Pregnancy and Prenatal PAHs and other Environmental Exposures and Breast Cancer

 描述（由申请人提供）：妊娠和产前多环芳烃和其他环境暴露与乳腺癌积累的人类和动物数据支持乳腺癌风险在易感性的关键窗口期间被修改的假设。这些包括产前和怀孕窗口，在此期间，乳房的结构和功能发生变化，乳房细胞迅速增殖。哥伦比亚儿童环境健康中心（CCCEH）出生队列是世界上少数几个拥有大量生物标本和环境监测数据的队列之一，这些数据反映了母亲怀孕期间和儿童产前期间收集的当代环境。除了在整个怀孕期间采集多份尿液样本和分娩时采集血液样本外，母亲们还在白天佩戴一个装有个人环境空气监测器的小背包，连续几天测量个人空气污染暴露。该队列仅由居住在纽约市的西班牙裔多米尼加人和非洲裔美国人妇女及其子女组成，他们在1998年至2006年期间出生在布朗克斯或北方曼哈顿（N = 543名母亲，其中52.5%（N = 285）为母女二人组）。这些家庭反映了我们当地的社区，也代表了年轻女性乳腺癌发病率迅速增加的人口亚群。我们建议建立在这个独特的出生队列，特别是通过测量乳腺组织特征和乳腺密度，通过光学光谱（OS）为所有母亲和女儿和乳房X线摄影为40岁以上的母亲乳腺癌风险的一个强有力的中间标记（项目1）。我们将收集现在青春期女孩（年龄范围10 - 16岁）及其母亲的乳房组织特征、人体测量学和生物标本的临床测量结果。很少有人体研究对接触相同污染物的情况进行测量，以便同时评估其对母亲和女儿患乳腺癌风险的影响。我们将重点关注多环芳烃（PAH），燃烧副产品被IARC和美国环保署列为可能的致癌物。我们将把我们的人类研究与强大的动物实验相结合，研究妊娠期间空气传播的PAH对改变乳腺组织和系统性DNA甲基化的作用，以及对母亲、其后代及其后代的DNA修复和凋亡重要的基因表达（项目2）。我们还将研究PAH对PPAR γ基因调控的作用，这是一种对脂质代谢很重要并与乳腺癌风险相关的基因，并检查动物和人类模型中的乳腺组织改变，并比较两种模型系统中PAH暴露较高的人类中甲基化的基因。项目3通过建立CCCEH社区外展和翻译核心将两个项目联系在一起，将我们的研究结果与我们的研究参与者和赫伯特欧文综合癌症中心（CCCC）和哥伦比亚大学集水区的更大社区的环境暴露和乳腺癌预防信息相结合。

 DESCRIPTION (provided by applicant): Pregnancy and Prenatal PAHs and other Environmental Exposures and Breast Cancer Accumulating human and animal data support the hypothesis that breast cancer risk is modified during key windows of susceptibility. These include the prenatal and pregnancy windows, during which time the breast changes in structure and function and breast cells rapidly proliferate. The Columbia Center for Children's Environmental Health (CCCEH) birth cohort is one of the few cohorts in the world with extensive biospecimens and environmental monitoring data that are reflective of the contemporary environment collected during the pregnancy time period for mothers and during the prenatal period for children. In addition to multiple samples of urine throughout pregnancy and blood at the time of delivery, mothers wore a small backpack containing a personal ambient air monitor during the daytime hours for several days to measure personal air pollution exposures. The cohort is comprised exclusively of Hispanic Dominican and African-American women residing in New York City and their children, who were born in the Bronx or Northern Manhattan between 1998 and 2006 (N=543 mothers of whom 52.5% (N=285) are mother-daughter dyads). These families reflect our local community, as well as represent the population subgroups experiencing a rapidly increasing breast cancer incidence in young women. We propose to build on this unique birth cohort specifically by measuring breast tissue characteristics and breast density, a strong intermediate marker of breast cancer risk through optical spectroscopy (OS) for all mothers and daughters and mammography for mothers over 40 years of age (Project 1). We will collect clinical measures of breast tissue characteristics, anthropometry and biospecimens in the now adolescent girls (age range 10-16 years) and their mothers. There are few human studies in which exposures to the same pollutants have been measured to allow for simultaneous evaluation of their effect on both the mother's breast cancer risk and that of her daughter. We will focus on Polycyclic Aromatic Hydrocarbons (PAH), by-products of combustion classified as possible carcinogens by IARC and the US EPA. We will couple our human study with robust animal experiments investigating the role of airborne PAH during gestation on altered mammary tissue and systemic DNA methylation and expression of genes important to DNA repair and apoptosis in mothers, their offspring, and their grandoffspring (Project 2). We also will investigate the role of PAH on PPARγ gene regulation, a gene important to lipid metabolism and associated with breast cancer risk, as well as examine mammary tissue alterations in both the animal and human models and compare genes that are methylated in humans with higher PAH exposure across both model systems. Project 3 ties together both projects by building on the CCCEH Community Outreach and Translation Core to integrate our research findings with messages about environmental exposures and breast cancer prevention in our study participants and larger community in our Herbert Irving Comprehensive Cancer Center (HICCC) and Columbia University catchment area.