Project description:Seven male C57BL/6 mice, at 10 weeks of age, were injected daily intraperitoneally with 0.5 mg/kg of haloperidol, for 28 days. A control group of six animals was injected with vehicle only (saline).
Project description:Gene expression training data set from rat blood samples exposed to either 150, 1500 or 2500 mg/kg of APAP for 6, 12 or 24 hours. Experiment Overall Design: Male F344/N rats, 10-12 weeks old, were exposed to 0 (vehicle only), 150, 1500 or 2500 mg/kg APAP in 0.5% ethyl cellulose by oral gavage in two doses to increase absorption. The animals were sacrificed after 6, 12 or 24 hours. Equal amounts of RNA from the blood from each of four vehicle-only treated animals at the 6 and 12 hour time point and from each of six vehicle-only treated animals at the 24 hour time point, were pooled for control gene expression. The pooled controls were compared with individual treated animals at each dose and time period. The samples were hybridized in duplicate for each individual rat for a total of 8 (exception due to insufficient RNA quality: 150 mg/kg APAP and 1500 mg/kg APAP at 12 hour time point only 3 animals) microarray chips per dose and time period. Experiment Overall Design: Experiments were performed according to the guidelines established in the NIH Guide for the Care and Use of Laboratory Animals and an approved Animal Study Protocol was on file prior to initiation of the study.
Project description:To investigate the potential role of peroxisome proliferator activated receptor–alpha (PPARa) activation in mice, RNA sequencing was conducted on paraffin-embedded liver sections from a 90-day toxicity study of GenX conducted in mice. the TempO-Seq platform was utilized for RNA sequencing data collection. Differentially expressed genes were identified for each treatment group, and gene set enrichment analysis was conducted using gene sets that represent biological processes and known canonical pathways. Significant enrichment of peroxisome signaling was evident in males and females exposed to 0.5 and 5 mg/kg GenX, with no enrichment at 0.1 mg/kg. PPAR signaling and fatty acid metabolism were among the most significantly enriched gene sets, and two gene sets specific to the PPARa subtype were also significantly enriched.
Project description:Toxicogenomics (tgx) is used as a tool to identify mechanisms and markers of necrosis in C57BL/6 mice treated by oral gavage using acetaminophen (APAP), isoniazid (INZ), and paraquat (PQ). Critical doses for tgx analysis were derived from a 25 day dose range finding study. For tgx analysis, livers of mice were collected 1 and 2 days after a single compound dose of 168.75, 225, and 300 mg/kg bw for APAP; 12.5, 25, and 50 mg/kg bw for PQ; and 22, 44, and 88 mg/kg bw for INZ. All samples were diluted in water.
Project description:<p>Individuals with Urea Cycle Disorders (UCD) cannot remove ammonia, a waste product, from the blood. At present there is little information on the use of sodium phenylbutyrate (Buphenyl™) in children with argininosuccinic aciduria (ASA). It is hoped that this drug may help lower ammonia and argininosuccinic acid levels in patients with ASA. Through this study we hope to learn whether the use of sodium phenylbutyrate (Buphenyl™) in patients with ASA, in addition to diet and arginine therapy, will decrease liver damage and the number of periods during which ammonia levels are high.</p> <p>The primary study objective is to determine if the treatment of ASA patients with sodium phenylbutyrate (Buphenyl™) in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production.</p> <p>Twelve patients with ASA will be studied using a randomized, cross-over design. Medical records will be reviewed to confirm the diagnosis prior to enrollment. Patients will be on the each arm of the study for one week each preceded by a three day washout period. Patients will come to the Baylor College of Medicine General Clinical Research Center in Texas Children's Hospital for an inpatient hospitalization. This hospitalization is for diet control, clinical evaluation, and stable isotope infusions for measurement of in vivo rates of ureagenesis and nitric oxide production. During the washout periods Buphenyl™ or other alternative route medications, e.g., benzoate, will be discontinued and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/m2. </p> <p>Following randomization, subjects will be maintained on either high-dose arginine (500 mg/kg/day or 10 grams/m2) alone, or the alternative of low-dose arginine (100 mg/kg/d or 2 grams/m2) along with sodium phenylbutyrate (500 mg/kg/day or 10 grams/m2). For the second week they will be crossed over to the other arm of the study preceded by another three day washout. Previous medications and dietary protein intake (0.6 g/kg/day or current metabolic diet) will be continued during both arms of the study. The two arms may be performed as separate ten-day admissions.