Putative Epimutagens in Maternal Peripheral and Cord Blood Samples Identified Using Human Induced Pluripotent Stem Cells.
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.
Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan ; Laboratory of Genomic Function Engineering, Department of Life Science, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan ; Laboratory of Developmental Engineering, Department of Life Science, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan.
Yoshikazu
Y
Arai
Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Koji
K
Hayakawa
Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Daisuke
D
Arai
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo 142-8501, Japan.
Rie
R
Ito
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo 142-8501, Japan.
Yusuke
Y
Iwasaki
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo 142-8501, Japan.
Koichi
K
Saito
Division of Food Chemistry, Osaka Prefectural Institute of Public Health, Osaka 537-0025, Japan.
Kazuhiko
K
Akutsu
Division of Food Chemistry, Osaka Prefectural Institute of Public Health, Osaka 537-0025, Japan.
Satoshi
S
Takatori
Saitama Prefectural Institute of Public Health, Saitama 355-0133, Japan.
Rie
R
Ishii
Department of Toxicology, Aichi Prefectural Institute of Public Health, Aichi 462-8576, Japan.
Rumiko
R
Hayashi
Department of Obstetrics and Gynecology, School of Medicine, Tokai University, Kanagawa 259-1193, Japan.
Shun-ichiro
S
Izumi
Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
Norihiro
N
Sugino
Department of Pharmacology, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan.
Fumio
F
Kondo
Faculty of Home Economics, Otsuma Women's University, Tokyo 102-8357, Japan.
Masakazu
M
Horie
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo 142-8501, Japan.
Hiroyuki
H
Nakazawa
Fuji-Oyama Hospital, Shizuoka 410-1326, Japan.
Tsunehisa
T
Makino
Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Mitsuko
M
Hirosawa
Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Kunio
K
Shiota
Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan ; Laboratory of Genomic Function Engineering, Department of Life Science, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan.
Jun
J
Ohgane
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003367:Cotinine / Q000633:toxicity; D019175:DNA Methylation / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D004987:Ethers / Q000633:toxicity; D005260:Female; D005312:Fetal Blood / Q000187:drug effects; D006570:Heterochromatin / Q000187:drug effects / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects*; D008628:Mercury / Q000633:toxicity; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D010755:Organophosphates / Q000633:toxicity; D012643:Selenium / Q000633:toxicity
D004987:Ethers; D006570:Heterochromatin; D009153:Mutagens; D010755:Organophosphates; C017970:bis(2,3,3,3-tetrachloropropyl) ether; C034789:diethyl phosphate; D008628:Mercury; D012643:Selenium; D003367:Cotinine