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学变化。综合组学方法将被用来确定受配体刺激的雌激素受体(ER)1阳性细胞的整体染色质分布。ER1信号的复杂调控网络被激活，伴随着反应基因中染色质的变化。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，当信号被下一周期的配体激活时，准备接受转录因子或抑制物。当上皮祖细胞持续暴露在雌激素增塑剂如双酚A(BPA)中时，染色质动态的动态平衡被扰乱。我们假设，响应基因的一个子集被重新编程，以经历永久沉默。抑制性组蛋白标记、多梳抑制物和DNA甲基转移酶的逐步获得可能发生在这些基因中。这种损伤信息可以遗传地传递给分化的后代，DNA甲基化逐渐积累在目标CpG岛上。这些CpG岛的表观基因组图谱可能识别潜在的生物标记物，这些生物标记物被用作环境传感器，用于监测人类对环境雌激素的暴露。与公共卫生的相关性：暴露于低剂量双酚A(BPA)--一种雌激素增塑剂--是否对人类健康有害仍有待确定。这项研究的目的是表明人类乳房的上皮祖细胞对双酚A的暴露很敏感。这种损伤记忆是由表观遗传机制维持的，导致分化的后代异常增殖，增加乳房肿瘤的风险。在拟议的研究中开发的细胞学测试可以用于筛选环境因素对人类细胞的潜在雌激素效应。此外，识别的表观遗传标记可用于识别有双酚A或其他环境雌激素暴露史的乳腺癌患者。我们希望这项研究的结果支持将双酚A等雌激素增塑剂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.