Transgenerational effects of maternal high fat diet during pregnancy on breast ca

孕期母亲高脂肪饮食对乳腺癌的跨代影响

基本信息

批准号：
8543663
负责人：
LEENA A. HILAKIVI-CLARKE
金额：
$ 49.86万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-11 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8543663
关键词：
Adult Animal Model Binding Breast Breast Cancer Cell Cardiovascular Diseases Cell division Cells Consumption Coupled DNA Methylation DNA Methyltransferase DNA Methyltransferase Inhibitor DNA Modification Methylases DNMT3B gene DNMT3a Data Daughter Diet Down-Regulation EZH2 gene Endocrine Disruptors Environment Epilepsy Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Ethinyl Estradiol Event Exhibits Exposure to Fatty acid glycerol esters Female Functional RNA Gene Expression Gene Targeting Generations Genes High Risk Woman Histone Deacetylase Histone Deacetylase Inhibitor Human Hydralazine Individual Lead Life MCF7 cell Malignant - descriptor Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary Tumorigenesis Mammary gland Maternal Exposure Methods Methylation MicroRNAs Mus Names Outcome Pattern Perinatal Exposure Peripheral Polycomb Predisposition Pregnancy RNA Rattus Research Risk Risk Factors Risk Marker Stem cells Testing Tissues Translating Tumor Suppressor Genes Undifferentiated Up-Regulation Valproic Acid Woman Work base cancer risk feeding in utero inhibitor/antagonist innovation malignant breast neoplasm offspring peripheral blood

项目摘要

DESCRIPTION (provided by applicant): Maternal exposure to a high fat (HF) diet during pregnancy increases estrogen receptor (ER+) and ER- mammary cancer risk among female offspring in animal models and in humans. The effect may not be limited to F1 generation daughters: we found that an exposure during pregnancy to a diet containing ethinyl estradiol (EE2) increased mammary cancer risk also in granddaughters (F2 generation) and great granddaughters (F3 generation). Since HF diet increases pregnancy E2 levels, we are proposing to investigate in mice whether maternal exposure to HF diet increases the risk of developing ER+ and/or ER- mammary cancer in F1-F4 generation offspring. In addition, we will investigate whether these transgenerational effects involve changes in DNA methylation. Our preliminary analysis performed using massively parallel sequencing identified 144 "named" genes which were either hypo- or hypermethylated in the mammary glands of F1-F3 generation offspring of EE2 exposed dams, compared to controls. 21% of these genes were polycomb target genes (PcGTs), which in turn included some tumor suppressor genes (TSGs), suggesting that maternal diet during pregnancy, including consumption of a HF diet, may induce methylation of PcTGs/TSGs in the offspring's breast. Interestingly, women at high risk of developing breast cancer exhibit methylation of PcGTs and TSGs. The increase in DNA methylation may be caused by up-regulation of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) and polycombs (EZH2, SUZ12), which we and others have found to occur in the offspring of estrogen exposed dams. Further, up-regulation of DNMTs and polycombs may have been initiated by estrogen-induced suppression of non-coding miRNAs which target them, as seen in MCF-7 human breast cancer cells and mammary glands of rats exposed to EE2 or HF diet in utero (our preliminary data). In this study, we test a hypothesis that maternal exposure to a HF diet during pregnancy induces a transgenerational increase in mammary cancer risk in the F1-F4 generation offspring by inducing DNA methylation of PcTGs/TSGs, via estrogen-induced down-regulation of miRNAs. A causal chain involving estrogen-induced down-regulation of miRNA, up-regulation of DNMTs and polycombs and subsequent methylation of PcGTs/TSGs, leading to increased mammary cancer in F1-F4 generation offspring, will be investigated by treating F1-F4 generation mice with histone deacetylase (HDAC) and DNMT inhibitors. Our preliminary study indicates that an exposure to HDAC+DNMT inhibitors during adult life completely reverses the increase in mammary cancer risk in in utero estrogen exposed mice, but whether these exposures reverse increased DNA methylation and increased mammary tumorigenesis in F2-F4 generations of estrogen exposed dams, is not known. Finally, as there is currently no way of knowing who might have been exposed to high in utero estrogenic environment, we will study whether these individuals can be identified by determining E2/ER regulated miRNA profile in the peripheral blood.

描述（由申请人提供）：孕妇在怀孕期间暴露于高脂饮食（HF）饮食会增加雌激素受体（ER+）和雌性癌症的风险，而动物模型中的女性后代和人类中的雌性后代的风险增加。这种影响可能不仅限于F1代女儿：我们发现，怀孕期间会暴露于含有乙基雌二醇的饮食（EE2）的饮食中，孙女（F2代）和曾孙女（F3代）也会增加乳腺癌的风险。由于HF饮食增加了妊娠E2水平，因此我们建议在小鼠中调查孕产妇对HF饮食的暴露是否会增加F1-F4生成后代中患ER+和/或ER-乳腺癌的风险。此外，我们将研究这些跨代作用是否涉及DNA甲基化的变化。我们使用大量平行测序进行的初步分析鉴定出144个“命名”基因，这些基因在F1-F3生成的EE2暴露水坝的F1-F3生成后代的乳腺中被甲基化或高甲基化，与对照组相比。这些基因中有21％是polycomb靶基因（PCGTS），进而包括一些肿瘤抑制基因（TSG），表明怀孕期间的母体饮食（包括食用HF饮食）可能会诱导甲基化的甲基化甲基，使后代乳房中的PCTGS/TSG甲基化。有趣的是，患乳腺癌的高风险女性表现出PCGT和TSG的甲基化。 DNA甲基化的增加可能是由DNA甲基转移酶（DNMT1，DNMT3A和DNMT3B）和Polycomb（Ezh2，Suz12）上调引起的，我们和其他我们和其他人都发现在雌激素暴露的大坝的后代中发生。此外，如MCF-7人类乳腺癌细胞中所见，雌激素诱导的非编码miRNA的抑制可能是通过雌激素诱导的非编码miRNA的抑制来引发的，这可能是引发的。在这项研究中，我们检验了一个假设，即产妇接触怀孕期间的HF饮食通过雌激素诱导的miRNA下调，通过诱导PCTGS/TSGS的DNA甲基化来诱导F1-F4生成后代的乳腺癌风险增加。涉及雌激素诱导的miRNA下调的因果链，DNMT和多肉液的上调以及随后的PCGTS/TSG的甲基化，从而将F1-F4生成后代的乳腺癌增加，通过使用HESTONE DEACETYLASE（HDAC）处理F1-F4生成的后代（HDAC）和DN。我们的初步研究表明，在成人生活期间暴露于HDAC+DNMT抑制剂完全逆转了子宫内雌激素暴露的小鼠乳腺癌风险的增加，但是这些暴露是否会逆转DNA甲基化和增加乳腺癌的增加，而乳腺癌增加了雌激素暴露的F2-F4世代。最后，由于目前无法知道谁可能在子宫雌激素环境中暴露于较高的情况下，我们将研究是否可以通过确定外周血中的E2/ER调节的miRNA概况来识别这些人。