</p> <p>The decision to design the study with two arms, high-dose arginine and low-dose arginine/Buphenyl™, was reached after weighing several considerations. First, the current accepted practice for treatment of ASA is high-dose arginine. Based on metabolic flux studies, we have quantified the effects of this dose of arginine as compared to standard doses of Buphenyl™/phenylacetate on ureagenesis. Since the study is not designed or intended to address the independent effects of Buphenyl™ as compared to arginine alone, Buphenyl™ was added for safety reasons to accommodate loss of clearance of nitrogen by decreasing the arginine dose.</p> <p>Moreover, based on our experience with recruiting for previous versions of this study, most ASA patients with liver dysfunction are on an alternative route ammonia scavenger medication in addition to arginine. We found that this has in fact become an accepted practice.</p> <p>Hence, when considering study design from both a safety and recruitment perspective, it was most reasonable to design the study to investigate specifically the hypothesis that the production and presence of argininosuccinic acid leads to liver dysfunction. Since both low-dose arginine with Buphenyl™ and high-dose arginine alone lead to a decreased production of argininosuccinic acid, and both are currently accepted therapies in ASA and UCDs in general, the need to address their effects distinctly is not being investigated at this time.</p> <p>Sodium phenylbutyrate dosage will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients. Daily dosage will be given in equally divided doses 4 times per day. In order to ensure that the study remains double-blind to investigators, study staff and subjects, the Investigational Pharmacy Service at Texas Children's Hospital will dispense both the Buphenyl™ and arginine in powder form which is compounded into capsules or will be mixed with syrpalta (up to 5 grams will dissolve in 10cc liquid) and administered orally or through nasogastric or gastrostomy tube. No nasogastric tube should be placed or gastrostomy performed solely for the purpose of inclusion in this study. Because the reported adverse effects of sodium phenylbutyrate include gastritis, participants will be started on a standard dose of ranitidine (Zantac™), or comparable drug, during both arms of the study. </p>
Project description:Toxicogenomics (tgx) is used as a tool to identify mechanisms and markers of steatosis in C57BL/6 mice treated by oral gavage using amiodarone (AMD), valproic acid (VPA), and tetracycline (TET). Critical doses for tgx analysis were derived from a 25 day dose range finding study. For tgx analysis, livers of mice were collected after 1, 4, and 11 days of repeated treatment with 6.7, 20, and 60 mg/kg bw for AMD; 125, 250, and 500 mg/kg bw for VPA; and 14.8, 44, and 133 mg/kg bw for TET.
Project description:The goal of this study was to provide insights into the adverse outcome pathways that underlie the liver tumor effects of androstenedione in the mouse liver by comparing gene expression patterns to two liver noncarcinogens, ethinyl estradiol and prednisone. B6C3F1 male mice were exposed for 7 days to control diet or diet containing ethinyl estradiol (EE2) at 1, 2.5, 5, or 10 ppm or prednisone (PRED) at 1.25, 2.5, 5, 25 ppm. Androstenedione (A4) was administered in 0.5% carboxymethyl cellulose by gavage at 2, 10, 20, and 50 mg/kg/day. Separate groups of mice were exposed to 50 mg/kg/day A4, 10 ppm EE2 or 25 ppm PRED for 28 days.
Project description:Genome-wide gene expression assay was used to map the genes affected in the liver of Atlantic cod treated with the persistent environmental pollutant polychlorinated biphenyl 153 (PCB 153) (0.5, 2 and 8 mg/kg body weight).