next-generation sequencing shows significant differences between fetal and adult livers. In adult livers, 5hmC occupancy is overrepresented in genes involved in active catabolic and metabolic processes, whereas 5hmC elements which are found in genes exclusively in fetal livers and disappear in the adult state, are more specific to pathways for differentiation and development. Conclusions: Our findings suggest that 5-hydroxymethylcytosine plays an important role in the development and function of the human liver and might be an important determinant for development of liver diseases as well as of the interindividual differences in drug metabolism and toxicity. 8 fetal and 7 adult human liver samples
2013-07-29 | E-GEOD-49291 | biostudies-arrayexpress
Project description:Although the effects of thyroid hormones (TH) on the brain development have been extensively studied perinatally, effects of TH of maternal origin on the fetal brain development have been largely unexplored. We applied a high throughput study on the mouse models with aberrant TH levels on gestation day (GD) 16, before the onset of fetal thyroid function. Although 3 day treatment with methimazole (MMI) and perchlorate significantly decreased TH levels in fetal cerebral cortex, few changes in the abundance of mRNA were revealed by the microarray analysis. Injection TH to dams 12 hours before sacrifice on GD 16 induced 161 genes significantly changed in fetal cortex. Nine out of 10 selected genes were confirmed with RT-PCR, including known TH responsive gene Klf9 and other novel TH responsive genes such as Appbp2, Ppap2b and Fgfr1op2. TH regulation of the expression of these genes was also confirmed with cultured N2aβ cells. Thyroid responsive elements (TREs) in the promoters of these genes were identified using electrophoresis mobility shift assay. TH effect on microRNA (miRNA) expression in developing cortex on GD 16 and postnatal day (PND) 15 was investigated with microarray and RT-PCR. Some of miRNAs and precursors decreased in fetal cortex from the dams injected with TH on GD 16, including miR-16 and miR-106. Using 3’ untranslate region reporter vector, we identified Klf9 is one of the target genes of miR-106, while Ppap2b is the target of miR-16. These results indicated that TH regulation on gene expression could through TR-TRE interaction and through regulating target miRNA expression. This study is the first report to identify TH responsive genes and miRNAs genome wide in the early fetal brain; it provides evidence to further understand the mechanism of TH effect on brain development.
2014-02-04 | GSE43927 | GEO
Project description:Although the effects of thyroid hormones (TH) on the brain development have been extensively studied perinatally, effects of TH of maternal origin on the fetal brain development have been largely unexplored. We applied a high throughput study on the mouse models with aberrant TH levels on gestation day (GD) 16, before the onset of fetal thyroid function. Although 3 day treatment with methimazole (MMI) and perchlorate significantly decreased TH levels in fetal cerebral cortex, few changes in the abundance of mRNA were revealed by the microarray analysis. Injection TH to dams 12 hours before sacrifice on GD 16 induced 161 genes significantly changed in fetal cortex. Nine out of 10 selected genes were confirmed with RT-PCR, including known TH responsive gene Klf9 and other novel TH responsive genes such as Appbp2, Ppap2b and Fgfr1op2. TH regulation of the expression of these genes was also confirmed with cultured N2a? cells. Thyroid responsive elements (TREs) in the promoters of these genes were identified using electrophoresis mobility shift assay. TH effect on microRNA (miRNA) expression in developing cortex on GD 16 and postnatal day (PND) 15 was investigated with microarray and RT-PCR. Some of miRNAs and precursors decreased in fetal cortex from the dams injected with TH on GD 16, including miR-16 and miR-106. Using 3’ untranslate region reporter vector, we identified Klf9 is one of the target genes of miR-106, while Ppap2b is the target of miR-16. These results indicated that TH regulation on gene expression could through TR-TRE interaction and through regulating target miRNA expression. This study is the first report to identify TH responsive genes and miRNAs genome wide in the early fetal brain; it provides evidence to further understand the mechanism of TH effect on brain development. Timed-pregnant C57BL/6 mice (n=20; Harlan, Indianapolis, IN) arrived on gestational day (GD) 11 and were housed individually in plastic cages under a 12:12 light cycle (0600 h–1800 h) with food available ad libitum. Mice were divided randomly into one of 4 groups (control, hypo, hypo+ and hyper; 5 per group) . Mice in the control and hyper groups were provided with fresh drinking water containing 2% sucrose from GD 13 to GD 16 until sacrifice. Mice in hypo and hypo+ were provided with fresh drinking water daily containing 1% Perchlorate (Per) and 0.025% Methimazole (MMI) supplemented with 2% sucrose (to mask bitterness) from GD 13 to sacrifice on GD 16. Twelve hours prior to sacrifice on GD 16 all mice received a single subcutaneous injection. Control and hypo mice received vehicle (0.9% saline in 100 µl volume); the hypo+ group received 25.0 µg/100g body weight thyroxine (T4) with 2.5 µg/100g body weight T3 to restore a physiological level of TH; the hyper group received 100.0 µg/100g body weight T4 with 10.0 µg/100g body weight T3 to model hyperthyroidism. Dams were killed by exposure to CO2. Fetuses were dissected from the uterine horn and embryonic membranes then frozen on pulverized dry ice. Tissue samples were taken from the fetuses to determine sex using PCR for SRY (Yang J and RT Zoeller, 2002). Fetal cerebral cortices were removed from each mouse and used for microarray and RT-PCR analysis. Total RNA was extracted from half cortices of individual female fetuses using RNeasy Lipid tissue Mini kits (Qiagen, Germantown, MD) according to the manufacturer's instructions. The quality of total RNA was evaluated by A260/A280 ratio (found to be at least 1.8 for each sample) and by electrophoresis on the Agilent Bioanalyzer. The Yale Center for the Neuroscience Microarray Consortium carried out the Affymetrix microarray analysis using The GeneChip Rat Genome 230 2.0 Array. Preparation of labeled cRNA for hybridization onto Affymetrix GeneChips followed the recommended Affymetrix protocol. Control versus each of the three treatment groups: hyper, hypo, and hypo+. 1 of 20 samples removed due to poor quality.
2014-02-04 | E-GEOD-43927 | biostudies-arrayexpress
Project description:Background: Interindividual differences in liver functions such as protein synthesis, lipid and carbohydrate metabolism and drug metabolism are influenced by epigenetic factors. The role of the epigenetic machinery in such processes has, however, been barely investigated. 5-hydroxymethylcytosine (5hmC) is a recently re-discovered epigenetic DNA modification that plays an important role in the control of gene expression. Results: In this study, we investigate 5hmC occurrence and genomic distribution in 8 fetal and 7 adult human liver samples in relation to ontogeny and function. LC-MS analysis shows that in the adult liver samples 5hmc comprises up to 1% of the total cytosine content, whereas in all fetal livers it is below 0.125%. Immunohistostaining of liver sections with a polyclonal anti-5hmC antibody shows that 5hmC is detected in most of the hepatocytes. Genome-wide mapping of the distribution of 5hmC in human liver samples by next-generation sequencing shows significant differences between fetal and adult livers. In adult livers, 5hmC occupancy is overrepresented in genes involved in active catabolic and metabolic processes, whereas 5hmC elements which are found in genes exclusively in fetal livers and disappear in the adult state, are more specific to pathways for differentiation and development. Conclusions: Our findings suggest that 5-hydroxymethylcytosine plays an important role in the development and function of the human liver and might be an important determinant for development of liver diseases as well as of the interindividual differences in drug metabolism and toxicity.
2013-07-29 | GSE49291 | GEO