Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development.
Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development.
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DOI：
10.1371/journal.pone.0099800
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Soto AM
中科院分区：
文献类型：
--
作者：
Dhimolea E;Wadia PR;Murray TJ;Settles ML;Treitman JD;Sonnenschein C;Shioda T;Soto AM
暴露于环境雌激素(异种雌激素)可能是过去50年来在欧洲和美国观察到的乳腺癌发病率上升的原因之一。异种雌激素双酚A(BPA)从塑料食品/饮料容器和牙科材料中渗出。胎儿暴露于双酚A可导致成年大鼠乳腺癌前病变和肿瘤性病变。以前的研究结果表明，BPA通过雌激素受体发挥作用，而雌激素受体在暴露期间仅在间充质中检测到，直接改变基因表达，导致间充质与上皮之间相互作用的改变。这启动了一长串改变的形态发生事件，导致肿瘤转化。此外，双酚A还会在某些组织中引起表观遗传学变化。为了探讨乳腺的这种机制，Wistar-Furth大鼠通过渗透泵或250微克BPA/kg体重/天(诱发原位导管癌的剂量)暴露于皮下。母猪暴露于妊娠第9天至出生后第1天(PND)，分别在PND4、PND21和PND50后的第一个发情期处死。从乳腺组织中提取基因组DNA(GDNA)，用抗5-甲基胞嘧啶抗体进行免疫沉淀。使用NimbleGen芯片阵列检测和量化gDNA甲基化状态，发现7412个差异甲基化的gDNA片段(58207个片段中)，大部分变化发生在PND21。转录分析表明，BPA处理的动物和赋形剂处理的动物之间的大部分基因表达差异是在后来观察到的(PND50)。双酚A暴露导致PND4处α-乳蛋白基因转录起始点的组蛋白H3K4三甲基化水平升高，同时增强了该基因的mRNA表达。这些结果表明，胎儿接触双酚A会引发出生后和成人乳腺表观基因组的变化，并改变基因表达模式。这些事件可能有助于肿瘤前病变和肿瘤病变的发展，这些病变表现在成年期。
Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns. These events may contribute to the development of pre-neoplastic and neoplastic lesions that manifest during adulthood.
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在大鼠中，围产期给予双足A作为潜在的乳腺癌。
影响因子：
10.4
作者：
Acevedo N;Davis B;Schaeberle CM;Sonnenschein C;Soto AM
通讯作者：
Soto AM
影响因子：
3.6
作者：
Lozada, Kristen Weber;Keri, Ruth A.
通讯作者：
Keri, Ruth A.
影响因子：
3.7
作者：
Guerrero-Bosagna, Carlos;Settles, Matthew;Skinner, Michael K.
通讯作者：
Skinner, Michael K.
影响因子：
10.4
作者：
Brotons JA;Olea-Serrano MF;Villalobos M;Pedraza V;Olea N
通讯作者：
Olea N
影响因子：
4.8
作者：
Muñoz-de-Toro, M;Markey, CM;Soto, AM
通讯作者：
Soto, AM