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Published on: May 4, 2016
Trichloroethylene-Induced DNA Methylation Changes in Male F344 Rat Liver
Yan Jiang1, Jiahong Chen1, Cong Yue1
1Department of Physiology, School of Biology and Basic Medical Sciences, ‡Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, §Department of Toxicology, School of Public Health, Soochow University , Suzhou 215123, China.
Abstract:
Trichloroethylene (TCE), a common environmental contaminant, causes hepatocellular carcinoma in mice but not in rats. To understand the mechanisms of the species-specific hepatocarcinogenecity of TCE, we examined the methylation status of DNA in the liver of rats exposed to TCE at 0 or 1000 mg/kg b.w. for 5 days using MeDIP-chip, bisulfite sequencing, COBRA, and LC-MS/MS. The related mRNA expression levels were measured by qPCR. Although no global DNA methylation change was detected, 806 genes were hypermethylated and 186 genes were hypomethylated. The genes with hypermethylated DNA were enriched in endocytosis, MAPK, and cAMP signaling pathways. We further confirmed the hypermethylation of Uhrf2 DNA and the hypomethylation of Hadhb DNA, which were negatively correlated with their mRNA expression levels. The transcriptional levels of Jun, Ihh, and Tet2 were significantly downregulated, whereas Cdkn1a was overexpressed. No mRNA expression change was found for Mki67, Myc, Uhrf1, and Dnmt1. In conclusion, TCE-induced DNA methylation changes in rats appear to suppress instead of promote hepatocarcinogenesis, which might play a role in the species-specific hepatocarcinogenecity of TCE.
Insights
Trichloroethylene (TCE) exposure alters DNA methylation in rat livers, affecting gene expression. These epigenetic changes may suppress, rather than promote, liver cancer, explaining species-specific differences in TCE carcinogenicity.
Area of Science:
- Environmental Toxicology
- Epigenetics
- Hepatocarcinogenesis Research
Background:
- Trichloroethylene (TCE) is a widespread environmental contaminant.
- TCE induces hepatocellular carcinoma in mice but not in rats, indicating species-specific effects.
- Understanding the epigenetic mechanisms behind TCE's differential carcinogenicity is crucial.
Purpose of the Study:
- To investigate the impact of TCE exposure on DNA methylation patterns in rat liver.
- To correlate DNA methylation changes with gene expression alterations.
- To elucidate the role of epigenetic modifications in the species-specific hepatocarcinogenicity of TCE.
Main Methods:
- Rats were exposed to TCE (1000 mg/kg b.w.) for 5 days.
- DNA methylation was analyzed using Methylated DNA Immunoprecipitation-chip (MeDIP-chip), bisulfite sequencing, COBRA, and LC-MS/MS.
- Messenger RNA (mRNA) expression levels were quantified by quantitative Polymerase Chain Reaction (qPCR).
Main Results:
- No global DNA methylation changes were observed, but 806 genes were hypermethylated and 186 were hypomethylated.
- Hypermethylated genes were enriched in pathways including endocytosis, MAPK, and cAMP signaling.
- Specific genes like Uhrf2 (hypermethylated) and Hadhb (hypomethylated) showed inverse correlation between DNA methylation and mRNA expression; Jun, Ihh, and Tet2 mRNA levels decreased, while Cdkn1a increased.
Conclusions:
- TCE exposure induces specific DNA methylation changes in rat liver, without global alterations.
- These epigenetic modifications appear to suppress hepatocarcinogenesis in rats.
- DNA methylation may be a key factor contributing to the observed species-specific differences in TCE-induced liver cancer.
