DNA methylation and copy number variation analyses of human embryonic stem cell-derived neuroprogenitors after low-dose decabromodiphenyl ether and/or bisphenol A exposure
DNA methylation and copy number variation analyses of human embryonic stem cell-derived neuroprogenitors after low-dose decabromodiphenyl ether and/or bisphenol A exposure
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低剂量十溴二苯醚和/或双酚 A 暴露后人胚胎干细胞来源的神经祖细胞的 DNA 甲基化和拷贝数变异分析
DOI：
10.1177/0960327117710535
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发表时间：
2018-05-01
影响因子：
2.8
通讯作者：
Chen, D.
中科院分区：
文献类型：
--
作者：
Du, L.;Sun, W.;Chen, D.
多溴二苯醚阻燃剂十溴二苯醚（BDE-209）和双酚A（BPA）是环境污染物，可穿过胎盘，对发育中的胎儿神经系统产生毒性。拷贝数变异体在许多遗传疾病中发挥作用，并可能与BDE-209/BPA致畸性有关。在这项研究中，我们发现BDE-209和/或BPA暴露降低了人胚胎干细胞（hESC）的神经分化效率，尽管暴露的hESC诱导出的神经元祖细胞（NPC）超过90%。然而，与其他组相比，BDE-209 + BPA处理的NPC中CNV数量的平均值显著较高，而与对照组相比，所有BDE-209和/或BPA处理组的DNA甲基化较低，DNA甲基转移酶（DNMT 1和DNMT 3A）表达显著降低。与对照组相比，接触BDE-209和/或BPA的NPC中染色体3、4、11、22和X的CNV数量更高。此外，无论BDE-209/BPA是否暴露，hESC和hESC衍生的NPC中第7、8、14和16号染色体上的CNVs都是稳定的，第20号染色体q11.21和第16号染色体p13.11上的CNVs可能是由神经分化诱导的。因此，BDE-209/BPA暴露是与神经分化本身不同的CNVs的潜在来源。接触BDE-209和/或BPA可能会通过降低DNA甲基转移酶的活性，导致培养的干细胞基因组不稳定，这表明这类环境毒素对人类胚胎神经发育具有毒性的新机制。
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.