ONTOLOGY SOURCE REFERENCE
Term Source Name	"CHEBI"	"BTO"	"NCBITAXON"	"PATO"	"NCIT"	"MP"	"PR"	"XCO"	"UO"	
Term Source File	"http://data.bioontology.org/ontologies/CHEBI"	"http://data.bioontology.org/ontologies/BTO"	"http://data.bioontology.org/ontologies/NCBITAXON"	"http://data.bioontology.org/ontologies/PATO"	"http://data.bioontology.org/ontologies/NCIT"	"http://data.bioontology.org/ontologies/MP"	"http://data.bioontology.org/ontologies/PR"	"http://data.bioontology.org/ontologies/XCO"	"http://data.bioontology.org/ontologies/UO"	
Term Source Version	"78"	"20"	"2"	"160"	"24"	"273"	"56"	"33"	"42"	
Term Source Description	"Chemical Entities of Biological Interest Ontology"	"BRENDA Tissue and Enzyme Source Ontology"	"National Center for Biotechnology Information (NCBI) Organismal Classification"	"Phenotypic Quality Ontology"	"National Cancer Institute Thesaurus"	"Mammalian Phenotype Ontology"	"Protein Ontology"	"Experimental Conditions Ontology"	"Units of Measurement Ontology"	
INVESTIGATION
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INVESTIGATION PUBLICATIONS
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INVESTIGATION CONTACTS
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STUDY
Study Identifier	"E-GEOD-49195"
Study Title	"Gene expression profiling of liver tissue from lean (WT) and obese (ob/ob) mice following a chronic exposure of low doses of pharmaceuticals"
Study Description	"Transcriptional profoling of mouse liver after a 4-month course of a mixture of 11 different drugs at low concentration. [original description: BACKGOUND: Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can have harmful consequences for the liver, especially in the context of obesity. OBJECTIVES: To determine whether chronic, low dose exposure to pharmaceuticals could have deleterious effects in livers of lean and obese mice. METHODS: Lean and ob/ob male mice (5-week-old) were treated for 4 months with a mixture of 11 drugs (acetaminophen, caffeine, carbamazepine, cotinine, diclofenac, erythromycin, ibuprofen, phenazone, roxithromycin, salicylic acid and sulfamethoxazole) provided in drinking water at a concentration of 1 mg/L (for each drug). At the end of the treatment, investigations were performed in liver and plasma. RESULTS: Some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 1 mg/L of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals indicated that expression of 8 different circadian genes was significantly modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 100-1,000 ng/L. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were confirmed in an independent study performed in female mice. CONCLUSIONS: Chronic, low dose exposure to pharmaceuticals disturbed hepatic expression of circadian genes, especially in obese mice. Because some of the 11 drugs can be found in the drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, in particular for obese individuals exposed to these contaminants. C57BL/6J lean and ob/ob male mice (5-week-old) were treated for 4 months with a mixture of 11 drugs provided in drinking water at a concentration of 1 mg/L (for each drug). 4 groups were designed: untreated versus treated WT and ob/ob mice (n=6 mice per group).]"
