an integrated functional genomic study of acute phenobarbital exposure in the rat一个集成的功能基因组研究急性暴露于苯巴比妥老鼠.pdfVIP

Waterman et al. BMC Genomics 2010, 11:9 /1471-2164/11/9 RESEARCH ARTICLE Open Access An integrated functional genomic study of acute phenobarbital exposure in the rat 1 2,3 2,3 2,3 2,3 2,3 Claire L Waterman , Richard A Currie , Lisa A Cottrell , Jacky Dow , Jayne Wright , Catherine J Waterfield , Julian L Griffin 1* Abstract Background: Non-genotoxic carcinogens are notoriously difficult to identify as they do not damage DNA directly and have diverse modes of action, necessitating long term in vivo studies. The early effects of the classic rodent non-genotoxic hepatocarcinogen phenobarbital have been investigated in the Fisher rat using a combination of metabolomics and transcriptomics, to investige early stage mechanistic changes that are predictive of longer term pathology. Results: Liver and blood plasma were profiled across 14 days, and multivariate statistics used to identify perturbed pathways. Both metabolomics and transcriptomics detected changes in the liver which were dose dependent, even after one day of exposure. Integration of the two datasets associated perturbations with specific pathways. Hepatic glycogen was decreased due to a decrease in synthesis, and plasma triglycerides were decreased due to an increase in fatty acid uptake by the liver. Hepatic succinate was increased and this was associated with increased heme biosynthesis. Glutathione synthesis was also increased, presumably in response to oxidative stress. Liquid Chromatography Mass Spectrometry demonstrated a remodeling of lipid species, possibly resulting from proliferation of the smooth endoplasmic reticulum. Conclusions: The data fusion of metabolomic and transcriptomic changes proved to be