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: 8150389
• 负责人: Tim H.-M. Huang
• 金额: $ 46.16万
• 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/8150389
• 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; 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物质的复杂混合物中。从这些化学物质在人类体内的浓度可以明显看出这一点，例如通过乳腺癌和环境研究计划招募的女孩体内的浓度。 研究人员的目标是确定在青春期前对大鼠口服低剂量组合暴露于这三种常见环境化学物质的潜力，以改变终生乳腺癌易感性。 研究人员推测，在啮齿动物乳腺癌模型中，同时接触双酚 A (BPA) 和邻苯二甲酸二-2-乙基己酯 (DEHP) 会导致乳腺癌发生的叠加或协同增加。 此外，他们还将研究金雀异黄素在同时给药时抑制 BPA 和 DEHP 增加乳腺癌易感性的能力的潜力。 具体目标是：1) 确定青春期前口服 BPA 和 DEHP 的组合是否会导致大鼠化学诱发乳腺癌的累加或协同增加，以及饮食金雀异黄素是否会导致消除 BPA 的影响和 DEHP； 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 岛恢复分析与大规模并行测序相结合）的信息，研究人员将识别候选 DNA 甲基化基因，并确定青春期前 BPA、DEHP 和金雀异黄酮是否会影响表观遗传 DNA 甲基化； 4) 研究细胞和蛋白质水平的体内作用机制（乳腺形态、细胞增殖、细胞凋亡和通过基因阵列和表观遗传学测定确定差异调节的信号通路）； 5) 测量在青春期前单独或组合暴露于 BPA、DEHP 和/或金雀异黄酮的大鼠血液和尿液中化学物质的浓度。据报道，生命早期的组合化学物质暴露通常会改变人类乳腺癌的易感性，而鉴定这些化学物质将有助于我们了解环境化学物质在乳腺癌致病和预防中所发挥的复杂作用。