Arsenic inhibits hedgehog signaling during P19 cell differentiation.
Arsenic inhibits hedgehog signaling during P19 cell differentiation.
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DOI：
10.1016/j.taap.2014.10.007
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发表时间：
2014-12-15
影响因子：
3.8
通讯作者：
Bain, Lisa J.
中科院分区：
文献类型：
--
作者：
Liu, Jui Tung;Bain, Lisa J.
砷是一种有毒物质，存在于世界各地的地下水中，人类接触砷主要来自饮用水或在土壤或水中含有砷的地区种植的作物。流行病学研究表明，发育期间的砷暴露降低了智力功能，降低了出生体重，改变了运动活动，而体外研究表明，亚砷酸盐降低了肌肉和神经细胞的分化。Shh信号通路在神经元和骨骼肌的分化过程中起着重要的作用。本研究的目的是探讨砷是否可以破坏P19小鼠胚胎干细胞中Shh信号，导致肌肉和神经细胞分化的变化。在细胞分化过程中，将P19胚胎干细胞暴露于0、0.25或0.5 µM亚砷酸钠中长达9天。我们发现，砷暴露显着降低转录水平的基因在Shh通路中的时间和剂量依赖性的方式。这包括Shh配体，其减少2至3倍，Gli2转录因子，其减少2至3倍，其下游靶基因Ascl1，其减少5倍。GLI2蛋白水平和转录活性也降低。然而，砷并没有改变GLI2初级纤毛积累或核转位。此外，额外的细胞外SHH抢救砷对细胞分化的抑制作用，由于GLI结合活性的增加。综上所述，我们得出结论，砷暴露影响Shh信号，最终降低Gli2转录因子的表达。这些结果表明砷破坏细胞分化的机制。
Arsenic is a toxicant found in ground water around the world, and human exposure mainly comes from drinking water or from crops grown in areas containing arsenic in soils or water. Epidemiological studies have shown that arsenic exposure during development decreased intellectual function, reduced birth weight, and altered locomotor activity, while in vitro studies have shown that arsenite decreased muscle and neuronal cell differentiation. The sonic hedgehog (Shh) signaling pathway plays an important role during the differentiation of both neurons and skeletal muscle. The purpose of this study was to investigate whether arsenic can disrupt Shh signaling in P19 mouse embryonic stem cells, leading to changes muscle and neuronal cell differentiation. P19 embryonic stem cells were exposed to 0, 0.25, or 0.5 µM of sodium arsenite for up to 9 days during cell differentiation. We found that arsenite exposure significantly reduced transcript levels of genes in the Shh pathway in both a time and dose-dependent manner. This included the Shh ligand, which was decreased 2- to 3-fold, the Gli2 transcription factor, which was decreased 2- to 3-fold, and its downstream target gene Ascl1, which was decreased 5-fold. GLI2 protein levels and transcriptional activity were also reduced. However, arsenic did not alter GLI2 primary cilium accumulation or nuclear translocation. Moreover, additional extracellular SHH rescued the inhibitory effects of arsenic on cellular differentiation due to an increase in GLI binding activity. Taken together, we conclude that arsenic exposure affected Shh signaling, ultimately decreasing the expression of the Gli2 transcription factor. These results suggest a mechanism by which arsenic disrupts cell differentiation.
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