Epigenomics of Bisphenol A Exposure and Disease Risk

描述（由申请人提供）：我们建议研究正常乳腺上皮细胞对生理刺激和环境扰动的表观遗传变化。整合组学方法将用于确定雌激素受体（ER）1阳性细胞与配体刺激的全球染色质概况。ER1信号传导的复杂调控网络被激活，伴随着响应基因中染色质的改变。然后这些基因的表达恢复到基础水平。染色质处于半开放状态，当配体的下一个循环激活信号时，染色质准备接受转录因子或阻遏物。当上皮祖细胞持续暴露于雌激素增塑剂如双酚A（BPA）时，染色质动态的稳态受到干扰。我们假设，一个子集的响应基因进行重新编程，进行永久沉默。在这些基因中可能会逐步获得抑制性组蛋白标记、多梳抑制物和DNA甲基转移酶。这种损伤信息可以遗传地传递给分化的后代，并且DNA甲基化在目标CpG岛中逐渐积累。这些CpG岛的表观基因组图谱可以识别潜在的生物标志物，用作监测人类暴露于环境雌激素的环境传感器。公共卫生相关性：暴露于低剂量的双酚A（BPA）（一种雌激素增塑剂）是否对人体健康有害仍有待最终确定。本研究的目的是证明人类乳腺上皮祖细胞对BPA暴露敏感。这种损伤记忆通过表观遗传机制维持，导致分化后代的异常增殖和乳腺肿瘤风险增加。在拟议的研究中开发的细胞学检测可用于筛选环境因子对人类细胞的潜在雌激素效应。此外，鉴定的表观遗传标记可用于鉴定具有暴露于BPA或其它环境雌激素的先前历史的乳腺癌患者。我们希望这项研究的结果支持将雌激素增塑剂（如BPA）的表观遗传效应纳入监管机构实施的风险评估。

DESCRIPTION (provided by applicant): We propose to study epigenetic changes in normal breast epithelial cells responding to physiological stimulation and environmentally perturbation. Integrative omic approaches will be used to determine global chromatin profiles in estrogen receptor (ER)1-positive cells stimulated with ligands. Complex regulatory networks of ER1 signaling are activated with concomitant alterations of chromatin in responsive genes. The expression of these genes then returns to the basal level. Chromatin is in a semi-open state, poised to receive transcription factors or repressors when signaling is activated by the next cycle of ligand. The homeostasis of chromatin dynamics is perturbed when epithelial progenitor cells are continually exposed to estrogenic plasticizers like bisphenol A (BPA). We hypothesize that a subset of responsive genes is reprogrammed to undergo permanent silencing. Step-wise acquisition of repressive histone marks, polycomb repressors, and DNA methyltransferases may take place in these genes. This injury information can be heritably transmitted to the differentiated progeny, and DNA methylation is progressively accumulated in target CpG islands. Epigenomic mapping of these CpG islands may identify potential biomarkers that are used as environmental sensors for monitoring human exposures to environmental estrogens. Public Health Relevance: It remains to be conclusively determined if exposure to low-dose bisphenol A (BPA), an estrogenic plasticizer, is harmful to human health. The purpose of this study is to show that epithelial progenitors in the human breast are sensitive to BPA exposure. This injury memory is maintained by an epigenetic mechanism, leading to aberrant proliferation of differentiated progeny and increased risk of breast neoplasm. The cytology assay developed in the proposed study can be used to screen environmental agents for potential estrogenic effects in human cells. Furthermore, the identified epigenetic markers may be used to identify breast cancer patients with a prior history of exposure to BPA or other environmental estrogens. It is our hope that the result of this study supports an inclusion of the epigenetic effects of estrogenic plasticizers, like BPA, into risk assessment implemented by regulatory agencies.