Sodium arsenite delays the differentiation of C2C12 mouse myoblast cells and alters methylation patterns on the transcription factor myogenin.
Sodium arsenite delays the differentiation of C2C12 mouse myoblast cells and alters methylation patterns on the transcription factor myogenin.
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DOI：
10.1016/j.taap.2010.10.006
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发表时间：
2011-01-15
影响因子：
3.8
通讯作者：
Bain LJ
中科院分区：
文献类型：
--
作者：
Steffens AA;Hong GM;Bain LJ
流行病学研究表明，砷暴露与癌症、皮肤病和不利的发育结果有关，如自然流产、新生儿死亡率、出生体重低和肌肉组织使用延迟。目前的研究使用C2 C12小鼠成肌细胞来检查低浓度的砷是否会改变它们向肌管的分化，这表明砷可以作为一种发育毒物。将成肌细胞暴露于20 nM亚砷酸钠，使其分化为肌管，并使用QPCR和免疫荧光研究肌特异性转录因子肌细胞生成素的表达，沿着原肌球蛋白、细胞因子信号传导抑制因子3（Socs 3）、前列腺素I2合成（Ptgis）和肌细胞增强因子2（Mef 2）的表达。暴露于20 nM亚砷酸钠的C2 C12细胞延迟了分化过程，这可以通过多核肌管数量的显著减少、肌细胞生成素mRNA表达的减少和表达肌细胞生成素蛋白的细胞核总数的减少来证明。参与肌管形成的mRNA表达，如Ptgis和Mef 2 mRNA，在分化过程中也显著降低了1.6倍和4倍。这通过Mef 2的免疫荧光证实，其显示核易位减少2.6倍。通过甲基化特异性PCR和亚硫酸氢盐基因组测序检查了肌细胞生成素启动子区域（−473至+90）甲基化模式的变化。高甲基化的CpG位于-236bp和-126bp，而低甲基化的CpG位于砷暴露的细胞中的-207bp。这项研究表明，20 nM亚砷酸钠可以改变成肌细胞分化，通过减少转录因子肌细胞生成素和Mef 2c的表达，这可能是由于启动子甲基化模式的变化。肌肉分化的延迟可能导致发育异常。
Epidemiological studies have correlated arsenic exposure with cancer, skin diseases, and adverse developmental outcomes such as spontaneous abortions, neonatal mortality, low birth weight, and delays in the use of musculature. The current study used C2C12 mouse myoblast cells to examine whether low concentrations of arsenic could alter their differentiation into myotubes, indicating that arsenic can act as a developmental toxicant. Myoblast cells were exposed to 20 nM sodium arsenite, allowed to differentiate into myotubes, and expression of the muscle-specific transcription factor myogenin, along with the expression of tropomyosin, suppressor of cytokine signaling 3 (Socs3), prostaglandin I2 synthesis (Ptgis), and myocyte enhancer 2 (Mef2) were investigated using QPCR and immunofluorescence. Exposing C2C12 cells to 20nM sodium arsenite delayed the differentiation process, as evidenced by a significant reduction in the number of multinucleated myotubes, a decrease in myogenin mRNA expression, and a decrease in the total number of nuclei expressing myogenin protein. The expression of mRNA involved in myotube formation, such as Ptgis and Mef2 mRNA, was also significantly reduced by 1.6-fold and 4-fold during differentiation. This was confirmed by immunofluorescence for Mef2, which showed a 2.6-fold reduction in nuclear translocation. Changes in methylation patterns in the promoter region of myogenin (−473 to +90) were examined by methylation-specific PCR and bisulfite genomic sequencing. Hypermethylated CpGs were found at −236bp and −126bp, whereas hypomethylated CpGs were found at −207bp in arsenic exposed cells. This study indicates that 20 nM sodium arsenite can alter myoblast differentiation by reducing the expression of the transcription factors myogenin and Mef2c, which is likely due to changes in promoter methylation patterns. The delay is muscle differentiation may lead to developmental abnormalities.
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