Transcription profiling of mouse liver from female MRL +/+ animals to assess toxicity of dichloroacetyl chloride and dichloroacetic anhydride

ABSTRACT: Dichloroacetyl chloride (DCAC) is a metabolic intermediate of trichloroethene (TCE), an industrial chemical and ubiquitous environmental contaminant. TCE and its metabolites have been implicated in the induction of organ-specific and systemic autoimmunity, in the acceleration of autoimmune responses, and in the development of liver toxicity. In humans, effects of environmental toxicants are often multifactorial and detected only after long-term exposure. Therefore, we developed a small-animal model to determine mechanisms by which DCAC and related acylating agents affect liver disease. Autoimmune-prone female MRL +/+ mice were injected i.p. with 0.2 mmole/kg of DCAC or the acylating agent dichloroacetic anhydride (DCAA) in corn oil twice weekly for six weeks. We then determined changes in the liver transcriptome using microarray gene expression analysis. After exposure to DCAC or DCAA, we observed changes in liver gene expression consistent with inflammatory processes. Both toxicants up-regulated expression of acute phase response and inflammatory genes. Further, metallothionein genes were strongly up-regulated, indicating effects of the toxicants on zinc ion homeostasis and stress responses. In addition, DCAC and DCAA induced up-regulation of several genes indicative of tumorogenesis. Microarray gene expression analysis using a restricted set of genes could be a valuable tool to screen for early changes in liver function following suspected exposure to environmental toxicants. Experiment Overall Design: Animals: Four-week-old female MRL +/+ mice were purchased from Jackson Laboratory (Bar Harbor, ME) and housed in an animal room maintained at ~22°C and 50-60% relative humidity with a 12-h light/dark cycle. Lab chow and drinking water was provided ad libitum, and mice were acclimatized for one week before starting the treatment. Mice were injected intraperitoneally with 0.2 mmol/kg of DCAC or DCAA in 100 µl of corn oil twice weekly for six weeks. Control animals received only corn oil. Mice were sacrificed 24 h after the last treatment. Experiment Overall Design: Samples: Livers from three mice per group were independently processed. The integrity of the RNA samples was tested using an Agilent 2100 Bioanalyzer and RNA 6000 LabChip® kit (Agilent Technologies, Palo Alto, CA). Only RNA samples without signs of degradation were used. Comprehensive gene expression profiles were analyzed.

ORGANISM(S): Mus musculus

SUBMITTER: Rolf Konig 

PROVIDER: E-GEOD-5241 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress