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: 8472494
• 负责人: Tim H.-M. Huang
• 金额: $ 41.14万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472494
• 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(申请人提供)：人类暴露在一种复杂的环境化学品混合物中。这一点从这些化学物质在人体内的浓度可以明显看出，比如那些通过乳腺癌和环境研究计划招募的女孩身上的化学物质。研究人员的目标是确定在青春期前对大鼠口服三种常见环境化学物质的组合、低剂量暴露对改变终生乳腺癌易感性的可能性。研究人员假设，双酚A(BPA)和邻苯二甲酸二乙基己酯(DEHP)联合暴露于双酚A(BPA)和邻苯二甲酸二乙基己酯(DEHP)将有利于在乳腺癌啮齿动物模型中相加或协同增加乳腺癌的发生。此外，他们将研究金雀异黄素同时给药时抑制BPA和DEHP增加乳腺癌易感性的可能性。其具体目标是：1)确定口服、青春期前接触BPA和DEHP是否会导致化学诱导的大鼠乳腺癌的相加或协同增加，以及饮食金雀异黄素是否会导致BPA和DEHP的作用被否定；2)通过基因芯片，从暴露于这些化学物质的大鼠乳腺中识别基因组特征，以阐明受影响的信号通路；3)使用基因阵列数据和Mira-Seq(甲基化CpG岛恢复分析结合大规模平行测序)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istein是否会影响表观DNA甲基化；4)在细胞和蛋白质水平上研究BPA、DEHP和/或染料木素在体内的作用机制(乳腺形态、细胞增殖、细胞凋亡和通过基因芯片和表观遗传学分析确定的差异调控的信号通路)；5)测量BPA、DEHP和/或染料木素在青春期前单独或联合暴露于大鼠血和尿中的化学物质浓度。识别早期生命中常见的组合化学暴露会改变乳腺癌的易感性，这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。

项目成果

Significance of rat mammary tumors for human risk assessment.

• DOI: 10.1177/0192623314532036
• 发表时间: 2015-02
• 期刊: Toxicologic pathology
• 影响因子: 1.5
• 作者: Russo J