Toxicological sciences : an official journal of the Society of Toxicology 20091007 1
To understand the molecular mechanisms underlying compound-induced hemangiosarcomas in mice, and therefore, their human relevance, a systems biology approach was undertaken using transcriptomics and Causal Network Modeling from mice treated with 2-butoxyethanol (2-BE). 2-BE is a hemolytic agent that induces hemangiosarcomas in mice. We hypothesized that the hemolysis induced by 2-BE would result in local tissue hypoxia, a well-documented trigger for endothelial cell proliferation leading to hema ...[more]
Project description:Furan is a mouse and rat hepatocarcinogen. We sought to determine the dose-dependent changes in gene expression upon exposure of B6C3F1 mice to furan in order to better understand furan’s mode of action. In this study we examined the transcriptional response in liver tissue of female B6C3F1 mice to BrdU treatment (in drinking water for 5 days before sacrifice). This was a toxicogenomic study in which mice were also exposed to 0, 1 or 8 mg/kg bw furan (by oral gavage) for 3 weeks. Mice were sacrificed four hours after the final furan exposure. Each dose group had 4-5 biological replicates. We used a two-colour reference design and SurePrint G3 Mouse GE 8x60K microarrays (Agilent). Please note that data for all non-BrdU treated animals was previously reported in GEO [GSE48644]. All samples (with or without BrdU) were part of the same randomized block design for the microarrays.
Project description:Susceptibility to the hepatocarcinogen Aflatoxin B1 (AFB1) varies among species and with age. Mice are refractory to carcinogenic and toxic effects of AFB1; however, B6C3F1 mice show transient sensitivity if dosed shortly after birth. We compared age-related differences in gene expression and transcriptional responses to AFB1 in livers of newborn (4-day-old) and adult mice. Experiment Overall Design: Experiments were carried out under the protocol approved by MIT Animal Care Committee. Pregnant C57BL/6J female mice, mated to C3H/HeJ males, and adult (at least 60 day-old) B6C3F1/J hybrid F1 male mice (C57BL/6J female x C3H/HeJ male) were obtained from Jackson Labs. They were housed in plastic cages (one per cage) under controlled environmental conditions and 12 h light/dark cycle. Food and water were supplied ad libitum. After female mice gave birth, the male B6C3F1 pups were dosed at 4 days by a single i.p. injection of AFB1 (6 mg/kg body weight) in DMSO (10 ml/kg body weight) or the same volume of just DMSO. The treatments were always performed at the same time of the day and the pups were returned to their mothers until they were sacrificed 4 or 24 h after treatment. Adult B6C3F1 males were treated with the same doses and volumes of AFB1 or DMSO after an acclimation period of at least two weeks and sacrificed 4 or 24 hours after treatment. We noticed that injection of a volume of 10 ml/kg (whether AFB1 or vehicle alone) is tolerated poorly by adult animals and thus another group of adult animals was added which was treated with the same (6 mg/kg) dose of AFB in lower (5 ml/kg) volume. Corresponding vehicle control animals (5ml/kg DMSO) were also used. In addition, untreated controls were used and sacrificed together with the treated animals. Three independant bilogical replicates were used for each experimental point. Total RNA was isolated from livers and processed according to standard Affymetrix protocol.
Project description:This SuperSeries is composed of the following subset Series: GSE34423: Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice [Expression array]. GSE34462: Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice [MeDIP array]. Refer to individual Series
Project description:Vinylidene Chloride has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increase in renal cell hyperplasias, adenomas, and carcinomas (RCCs). Global gene expression analysis showed overrepresentation of pathways associated with chronic xenobiotic and oxidative stress in RCCs from VDC-exposed B6C3F1 mice, as well as cMyc overexpression and dysregulation of Tp53 cell cycle checkpoint and DNA damage repair pathways. Trend analysis comparing RCC, VDC-exposed kidney, and vehicle control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the development of RCC in VDC-exposed mice. Compare mouse renal cell carcinoma versus treated kidney and vehicle control normal kidney, 6 replicates each group.