Effects of bisphenol A exposure during cardiac cell differentiation
Effects of bisphenol A exposure during cardiac cell differentiation
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DOI：
10.1016/j.envpol.2021.117567
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发表时间：
2021-06-11
影响因子：
8.9
通讯作者：
Lombo, Marta
中科院分区：
文献类型：
--
作者：
Escarda-Castro, Enrique;Paz Herraez, Maria;Lombo, Marta
心脏发育需要精确的成心肌细胞基因表达的时间调控。因此，分化细胞中的转录变化可导致先天性心脏病。虽然基因突变是大多数这些改变的基础，但暴露于环境污染物，如双酚A（BPA），最近也被认为是一个风险因素。在这项研究中，我们研究了BPA在心肌细胞分化过程中的遗传毒性和表观遗传毒性作用。H9c2细胞（大鼠成肌细胞）暴露于10和30 μ M BPA之前和心脏驱动的分化的最后两天期间。然后，我们分析了表型和分子修饰（在转录，遗传和表观遗传水平）。结果表明，处理的成肌细胞发展成骨骼肌细胞样表型。BPA在编码心脏分化和功能相关蛋白质的基因中诱导的转录变化取决于暴露于BPA的窗口。分化前的暴露抑制了心脏转录因子（Hand2和Gata4）的表达，而分化期间的暴露降低了心脏特异性基因（Tnnt2，Myom2，Sln和Atp2a1）的表达。此外，在BPA暴露的两个时期后，观察到关于DNA损伤和组蛋白乙酰化水平的显著影响：在暴露于毒物的细胞中，DNA修复灶（由γ H2AX和53BP1的共定位形成）的百分比以剂量依赖性方式增加，而用毒物处理引发了表观遗传标记H3K9ac和H3K27ac的减少。我们的体外研究结果表明，BPA严重干扰心肌细胞分化的过程中，这可能是有关在体内的影响，这种毒物对心脏发生的报告。
Heart development requires a precise temporal regulation of gene expression in cardiomyoblasts. Therefore, the transcriptional changes in differentiating cells can lead to congenital heart diseases. Although the genetic mutations underlie most of these alterations, exposure to environmental contaminants, such as bisphenol A (BPA), has been recently considered as a risk factor as well. In this study we investigated the genotoxic and epigenotoxic effects of BPA throughout cardiomyocyte differentiation. H9c2 cells (rat myoblasts) were exposed to 10 and 30 mu M BPA before and during the last two days of cardiac-driven differentiation. Then, we have analysed the phenotypic and molecular modifications (at transcriptional, genetic and epigenetic level). The results showed that treated myoblasts developed a skeletal muscle cell-like phenotype. The transcriptional changes induced by BPA in genes codifying proteins involved in heart differentiation and function depend on the window of exposure to BPA. The exposure before differentiation repressed the expression of heart transcription factors (Hand2 and Gata4), whereas exposure during differentiation reduced the expression of cardiac-specific genes (Tnnt2, Myom2, Sln, and Atp2a1). Additionally, significant effects were observed regarding DNA damage and histone acetylation levels after the two periods of BPA exposure: in cells exposed to the toxicant the percentage of DNA repair foci (formed by the co-localization of gamma H2AX and 53BP1) increased in a dose-dependent manner, whereas the treatment with the toxicant triggered a decrease in the epigenetic marks H3K9ac and H3K27ac. Our in vitro results reveal that BPA seriously interferes with the process of cardiomyocyte differentiation, which could be related to the reported in vivo effects of this toxicant on cardiogenesis.