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Study Public Release Date	"2014-03-04"
Study File Name	"s_E-GEOD-49195_study_samples.txt"
STUDY DESIGN DESCRIPTORS
Study Design Type	"transcription profiling by array"
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STUDY FACTORS
Study Factor Name	"dose"	"genotype"
Study Factor Type	"dose"	"genotype"
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STUDY ASSAYS
Study Assay File Name	"a_E-GEOD-49195_GeneChip_assay.txt"
Study Assay Measurement Type	"transcription profiling"
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Study Assay Technology Type	"DNA microarray"
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STUDY PROTOCOLS
Study Protocol Name	"P-GSE49195-3"	"P-GSE49195-2"	"P-GSE49195-4"	"P-GSE49195-5"	"P-GSE49195-6"	"P-GSE49195-7"	"P-GSE49195-1"
Study Protocol Type	"growth protocol"	"sample treatment protocol"	"nucleic acid extraction protocol"	"labeling protocol"	"hybridization protocol"	"array scanning protocol"	"normalization data transformation protocol"
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Study Protocol Description	"Five-week-old male C57BL/6J-+/+ mice (wild-type, also referred to as lean mice) weighing 19 to 20 g and C57BL/6J-ob/ob mice, weighing 28 to 32 g, and were purchased from Janvier (Le-Genest-St-Isle, France) and housed in the animal house facility of Rennes 1 University under a 12 h light-dark cycle. All mice were fed ad libitum on a normal diet bringing 2820 kcal per kg of food (A04 biscuits; UAR, Villemoisson-sur-Orge, France)."	"After 1 week of acclimatization, mice were further split into 4 subgroups (n=6 mice per group) that were treated or not with a mixture of 11 drugs at a concentration of 1 mg/L (for each drug). All these drugs (acetaminophen, caffeine, carbamazepine, cotinine, diclofenac, erythromycin, ibuprofen, phenazone, roxithromycin, salicylic acid and sulfamethoxazole) were purchased from Sigma-Aldrich (St. Quentin-Fallavier, France). Considering the molecular weight of the molecules, 1 mg/L corresponded to concentrations ranging from 1.2 µmol/L for roxithromycin to 7.2 µmol/L for salicylic acid. Mice were exposed during 4 months to these drugs by way of the drinking water, which was renewed every week."	"Mice were then sacrificed by cervical dislocation and liver was quickly removed. While a majority of the liver fragments were immediately frozen in liquid nitrogen some of them were rapidly processed for appropriate histological staining. Collected tissues frozen in liquid nitrogen were subsequently stored at -80°C until total RNA extraction. All experiments were performed according to national guidelines for the use of animals in biomedical research and approved by the local Ethics Committee in Animal Experiment of Rennes 1 University and Robert DebrĂ© Hospital. Total RNA was extracted from liver samples using a standard RNA extraction protocol (Trizol) and quality-checked with an Agilent 2100 Bioanalyzer platform. All RNA samples revealed RNA Integrity Number (RIN) values between 7.2 and 8"	"Total RNA was amplified and labeled with Cy3 fluorescent dye using Agilent one color low-input QuickAmp labeling kit following according to the manufacturer's instructions. Starting material was 1µg of total RNA. Dye incorporation and cRNA yield were checked with the NanoDrop ND-1000 Spectrophotometer."	"The hybridization procedure was performed according to the Agilent 60-mer oligo microarray processing protocol using the Agilent Gene Expression Hybridization Kit (Agilent Technologies). Briefly, 1.65 ÎĽg Cy3-labeled fragmented cRNA was hybridized overnight (17 hours, 65 °C) to Agilent Whole Mouse Genome Oligo Microarrays 4x44K using Agilent’s recommended hybridization chamber and oven. Microarrays were then washed once with the Agilent Gene Expression Wash Buffer 1 for 1 min at room temperature followed by a second wash with preheated Agilent Gene Expression Wash Buffer 2 (37 °C) for 1 min. The last washing step was performed with acetonitrile. Finally, fluorescence signals of the hybridized Agilent Microarrays were detected using Agilent’s Microarray Scanner System (Agilent Technologies)."	"Slides were scanned immediately after washing on the Agilent DNA Microarray C Scanner (G2505C) using one color scan setting for 4x44k array slides (scan resolution 5µm)."	"The scanned images were analyzed with Feature Extraction Software version 10.5.1.1 (Agilent Technologies) using default parameters (protocol GE1_105_Jan09 and Grid: 014868_D_F_20070820). Gene expression data were further analyzed by using the GeneSpring software (Agilent Technologies). Normalization was performed with the 75th percentile shift algorithm. A baseline transformation to the median of all samples was applied. Filtration by flag and signal intensity was applied. Briefly, were retained only the entities in which at least 50% of the values had a detected flag (i.e. a positive and significant feature as defined by GeneSpring). For the filtration by signal intensity, were retained the entities in which at least 50% of the values were within the range of interest (i.e. 40-100th percentile). ID_REF =  VALUE = Normalized signal intensity"
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STUDY CONTACTS
Study Person Last Name	"Coulouarn"	"Coulouarn"	"Fromenty"
Study Person First Name	"Cedric"	"Cedric"	"Bernard"
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Study Person Email	"cedric.coulouarn@inserm.fr"	""	""
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Study Person Address	"U991, INSERM, HĂ´pital Pontchaillou, Rennes, France"	""	""
Study Person Affiliation	"INSERM"	""	""
Study Person Roles	"submitter"	""	""
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