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Epigenetic disruption and glucose homeostasis changes following low-dose maternal bisphenol A exposure.
Toxicology Research ( IF 2.2 ) Pub Date : 2016-06-20 , DOI: 10.1039/c6tx00047a
Huailong Chang 1 , Danqi Wang 2 , Wei Xia 1 , Xinyun Pan 1 , Wenqian Huo 1 , Shunqing Xu 1 , Yuanyuan Li 1
Affiliation  

Developmental exposure to bisphenol A (BPA) has been linked to impaired glucose homeostasis and pancreatic function in adulthood, which has been hypothesized to result from the disruption of pancreatic β-cell development at early life. Here we evaluated whether maternal BPA exposure disrupts β-cell development and glucose tolerance and the role of epigenetic modifications of key regulator in this process. We found that maternal exposure to BPA (10 μg kg-1 d-1) reduced the pancreatic β-cell mass and the expression of pancreatic and duodenal homeobox 1 (Pdx1) at birth, as well as the expression of Pdx1 at gestational day (GD) 15.5. In parallel with the decreased expression of Pdx1, histones H3 and H4 deacetylation, along with demethylation of histone 3 lysine 4 (H3K4) and methylation of histone 3 lysine 9 (H3K9), were found at the promoter of Pdx1, while no significant changes in DNA methylation status were detected at this region. Moreover, these alterations were observed in adult life along with impaired glucose tolerance. We conclude that maternal exposure to BPA reduces pancreatic β-cell mass at birth by reducing PDX1+ progenitors during fetal development through altering the histone modifications of Pdx1, which can be propagated to later life and increase the susceptibility to glucose intolerance.

中文翻译:

低剂量孕妇双酚A暴露后表观遗传破坏和葡萄糖稳态变化。

双酚A(BPA)的发育暴露与​​成年期葡萄糖稳态和胰腺功能受损有关,据推测这是由于生命早期胰腺β细胞发育受到破坏所致。在这里,我们评估了母体BPA暴露是否会破坏β细胞发育和葡萄糖耐量,以及在此过程中关键调节因子的表观遗传修饰的作用。我们发现,母体暴露于BPA(10μgkg-1 d-1)会降低出生时的胰腺β细胞质量以及胰腺和十二指肠同源盒1(Pdx1)的表达,以及在妊娠当天的Pdx1的表达( GD)15.5。在Pdx1的启动子上发现了与Pdx1表达下降同时的组蛋白H3和H4脱乙酰化,以及组蛋白3赖氨酸4(H3K4)的去甲基化和组蛋白3赖氨酸9(H3K9)的甲基化,而在该区域未检测到DNA甲基化状态的显着变化。此外,在成年人中观察到这些改变以及葡萄糖耐量降低。我们得出的结论是,母亲通过改变Pdx1的组蛋白修饰,可以减少胎儿发育过程中的PDX1 +祖细胞,从而降低出生时的胰腺β细胞质量,从而可以传播到以后的生活中,并增加对葡萄糖耐量的敏感性。
更新日期:2019-11-01
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