DNA methylation and copy number variation analyses of human embryonic stem cell-derived neuroprogenitors after low-dose decabromodiphenyl ether and/or bisphenol A exposure

Hum Exp Toxicol. 2018 May;37(5):475-485. doi: 10.1177/0960327117710535. Epub 2017 Jun 9.

Abstract

The polybrominated diphenyl ether flame retardants decabromodiphenyl ether (BDE-209) and bisphenol A (BPA) are environmental contaminants that can cross the placenta and exert toxicity in the developing fetal nervous system. Copy number variants (CNVs) play a role in a number of genetic disorders and may be implicated in BDE-209/BPA teratogenicity. In this study, we found that BDE-209 and/or BPA exposure decreased neural differentiation efficiency of human embryonic stem cells (hESCs), although there was a >90% induction of neuronal progenitor cells (NPCs) from exposed hESCs. However, the mean of CNV numbers in the NPCs with BDE-209 + BPA treatment was significantly higher compared to the other groups, whereas DNA methylation was lower and DNA methyltransferase(DNMT1 and DNMT3A) expression were significantly decreased in all of the BDE-209 and/or BPA treatment groups compared with the control groups. The number of CNVs in chromosomes 3, 4, 11, 22, and X in NPCs with BDE-209 and/or BPA exposure was higher compared to the control group. In addition, CNVs in chromosomes 7, 8, 14, and 16 were stable in hESCs and hESCs-derived NPCs irrespective of BDE-209/BPA exposure, and CNVs in chromosomes 20 q11.21 and 16 p13.11 might be induced by neural differentiation. Thus, BDE-209/BPA exposure emerges as a potential source of CNVs distinct from neural differentiation by itself. BDE-209 and/or BPA exposure may cause genomic instability in cultured stem cells via reduced activity of DNA methyltransferase, suggesting a new mechanism of human embryonic neurodevelopmental toxicity caused by this class of environmental toxins.

Keywords: DNA methylation; Decabromodiphenyl ether; bisphenol A; copy number variants; human embryonic stem cells; neurodevelopmental toxicity.

MeSH terms

  • Benzhydryl Compounds / toxicity*
  • Cell Differentiation / drug effects
  • Cell Line
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Copy Number Variations
  • DNA Methylation
  • DNA Methyltransferase 3A
  • DNA Methyltransferase 3B
  • Flame Retardants / toxicity*
  • Halogenated Diphenyl Ethers / toxicity*
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / drug effects*
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Nestin / metabolism
  • Neurons / cytology
  • PAX6 Transcription Factor / genetics
  • Phenols / toxicity*
  • Plasticizers / toxicity*

Substances

  • Benzhydryl Compounds
  • DNMT3A protein, human
  • Flame Retardants
  • Halogenated Diphenyl Ethers
  • NES protein, human
  • Nestin
  • PAX6 Transcription Factor
  • PAX6 protein, human
  • Phenols
  • Plasticizers
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • DNMT1 protein, human
  • bisphenol A
  • decabromobiphenyl ether