Bisphenol a exposure disrupts genomic imprinting in the mouse.
Bisphenol a exposure disrupts genomic imprinting in the mouse.
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DOI：
10.1371/journal.pgen.1003401
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发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Bartolomei MS
中科院分区：
文献类型：
--
作者：
Susiarjo M;Sasson I;Mesaros C;Bartolomei MS
暴露于内分泌干扰物与发育缺陷有关。双酚A（BPA）是人类广泛接触的一种化合物。在模式生物中，BPA暴露与代谢紊乱、不育、癌症和行为异常有关。最近，BPA暴露与DNA甲基化变化有关，表明表观遗传机制可能相关。我们研究了暴露对小鼠基因组印迹的影响，因为印迹基因受差异DNA甲基化的调节，异常印迹会破坏胎儿、胎盘和出生后的发育。通过等位基因特异性和定量实时PCR分析，我们证明了在卵母细胞发育的后期和胚胎发育的早期阶段，母体BPA暴露显着破坏了胚胎日（E）9.5和12.5胚胎和胎盘的印记基因表达。受影响的基因包括Snrpn、Ube 3a、Igf 2、Kcnq 1 ot 1、Cdkn 1c和Ascl 2;这些基因的突变和异常调节与人类的印记疾病有关。此外，大多数受影响的基因在胎盘中表达异常。DNA甲基化研究表明，BPA暴露显著改变了差异甲基化区域（DMR）的甲基化水平，包括Snrpn印迹控制区（ICR）和Igf 2 DMR 1。此外，暴露显着降低了胎盘的全基因组甲基化水平，但不是胚胎。组织学和免疫组化检查显示，这些表观遗传缺陷与异常胎盘发育有关。与这种早期暴露模式相反，在表观遗传重编程窗口之外的暴露不会引起显著的印记扰动。我们的数据表明，早期暴露于常见的环境化合物有可能通过胚胎的表观遗传变化和胎盘的异常发育破坏胎儿和产后健康。BPA是一种广泛使用的化合物，人类暴露于其中，最近的研究表明，在动物模型和人类中，暴露与不良发育结果之间存在关联。不幸的是，BPA引起的健康异常的确切机制尚不清楚，阐明这些相关的生物学途径对于理解暴露的公共卫生影响至关重要。最近，越来越多的数据表明BPA能够诱导DNA甲基化的变化，这表明表观遗传机制是相关的。在这项工作中，我们研究了BPA暴露对小鼠印迹基因表达和调控的影响。印记基因受DNA甲基化的调控，在胎儿、胎盘和出生后的发育过程中发挥着重要作用。我们发现，胎儿暴露于生理相关剂量的BPA会改变小鼠胚胎和胎盘中印记基因的表达和甲基化状态，后者组织表现出更显着的变化。此外，异常印迹与胎盘发育缺陷有关。我们的数据表明，BPA暴露可能会扰乱胎儿和产后健康，通过胚胎的表观遗传变化以及通过改变胎盘发育。
Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta. BPA is a widely used compound to which humans are exposed, and recent studies have demonstrated the association between exposure and adverse developmental outcomes in both animal models and humans. Unfortunately, exact mechanisms of BPA–induced health abnormalities are unclear, and elucidation of these relevant biological pathways is critical for understanding the public health implication of exposure. Recently, increasing data have demonstrated the ability of BPA to induce changes in DNA methylation, suggesting that epigenetic mechanisms are relevant. In this work, we study effects of BPA exposure on expression and regulation of imprinted genes in the mouse. Imprinted genes are regulated by differential DNA methylation, and they play critical roles during fetal, placental, and postnatal development. We have found that fetal exposure to BPA at physiologically relevant doses alters expression and methylation status of imprinted genes in the mouse embryo and placenta, with the latter tissue exhibiting the more significant changes. Additionally, abnormal imprinting is associated with defective placental development. Our data demonstrate that BPA exposure may perturb fetal and postnatal health through epigenetic changes in the embryo as well as through alterations in placental development.
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影响因子：
64.8
作者：
Hajkova, Petra;Ancelin, Katia;Waldmann, Tanja;Lacoste, Nicolas;Lange, Ulrike C.;Cesari, Francesca;Lee, Caroline;Almouzni, Genevieve;Schneider, Robert;Surani, M. Azim
通讯作者：
Surani, M. Azim
影响因子：
10.4
作者：
Braun JM;Yolton K;Dietrich KN;Hornung R;Ye X;Calafat AM;Lanphear BP
通讯作者：
Lanphear BP
DOI：
10.1002/bdrc.20039
发表时间：
2005-06-01
期刊：
Birth defects research. Part C, Embryo today : reviews
影响因子：
--
作者：
Arnaud, Philippe;Feil, Robert
通讯作者：
Feil, Robert
关于出生结果和脂肪因子表达的母体和脐带血液中双酚A浓度的生物监测：台湾的一项出生队列研究。
DOI：
10.1186/1476-069x-10-94
发表时间：
2011-11-03
期刊：
Environmental health : a global access science source
影响因子：
--
作者：
Chou WC;Chen JL;Lin CF;Chen YC;Shih FC;Chuang CY
通讯作者：
Chuang CY
DOI：
10.1073/pnas.0703739104
发表时间：
2007-08-07
影响因子：
11.1
作者：
Dolinoy, Dana C.;Huang, Dale;Jirtle, Randy L.
通讯作者：
Jirtle, Randy L.