Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of hepatitis development and hepatocarcinogenesis initiation in LEC rats.

ABSTRACT: LEC rats are considered as interesting model for studying hepatitis and development of hepatocarcinogenesis related to copper accumulation and oxidative stress. LEC rats have a mutation in a gene related to liver copper excretion, the Atp7b gene. As a consequence, this rat strain shows an abnormal copper accumulation in the liver. This is believed to be the origin of the acute hepatitis and the subsequent hepatocellular carcinoma that spontaneously develop in these rats. Here, we present the gene expression profiles of LEC rats at different disease stages. LEC rats were classified as normal 6 weeks old (6w), normal 9 weeks old (9w), slight jaundice and jaundice according to age and disease state. D-penicillamine, a copper chelator agent, blocks both hepatitis and tumor development. D-penicillamine-trated LEC rats were used as control rats for gene expression comparison as they showed neither hepatitis development nor tumor marker expression. Gene expression differences in protein metabolism and tumor marker proteins add to the known oxidative stress and inflammation characterization of the hepatitis process, leading to new insights concerning hepatitis and hepatocarcinogenesis development. Keywords: disease state analysis 6 weeks old LEC rats, 6 rats per group, were sacrified at different hepatitis stages. Biochemical and histological analyses were performed in order to classify the rats into normal, slight jaundice or jaundice groups. D-penicillamine-treated LEC rats (100 mg/kg/day p.o.) were used as control rats since they behave as normal rats. Microarray analysis was performed on liver samples, one replicate per rat, using dyes swap.

ORGANISM(S): Rattus norvegicus

SUBMITTER: FranÃ§oise GuÃ©raud

PROVIDER: E-GEOD-7654 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 M-BM-5g Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week).

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Gene expression profiling of hepatitis development and hepatocarcinogenesis initiation in LEC rats.

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