双酚A（BPA）是一种生活中广泛存在的化合物，存在于塑料和树脂中。Duke大学医学院的研究人员在小鼠、大鼠和人类的皮层神经元中发现，环境中的双酚A会抑制对神经细胞功能和中枢神经系统发育至关重要的基因，文章发表在美国国家科学院院刊PNAS杂志上。
“我们的研究发现，BPA会影响中枢神经系统的发育，暴露在BPA环境中会使动物和人类更易患神经发育性疾病，”领导这项研究的Duke大学副教授Wolfgang Liedtke说。
BPA存在于多种工业产品中，包括热敏打印纸、一些塑料水瓶和金属罐内壁。如果这一化合物从食品/饮料包装上渗入到内容物中，就会被人体摄取。BPA分子有模拟雌激素的效果，会影响机体的内分泌系统。
近年来的动物研究使人们越来越担心BPA对健康的影响，这种分子可能造成内分泌紊乱、行为异常、生殖问题、肥胖、癌症和免疫系统疾病等。有研究显示，婴幼儿对BPA影响最为敏感，正因如此，美国FDA于2012年7月禁止在婴儿奶瓶中使用这种化合物。
BPA会影响发育中的神经系统，但此前人们并不清楚这其中的机制。研究团队对鼠类和人类神经细胞进行了一系列实验，以分析BPA对基因调控的破坏。
在神经元发育早期，细胞中的氯离子水平很高。当神经元成熟时，氯离子水平就会下降，这是因为氯离子转运蛋白KCC2将氯离子运出细胞。如果神经元中的氯离子水平一直很高，就会破坏神经回路，阻碍神经细胞移动到大脑中的正确位置。
将神经元暴露在BPA中，会使其Kcc2基因关闭，导致KCC2蛋白无法及时将神经元中的氯离子移出，从而改变细胞内的氯离子水平，影响大脑发育。研究显示，MECP2蛋白是这一过程中的关键。当环境中存在BPA时，神经元中的MECP2丰度更高，这些蛋白大量与Kcc2基因结合，导致Kcc2基因关闭。
这些发现使研究人员好奇，BPA是否会引发Rett综合症等神经发育障碍。Rett综合症是一种严重的自闭症谱系障碍，其标志是MECP2合成基因发生突变，这种疾病只影响女孩。
在这项研究中，雄性和雌性的神经元都受到了BPA的影响，但雌性的神经元对其毒性更为敏感。研究人员计划深入分析BPA对不同性别的影响，看BPA对KCC2的影响是否涉及了特定性激素受体。
“我们的发现增进了人们对BPA影响基因调控机制的理解，我们希望未来可以发现其它受BPA影响的目标，” Liedtke说。(生物谷Bioon.com)
doi: 10.1073/pnas.1300959110
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Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter
Michele Yeo, Ken Berglund, Michael Hanna, Junjie U. Guo, Jaya Kittur, Maria D. Torres, Joel Abramowitz, Jorge Busciglio, Yuan Gao, Lutz Birnbaumer, and Wolfgang B. Liedtke.
Bisphenol A (BPA) is a ubiquitous compound that is emerging as a possible toxicant during embryonic development. BPA has been shown to epigenetically affect the developing nervous system, but the molecular mechanisms are not clear. Here we demonstrate that BPA exposure in culture led to delay in the perinatal chloride shift caused by significant decrease in potassium chloride cotransporter 2 (Kcc2) mRNA expression in developing rat, mouse, and human cortical neurons. Neuronal chloride increased correspondingly. Treatment with epigenetic compounds decitabine and trichostatin A rescued the BPA effects as did knockdown of histone deacetylase 1 and combined knockdown histone deacetylase 1 and 2. Furthermore, BPA evoked increase in tangential interneuron migration and increased chloride in migrating neurons. Interestingly, BPA exerted its effect in a sexually dimorphic manner, with a more accentuated effect in females than males. By chromatin immunoprecipitation, we found a significant increase in binding of methyl-CpG binding protein 2 to the “cytosine-phosphate-guanine shores” of the Kcc2 promoter, and decrease in binding of acetylated histone H3K9 surrounding the transcriptional start site. Methyl-CpG binding protein 2-expressing neurons were more abundant resulting from BPA exposure. The sexually dimorphic effect of BPA on Kcc2 expression was also demonstrated in cortical neurons cultured from the offspring of BPA-fed mouse dams. In these neurons and in cortical slices, decitabine was found to rescue the effect of BPA on Kcc2 expression. Overall, our results indicate that BPA can disrupt Kcc2 gene expression through epigenetic mechanisms. Beyond increase in basic understanding, our findings have relevance for identifying unique neurodevelopmental toxicity mechanisms of BPA, which could possibly play a role in pathogenesis of human neurodevelopmental disorders.
