Genome‐wide analysis of DNA methylation changes induced by gestational arsenic exposure in liver tumors

• Published in: Cancer science 2013-12, Vol.104 (12), p.1575-1585
• Main Authors: Suzuki, Takehiro, Yamashita, Satoshi, Ushijima, Toshikazu, Takumi, Shota, Sano, Tomoharu, Michikawa, Takehiro, Nohara, Keiko
• Format: Article
• Language: English
• Subjects: Animals; Arsenic - toxicity; Base Sequence; Carcinogenesis - chemically induced; CpG Islands - genetics; DNA Methylation; Genome-Wide Association Study; Liver - drug effects; Liver - metabolism; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - metabolism; Male; Mice; Mice, Inbred C3H; Oligonucleotide Array Sequence Analysis; Original; Proto-Oncogene Proteins c-fos - biosynthesis; Proto-Oncogene Proteins c-fos - genetics; Sequence Analysis, DNA
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12298

Inorganic arsenic is known to be a human carcinogen. Previous studies have reported that DNA methylation changes are involved in arsenic‐induced carcinogenesis, therefore, DNA methylation changes that are specific to arsenic‐induced tumors would be useful to distinguish tumors induced by arsenic from tumors caused by other factors and to dissect arsenic carcinogenesis. Previous studies have shown that gestational arsenic exposure of C3H mice, which tend to spontaneously develop liver tumors, increases the incidence of tumors in male offspring. In this study we used the same experimental protocol as in those previous studies and searched for DNA regions where methylation status was specifically altered in the liver tumors of arsenic‐exposed offspring by using methylated DNA immunoprecipitation–CpG island microarrays. The methylation levels of the DNA regions selected were measured by quantitative methylation‐specific PCR and bisulfite sequencing. The results of this study clarified a number of regions where DNA methylation status was altered in the liver tumors in the C3H mice compared to normal liver tissues. Among such regions, we showed that a gene body region of the oncogene Fosb underwent alteration in DNA methylation by gestational arsenic exposure. We also showed that Fosb expression significantly increased corresponding to the DNA methylation level of the gene body in the arsenic‐exposed group. These findings suggest that the DNA methylation status can be used to identify tumors increased by gestational arsenic exposure. This study further revealed that the gene body region of the oncogene Fosb is highly methylated and its expression is greatly increased in the tumors of gestationally arsenic‐exposed mice in comparison with the tumors of control mice. These results suggest that DNA methylation changes are involved in the alteration in tumor phenotype by gestational arsenic exposure.