Putative Epimutagens in Maternal Peripheral and Cord Blood Samples Identified Using Human Induced Pluripotent Stem Cells

Yoshikazu Arai, Koji Hayakawa, Daisuke Arai, Rie Ito, Yusuke Iwasaki, Koichi Saito, Kazuhiko Akutsu, Satoshi Takatori, Rie Ishii, Rumiko Hayashi, Shun Ichiro Izumi, Norihiro Sugino, Fumio Kondo, Masakazu Horie, Hiroyuki Nakazawa, Tsunehisa Makino, Mitsuko Hirosawa, Kunio Shiota, Jun Ohgane

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Abstract

The regulation of transcription and genome stability by epigenetic systems are crucial for the proper development of mammalian embryos. Chemicals that disturb epigenetic systems are termed epimutagens. We previously performed chemical screening that focused on heterochromatin formation and DNA methylation status in mouse embryonic stem cells and identified five epimutagens: diethyl phosphate (DEP), mercury (Hg), cotinine, selenium (Se), and octachlorodipropyl ether (S-421). Here, we used human induced pluripotent stem cells (hiPSCs) to confirm the effects of 20 chemicals, including the five epimutagens, detected at low concentrations in maternal peripheral and cord blood samples. Of note, these individual chemicals did not exhibit epimutagenic activity in hiPSCs. However, because the fetal environment contains various chemicals, we evaluated the effects of combined exposure to chemicals (DEP, Hg, cotinine, Se, and S-421) on hiPSCs. The combined exposure caused a decrease in the number of heterochromatin signals and aberrant DNA methylation status at multiple gene loci in hiPSCs. The combined exposure also affected embryoid body formation and neural differentiation from hiPSCs. Therefore, DEP, Hg, cotinine, Se, and S-421 were defined as an "epimutagen combination" that is effective at low concentrations as detected in maternal peripheral and cord blood.

Original languageEnglish
Article number876047
JournalBioMed Research International
Volume2015
DOIs
Publication statusPublished - 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Arai, Y., Hayakawa, K., Arai, D., Ito, R., Iwasaki, Y., Saito, K., Akutsu, K., Takatori, S., Ishii, R., Hayashi, R., Izumi, S. I., Sugino, N., Kondo, F., Horie, M., Nakazawa, H., Makino, T., Hirosawa, M., Shiota, K., & Ohgane, J. (2015). Putative Epimutagens in Maternal Peripheral and Cord Blood Samples Identified Using Human Induced Pluripotent Stem Cells. BioMed Research International, 2015, [876047]. https://doi.org/10.1155/2015/876047