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Global DNA methylation in the mouse liver is affected by methyl deficiency and arsenic in a sex-dependent manner

  • Molecular Toxicology
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Abstract

Arsenic, a carcinogen, is assumed to induce global DNA hypomethylation by consuming the universal methyl donor S-adenosylmethionine (SAM) in the body. A previous study reported that a methyl-deficient diet (MDD) with arsenic intake greatly reduced global DNA methylation (the content of 5-methylcytosine) in the liver of male C57BL/6 mice. In the present study, we investigated the DNA methylation level, SAM content, and expression of DNA methyltransferases (DNMTs) in the liver of male and female C57BL/6 mice fed a methyl-sufficient diet (MSD), an MDD, or an MDD + arsenic. The DNA methylation level was accurately determined by measuring the content of genomic 5-methyldeoxycytidine (5medC) by high-performance liquid chromatography/electrospray ionization mass spectrometry (LC/ESI–MS) using stable-isotope-labeled 5medC and deoxycytidine (dC) as internal standards. The results of this study revealed that while the MDD and arsenic tended to reduce the genomic 5meC content in the male mice livers, the MDD + arsenic significantly increased the 5meC content in the female mice livers. Another unexpected finding was the small differences in 5meC content among the groups. The MDD and MDD + arsenic suppressed DNMT1 expression only in the male mice livers. In contrast, SAM content was reduced by the MDD and MDD + arsenic only in the livers of female mice, showing that the changes in 5meC content were not attributable to SAM content. The sex-dependent changes in 5meC content induced by methyl deficiency and arsenic may be involved in differences in male and female susceptibility to diseases via epigenetic modification of physiological functions.

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Acknowledgments

This work was supported by the National Institute for Environmental Studies [0406AG337] and the Ministry of the Environment Japan [Environment Technology Development Fund, S-01]. We wish to thank Ms. Sayuri Itaki for her excellent secretarial assistance and Ms. Kimiyo Nagano for her superior technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, 305-8506, Japan

    Keiko Nohara, Takashi Baba, Hikari Murai, Yayoi Kobayashi, Takehiro Suzuki, Yukiyo Tateishi & Michiyo Matsumoto

  2. Research Center for Environmental Risk, National Institute for Environmental Studies, Tsukuba, 305-8506, Japan

    Noriko Nishimura

  3. Laboratory of Intellectual Fundamentals for Environmental Studies, National Institute for Environmental Studies, Tsukuba, 305-8506, Japan

    Tomoharu Sano

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  1. Keiko Nohara
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  2. Takashi Baba
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Correspondence to Keiko Nohara.

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Nohara, K., Baba, T., Murai, H. et al. Global DNA methylation in the mouse liver is affected by methyl deficiency and arsenic in a sex-dependent manner. Arch Toxicol 85, 653–661 (2011). https://doi.org/10.1007/s00204-010-0611-z

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  • DOI: https://doi.org/10.1007/s00204-010-0611-z

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