雙酚A（BPA）是一種生活中廣泛存在的化合物，存在于塑料和樹脂中,。Duke大學(xué)醫(yī)學(xué)院的研究人員在小鼠、大鼠和人類的皮層神經(jīng)元中發(fā)現(xiàn),，環(huán)境中的雙酚A會抑制對神經(jīng)細胞功能和中樞神經(jīng)系統(tǒng)發(fā)育至關(guān)重要的基因,，文章發(fā)表在美國國家科學(xué)院院刊PNAS雜志上。
“我們的研究發(fā)現(xiàn),，BPA會影響中樞神經(jīng)系統(tǒng)的發(fā)育,，暴露在BPA環(huán)境中會使動物和人類更易患神經(jīng)發(fā)育性疾病，”領(lǐng)導(dǎo)這項研究的Duke大學(xué)副教授Wolfgang Liedtke說,。
BPA存在于多種工業(yè)產(chǎn)品中,，包括熱敏打印紙、一些塑料水瓶和金屬罐內(nèi)壁,。如果這一化合物從食品/飲料包裝上滲入到內(nèi)容物中,，就會被人體攝取。BPA分子有模擬雌激素的效果,，會影響機體的內(nèi)分泌系統(tǒng),。
近年來的動物研究使人們越來越擔(dān)心BPA對健康的影響，這種分子可能造成內(nèi)分泌紊亂,、行為異常,、生殖問題、肥胖,、癌癥和免疫系統(tǒng)疾病等,。有研究顯示，嬰幼兒對BPA影響最為敏感,，正因如此,，美國FDA于2012年7月禁止在嬰兒奶瓶中使用這種化合物。
BPA會影響發(fā)育中的神經(jīng)系統(tǒng)，但此前人們并不清楚這其中的機制,。研究團隊對鼠類和人類神經(jīng)細胞進行了一系列實驗,，以分析BPA對基因調(diào)控的破壞。
在神經(jīng)元發(fā)育早期,，細胞中的氯離子水平很高,。當(dāng)神經(jīng)元成熟時，氯離子水平就會下降,，這是因為氯離子轉(zhuǎn)運蛋白KCC2將氯離子運出細胞,。如果神經(jīng)元中的氯離子水平一直很高，就會破壞神經(jīng)回路,，阻礙神經(jīng)細胞移動到大腦中的正確位置,。
將神經(jīng)元暴露在BPA中，會使其Kcc2基因關(guān)閉,，導(dǎo)致KCC2蛋白無法及時將神經(jīng)元中的氯離子移出,，從而改變細胞內(nèi)的氯離子水平，影響大腦發(fā)育,。研究顯示,，MECP2蛋白是這一過程中的關(guān)鍵。當(dāng)環(huán)境中存在BPA時,，神經(jīng)元中的MECP2豐度更高,，這些蛋白大量與Kcc2基因結(jié)合，導(dǎo)致Kcc2基因關(guān)閉,。
這些發(fā)現(xiàn)使研究人員好奇,，BPA是否會引發(fā)Rett綜合癥等神經(jīng)發(fā)育障礙。Rett綜合癥是一種嚴重的自閉癥譜系障礙,，其標(biāo)志是MECP2合成基因發(fā)生突變,，這種疾病只影響女孩。
在這項研究中,，雄性和雌性的神經(jīng)元都受到了BPA的影響,，但雌性的神經(jīng)元對其毒性更為敏感。研究人員計劃深入分析BPA對不同性別的影響,，看BPA對KCC2的影響是否涉及了特定性激素受體,。
“我們的發(fā)現(xiàn)增進了人們對BPA影響基因調(diào)控機制的理解，我們希望未來可以發(fā)現(xiàn)其它受BPA影響的目標(biāo),，” Liedtke說,。(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.
