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Breast Cancer Genomics in Windows of Susceptibility to Endocrine Disruptors

乳腺癌基因组学对内分泌干扰物的易感性窗口

基本信息

批准号：
8914808
负责人：
Jia Chen
金额：
$ 16.95万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-07 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914808
关键词：
Address Animals Biological Carbon Communication Communities Complex Mixtures Databases Development Dietary intake Dose Endocrine Disruptors Endocrine system Environmental Exposure Epidemiologic Studies Exogenous Factors Exposure to Future Gene Expression Genes Genetic Polymorphism Genome Goals Hormonal Hormones Human Individual Investigation Laboratories Laboratory Finding Lead Life Cycle Stages Link Long Island Breast Cancer Study Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Metabolism Methylation Modeling Molecular Molecular Profiling Neonatal Phenols Physiological Policy Maker Population Population Study Predisposition Principal Investigator Rattus Research Design Research Personnel Resources Reverse Transcriptase Polymerase Chain Reaction Risk Scheme Testing Time Tissues Translations Woman animal model development biobank cancer genomics endocrine disruptor exposure exposed human population human disease innovation malignant breast neoplasm member neglect outreach phthalates population based prenatal exposure programs promoter research study urinary

项目摘要

DESCRIPTION (provided by applicant): Breast cancer (BC) is a hormone-dependent malignancy. Endocrine disrupters (EDs) are exogenous substances with hormonal activity in the endocrine system that disrupts the physiologic function of endogenous hormones. Animal studies unequivocally demonstrated that EDs disrupt development of mammary tissues and increase the risk of mammary tumors depending upon the dose and timing of exposure. However, evidence directly linking EDs and BC in human populations is far from conclusive. Two major issues have seriously limited translation of laboratory experiments into population studies. First, the window of susceptibility has not been clearly elucidated in humans. Second, most animal studies have tested one ED at a time often with doses orders of magnitude higher than common human exposure. Thus dose-extrapolations are usually performed neglecting possible synergistic or antagonist effects in a complex mixture of EDs that humans are more likely to encounter. Population studies of ED-BC associations are urgently needed that incorporate realistic exposure schemes and the concept of susceptibility windows. This proposed study uses an innovative approach of combining both an animal and a population study. First, animals will be exposed to three commonly-used EDs (individually and in combination) in physiological relevant doses at 6 different windows of development. Whole-genome expression and pathological features of rat mammary tissues will be profiled to provide both quantitative and qualitative biological effects of EDs. The investigators will then validate the laboratory findings in the population-based Long Island Breast Cancer Study Project (LIBCSP) through the use of its extensive database and biorepository. The overarching goal is to explore whether environmental EDs are acting in specific developmental windows and whether they exert their biological effects independently or synergistically/antagonistically in breast tissue leading to breast cancer development. Results from this study would provide invaluable information on effects of environmental exposure during women's life course, which may be used to direct future molecular epidemiological studies on ED exposure and BC. Should this study approach provide the information as expected, it will lead to the development of an animal model that can be used to study a wide range of EDs and other exogenous factors with significant implications for future investigations on the timing of environmental exposures to human diseases.

描述(申请人提供)：乳腺癌(BC)是一种激素依赖的恶性肿瘤。内分泌干扰物(EDs)是内分泌系统中具有荷尔蒙活性的外源性物质，破坏内源性激素的生理功能。动物研究明确表明，EDs干扰乳腺组织的发育，并增加乳腺肿瘤的风险，这取决于暴露的剂量和时间。然而，在人类群体中直接将EDS和BC联系起来的证据还远远不是决定性的。两个主要问题严重限制了将实验室实验转化为人口研究。首先，人类的易感窗口尚未明确阐明。其次，大多数动物研究一次测试一种ED，剂量往往比普通人类暴露的剂量高出几个数量级。因此，剂量外推通常忽略了人类更有可能遇到的复杂的EDs混合物中可能的协同或拮抗效应。迫切需要对ED-BC相关性进行人口研究，纳入现实的暴露方案和易感窗口的概念。这项拟议的研究采用了一种创新的方法，将动物研究和种群研究结合起来。首先，动物将在6个不同的发育窗口暴露于三种常用的EDs(单独和联合使用)，剂量与生理相关。将描述大鼠乳腺组织的全基因组表达和病理特征，以提供EDS的定量和定性生物学效应。然后，研究人员将通过使用其广泛的数据库和生物库来验证基于人群的长岛乳腺癌研究项目(LIBCSP)的实验室结果。首要目标是探索环境ED是否在特定的发育窗口中发挥作用，以及它们是否在乳腺组织中独立地或协同/拮抗地发挥其生物学效应，从而导致乳腺癌的发生。这项研究的结果将为女性生命过程中环境暴露的影响提供宝贵的信息，这些信息可能被用于指导未来关于ED暴露和BC的分子流行病学研究。如果这种研究方法提供了预期的信息，它将导致一种动物模型的发展，该模型可用于研究广泛的ED和其他外部因素，对未来关于环境暴露于人类疾病的时间的调查具有重要意义。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Paired Serum and Urine Concentrations of Biomarkers of Diethyl Phthalate, Methyl Paraben, and Triclosan in Rats.

大鼠中邻苯二甲酸二乙酯、对羟基苯甲酸甲酯和三氯生生物标志物的配对血清和尿液浓度。

DOI：
10.1289/ehp.1409586
发表时间：
2016-01
期刊：
Environmental health perspectives
影响因子：
10.4
作者：
Teitelbaum SL;Li Q;Lambertini L;Belpoggi F;Manservisi F;Falcioni L;Bua L;Silva MJ;Ye X;Calafat AM;Chen J
通讯作者：
Chen J

Changes in mammary histology and transcriptome profiles by low-dose exposure to environmental phenols at critical windows of development.

DOI：
10.1016/j.envres.2016.10.021
发表时间：
2017-01
期刊：
ENVIRONMENTAL RESEARCH
影响因子：
8.3
作者：
Gopalakrishnan, Kalpana;Teitelbaum, Susan L.;Lambertini, Luca;Wetmur, James;Manservisi, Fabiana;Falcioni, Laura;Panzacchi, Simona;Belpoggi, Fiorella;Chen, Jia
通讯作者：
Chen, Jia

Effect of postnatal low-dose exposure to environmental chemicals on the gut microbiome in a rodent model.

DOI：
10.1186/s40168-016-0173-2
发表时间：
2016-06-14
期刊：
Microbiome
影响因子：
15.5
作者：
Hu J;Raikhel V;Gopalakrishnan K;Fernandez-Hernandez H;Lambertini L;Manservisi F;Falcioni L;Bua L;Belpoggi F;L Teitelbaum S;Chen J
通讯作者：
Chen J

Exposure to fogger trucks and breast cancer incidence in the Long Island Breast Cancer Study Project: a case-control study.