Combinational Environmental Chemicals Altering Susceptibility for Mammary Cancer

描述（由申请人提供）：人类暴露于环境化学物质的复杂混合物中。从这些化学物质在人体内的浓度就可以看出这一点，比如通过乳腺癌和环境研究项目招募的女孩。研究人员的目标是确定在大鼠青春期前口服三种常见环境化学物质的组合低剂量暴露的潜力，以改变终生乳腺癌易感性。研究人员推测，双酚A （BPA）和邻苯二甲酸二乙己基酯（DEHP）的联合暴露会增加或协同增加啮齿动物乳腺癌模型的乳腺癌发展。此外，他们将研究染料木素在同时使用时抑制双酚a和DEHP增加乳腺癌易感性的能力的潜力。具体目的是：1)确定口服、青春期前暴露于双酚a和DEHP是否会导致化学诱导的大鼠乳腺癌的添加性或协同性增加，以及膳食染料木素是否会导致双酚a和DEHP的负面作用；2)通过基因微阵列识别暴露于这些化学物质的大鼠乳腺的基因组特征，以阐明受影响的信号通路；3)利用基因阵列数据和MIRA-seq（甲基化CpG岛恢复试验结合大规模平行测序）的信息，研究人员将确定候选DNA甲基化基因，并确定青春期前BPA、DEHP和染料木素是否会影响表观遗传DNA甲基化；4)在细胞和蛋白质水平上研究其在体内的作用机制（通过基因阵列和表观遗传实验确定乳腺形态、细胞增殖、凋亡和信号通路的差异调节）；5)测量在青春期前单独或联合暴露于BPA、DEHP和/或染料木素的大鼠血液和尿液中的化学物质浓度。鉴别早期生活中通常发生在人类中改变乳腺癌易感性的组合化学物质，将有助于我们理解环境化学物质在乳腺癌病因和预防中所起的复杂作用。

DESCRIPTION (provided by applicant): Humans are exposed to a complex mixture of environmental chemicals. This is evident from the internal concentrations of these chemicals in humans, such as those from girls recruited via the Breast Cancer and the Environment Research Program. It is the investigators' goal to determine the potential of combinational, low dose exposures to three of these common environmental chemicals, administered orally in rats during the prepubertal period, to alter lifetime mammary cancer susceptibility. The investigators hypothesize that combinational exposure to Bisphenol A (BPA) and di-2-ethylhexyl phthalate (DEHP) will predispose for an additive or synergistic increase in mammary cancer development in a rodent model of mammary cancer. Furthermore, they will investigate the potential of genistein, when administered concurrently, to suppress the ability of BPA and DEHP to increase mammary cancer susceptibility. The specific aims are: 1) to determine if oral, prepubertal exposure to the combination of BPA and DEHP will result in an additive or synergistic increase in chemically-induced mammary cancer in rats, and if dietary genistein will result in negating the effects of BPA and DEHP; 2) to identify genomic signatures, via gene microarrays, from mammary glands of rats exposed to these chemicals to elucidate affected signaling pathways; 3) using the information from the gene array data and MIRA-seq (methylated CpG islands recovery assay coupled with massively parallel sequencing), the investigators will identify candidate DNA methylated genes and determine if prepubertal BPA, DEHP and genistein will effect epigenetic DNA methylation; 4) to investigate in vivo mechanisms of action at the cellular and protein levels (mammary gland morphology, cell proliferation, apoptosis and signaling pathways determined to be differentially regulated via gene array and eipigenetic assays); and 5) to measure concentrations of chemicals in blood and urine of rats exposed, alone or in combination, to BPA, DEHP and/or genistein during the prepubertal period. The identification of early life combinational chemical exposures commonly reported to occur in humans to alter mammary cancer susceptibility will facilitate our understanding of the complex role environmental chemicals play in breast cancer causation and prevention.