PDF(Pubmed)
Abstract：
Bisphenol A (BPA) is a common industrial chemical widely used to produce various plastics and is known to impair neural stem cells (NSCs). However, the effects of low-dose BPA exposure on the stemness maintenance and differentiation fate of NSCs remain unclear in the infant brain. The present study demonstrated that 1 µM BPA promoted human NSC proliferation and stemness, without significantly increasing apoptosis. The Chip-seq experiments demonstrated that both the cell cycle and the TGF-β signaling pathway were accelerated after treatment with 1 µM BPA. Subsequently, estrogen-related receptor α (ERRα) gene knockout cell lines were constructed using CRISPR/Cas9. Further western blotting and chromatin immunoprecipitation-PCR experiments demonstrated that BPA maintained cell stemness by binding to an EERα receptor and activating the TGF-β1 signaling pathway, including the downstream factors Aurora kinases B and Id2. In conclusion, the stemness of NSCs could be maintained by BPA at 1 µM through the activation of the ERRα and TGF-β1 signaling pathways and could restrain the differentiation of NSCs into neurons. The present research further clarified the mechanism of BPA toxicity on NSCs from the novel perspective of ERRα and TGF-β1 signaling pathways regulated by BPA and provided insights into potential novel methods of prevention and therapy for neurogenic diseases.
摘要：
双酚A（BPA）是广泛用于生产各种塑料的常见工业化学品，并且已知会损害神经干细胞（NSC）。然而,在婴儿脑中,低剂量BPA暴露对神经干细胞的干性维持和分化命运的影响尚不清楚.本研究表明，1µMBPA促进人NSC增殖和干性，而不显著增加细胞凋亡。Chip-seq实验表明，用1μMBPA处理后，细胞周期和TGF-β信号通路均加速。随后，使用CRISPR/Cas9构建雌激素相关受体α（ERRα）基因敲除细胞系。进一步的蛋白质印迹和染色质免疫沉淀-PCR实验表明，BPA通过与EERα受体结合并激活TGF-β1信号通路来维持细胞的干性。包括下游因子Aurora激酶B和Id2。总之,BPA可以通过激活ERRα和TGF-β1信号通路将神经干细胞的干性维持在1µM，并可以抑制神经干细胞向神经元的分化。本研究从BPA调控的ERRα和TGF-β1信号通路的新视角进一步阐明了BPA对神经源性疾病的毒性机制，为神经源性疾病的预防和治疗提供了新的思路。
