Combinational Environmental Chemicals Altering Susceptibility for Mammary Cancer

组合环境化学物质改变乳腺癌的易感性

• 批准号: 8280369
• 负责人: Tim H.-M. Huang
• 金额: $ 43.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280369
• 关键词: Affect; Apoptosis; Biological Assay; Blood; Body measure procedure; Body of uterus; Candidate Disease Gene; Cell Proliferation; Chemical Exposure; Chemicals; Complex; Complex Mixtures; Coupled; CpG Islands; DNA; DNA Methylation; Data; Development; Diet; Dose; Early identification; Environment; Epigenetic Process; Etiology; Exposure to; Genes; Genistein; Genomics; Goals; Human; Immunohistochemistry; Life; Mammary Neoplasms; Mammary gland; Measures; Methylation; Morphology; Oral; Play; Predisposition; Prevention; Principal Investigator; Proteins; Rattus; Recovery; Recruitment Activity; Regulation; Reporting; Research; Research Personnel; Rodent Model; Role; Signal Pathway; Technology; Toxic effect; Urine; Vagina; Weight; Western Blotting; bisphenol A; coral; environmental chemical; girls; in vivo; malignant breast neoplasm; phthalates; prepuberty; programs

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.

描述（由申请人提供）：人类暴露于环境化学品的复杂混合物。这一点从这些化学物质在人体内的内部浓度可以看出，例如通过乳腺癌和环境研究方案招募的女孩。 研究人员的目标是确定这些常见环境化学品中的三种的组合低剂量暴露的潜力，在青春期前口服给药大鼠，以改变终生乳腺癌易感性。 研究人员假设，在啮齿动物乳腺癌模型中，双酚A（BPA）和邻苯二甲酸二（2-乙基己基）酯（DEHP）的联合暴露将使乳腺癌的发生增加或协同增加。 此外，他们还将研究染料木黄酮在同时给药时抑制BPA和DEHP增加乳腺癌易感性的能力。 具体目标是：1）确定青春期前口服BPA和DEHP组合是否会导致大鼠化学诱导乳腺癌的叠加或协同增加，以及膳食染料木黄酮是否会导致抵消BPA和DEHP的影响; 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）使用来自基因阵列数据和MIRA-seq的信息（甲基化CpG岛恢复试验结合大规模平行测序），研究者将鉴定候选DNA甲基化基因，并确定青春期前BPA、DEHP和染料木黄酮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体内作用机制（乳腺形态、细胞增殖、细胞凋亡和通过基因阵列和表型遗传学测定确定的差异调节的信号传导途径）;和5）测量在青春期前单独或联合暴露于BPA、DEHP和/或染料木黄酮的大鼠血液和尿液中的化学物质浓度。早期生活的组合化学品暴露的识别通常报告发生在人类改变乳腺癌的易感性，将有助于我们了解复杂的作用，环境化学品在乳腺癌的病因和预防。