Decrease of 5-hydroxymethylcytosine in rat liver with subchronic exposure to genotoxic carcinogens riddelliine and aristolochic acid
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In Vivo Alkaline Comet Assay and Enzyme-modified Alkaline Comet Assay for Measuring DNA Strand Breaks and Oxidative DNA Damage in Rat Liver
Published on: May 4, 2016
Christine Guo Lian1, Shuyun Xu1, Weimin Guo1
1Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Abstract:
The level of 5-hydroxymethylcytosine (5-hmC) converted by ten-eleven translocation (TET) family is decreased in cancers. However, whether 5-hmC level is perturbed in early stages of carcinogenesis caused by genotoxic carcinogens is not defined. 5-hmC levels and TET2 expression were measured in liver of rats treated with genotoxic carcinogens, riddelliine, or aristolochic acid. Levels of 5-hmC and TET2 expression decreased in the liver of the carcinogens-treated rats. Loss of 5-hmC correlates well with documented induction of genetic mutations by the carcinogens, suggesting that TET2-mediated 5-hydroxymethylation plays an epigenetic role in early state of carcinogenesis.
Insights
Levels of 5-hydroxymethylcytosine (5-hmC) and TET2 expression decreased in rat livers exposed to genotoxic carcinogens. This epigenetic alteration suggests a role for TET2-mediated 5-hydroxymethylation in early carcinogenesis.
Area of Science:
- Epigenetics
- Cancer Biology
- Toxicology
Background:
- 5-hydroxymethylcytosine (5-hmC) levels are reduced in established cancers.
- The role of 5-hmC in the early stages of carcinogenesis induced by genotoxic agents remains unclear.
Purpose of the Study:
- To investigate the impact of genotoxic carcinogens on 5-hmC levels and TET2 expression in early carcinogenesis.
- To determine if alterations in 5-hmC are associated with carcinogen-induced genetic mutations.
Main Methods:
- Rats were treated with genotoxic carcinogens (riddelliine or aristolochic acid).
- Liver tissues were analyzed for 5-hmC levels and TET2 expression.
Main Results:
- Both 5-hmC levels and TET2 expression were significantly decreased in the livers of carcinogen-treated rats.
- The observed loss of 5-hmC correlated with the induction of genetic mutations by the carcinogens.
Conclusions:
- Genotoxic carcinogens disrupt TET2-mediated 5-hydroxymethylation in the early stages of carcinogenesis.
- Epigenetic modifications, specifically the loss of 5-hmC, may play a crucial role in the initial development of cancer.
