Category: the National Nature Science Foundation of China PI: Zhang Jie Execution time: 2015.01-2017.12 Arsenic pollution has become a global problem, and the contaminated groundwater is one of the major sources of arsenic exposure. Epidemiological and in-vivo studies have proved the long term exposure to arsenic induced damage to central nervous system of children and adolescents. DNA epigenetic change is considered an important mechanism of chronic arsenic poisoning. However, so far the adverse effects and the specific molecular mechanism of arsenic exposure on DNA epigenetic modification in brain tissues remained unclear. Arsenic is proven to alter DNA methylation at both the genome-wide and gene-specific levels. Previous epigenetic studies focused on the liver and DNA methylation process. Few reports have addressed arsenic toxicity on DNA demethylation process in brain. Our preliminary study found that low-dose arsenic exposure via drinking water induced the tissue-specific changes of 5mC and 5hmC levels in rat brain, suggesting that arsenic would affect DNA epigenetic processes in brain and its toxicity may be tissue specific. On the basis of previous reports and our preliminary study, this project intends to investigate the influence of arsenic exposure on DNA epigenetic modification in hippocampus and cortex of young rats. Firstly, young rats are exposed to arsenic via drinking water (0.05 ppm, 0.5ppm, 5ppm and 50 ppm) for 24 or more weeks, and then evaluate their learning and memory ability using Morris water maze and slice electrophysiology method. The DNA methylation and hydroxymethylation of total genome and promoter regions of featured learning and memory –related genes were measured for hippocampus and cortex. Furthermore, we aims to study the DNA epigenetic mechanism of arsenic exposure on hippocampus and cortex from the levels of DNA methylation and demethylation processes: investigate the interaction of arsenic methylation and DNA methylation via the consumption of the same methyl donor SAM; investigate and verify the hypothesis that arsenic exposure may induce oxidative stress and consequently influence the DNA demethylation process; systematically investigate the interaction network of arsenic methylation, DNA methylation, DNA demethylation, oxidative stress and tricarboxylic acid cycle in brain tissues, finally reveal the DNA epigenetic molecular mechanism of arsenic exposure in hippocampus and cortex.