Prenatal Exposures & Procarcinogenic Mutations

产前暴露

• 批准号: 6827616
• 负责人: Manuela A Orjuela
• 金额: $ 36.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827616
• 关键词: acute lymphocytic leukemia; cancer risk; carbopolycyclic compound; chemical carcinogenesis; chromosome aberrations; chromosome deletion; chromosome translocation; clinical research; cord blood; embryo /fetus toxicology; environmental exposure; enzyme activity; fluorescence microscopy; fluorescent in situ hybridization; gene environment interaction; genotype; human genetic material tag; human pregnant subject; longitudinal human study; low socioeconomic status; newborn human (0-6 weeks); organophosphorus insecticide; pediatric neoplasm /cancer; polymerase chain reaction; questionnaires

DESCRIPTION (provided by applicant): Molecular and traditional epidemiology studies have indicated a possible relationship between in utero environmental exposures and increased risk for childhood cancers, especially acute leukemias. We propose to evaluate pre- natal environmental exposures that may increase the risk of childhood ALL. We propose to measure chromosomal aberrations, a validated biomarker of cancer risk, in a subset of newborns from the Columbia Center for Children's Environmental Health (CCCEH) Prospective Cohort Study. The parent study population is comprised of non-smoking mothers and newborns residing in low-income, minority neighborhoods in New York City, who are subject to varying levels of environmental exposures including polycyclic aromatic hydrocarbons (PAH) and organophosphate pesticides such as chlorpyrifos. Prenatal exposures have been assessed by questionnaires, air monitoring, and biomarkers. In a pilot study, we have examined the frequency and range of chromosome aberrations in cord blood in a small subset of the CCCEH population using fluorescence in situ hybridization (FISH) with whole chromosome painting probes for chromosomes 1-6. After adjustment for whole genome equivalents, we have found that the frequencies of stable and total chromosomal aberrations are significantly associated with exposure to PAH and chlorpyrifos, measured in air samples obtained by personal air monitoring during the third trimester of pregnancy. Contrary to expectation, the number of aberrations observed per painted chromosome in this study population is not proportional to DNA content, suggesting that certain chromosomes are more sensitive to certain chemical agents. In addition, our pilot data suggest that presence of certain metabolizing enzyme polymorphisms (GSTPI/CYPlal) in infants and their mothers predicts response to prenatal exposures in terms of increased chromosomal aberrations in the infants' cord blood. Other studies indicate that polymorphisms in the PON1 gene involved in the detoxification of organophosphates are also likely to affect the development of chromosomal aberrations. Infant DNA repair capacity (XPD/XRCC1) probably also plays a role in the persistence of chromosomal damage. We therefore wish to explore the role of fetal and maternal genotypes on the mediation of environmental exposures and the development of chromosomal aberrations in the fetus. We propose to expand our pilot study to include a total of 300 newborns from the CCCEH cohort in order to better examine the relationship between exposures to PAH and household pesticides and levels of chromosomal aberrations. We have previously shown that chromosomal translocations characteristic of pediatric leukemia often arise pre-natally, probably as initiating events. In order to better understand a possible link to the first step in leukemogenesis, we will examine samples obtained at delivery from 300 cohort members and an additional 100 samples from a subset of the same children at age two, for the presence of chromosomal aberrations. As a pilot initiative, we will also examine the fusion product, TEL-AMLI. We have previously found TEL-AML1, which is thought to be a necessary but not sufficient step for the development of childhood ALL, to be present in healthy newborns at a frequency 100- fold that of the incidence of ALL. The origin of these initial chromosomal translocations is not known but appears to be linked to prenatal environmental exposures. Chromosomal abnormalities, both those involving specific leukemogenic translocations and those in other areas of the genome, may offer useful information on the etiologic agents involved in leukemogenesis and/or the chromosomes susceptible to these toxicants. Moreover, the utility of chromosomal aberrations to measure genetic damage incurred in utero from PAH and pesticide exposures has not been assessed in a minority population with disproportionately high exposure to these pollutants. Increases in chromosomal aberrations are an established risk marker for cancer, particularly hematological cancers. Thus they may be able to provide information on cancer risk in relationship to PAH and pesticides. Thus far, the link between these exposures and cancer risk has not been adequately studied in more susceptible populations such as fetuses or children exposed to high levels of common urban contaminants. Our proposed study also offers a unique opportunity to explore variations in susceptibility to chromosomal aberrations. Such data can help inform us of the full range of carcinogenic risk from environmental exposures and thus contribute to the formation of policies that will protect populations at greatest risk. Thus, the ultimate goal of this research is to contribute to the prevention of future childhood ALL.

描述（由申请人提供）：分子和传统流行病学研究表明，子宫内环境暴露与儿童癌症（尤其是急性白血病）风险增加之间可能存在关系。我们建议评估可能增加儿童 ALL 风险的产前环境暴露。我们建议在哥伦比亚儿童环境健康中心 (CCCEH) 前瞻性队列研究的一部分新生儿中测量染色体畸变，这是一种经过验证的癌症风险生物标志物。家长研究人群由居住在纽约市低收入少数民族社区的不吸烟母亲和新生儿组成，他们受到不同程度的环境暴露，包括多环芳烃 (PAH) 和毒死蜱等有机磷农药。通过问卷、空气监测和生物标志物评估产前暴露。在一项试点研究中，我们检查了一小部分脐带血中染色体畸变的频率和范围。 使用荧光原位杂交 (FISH) 和全染色体染色探针对 1-6 号染色体进行 CCCEH 群体分析。在对全基因组当量进行调整后，我们发现稳定和总染色体畸变的频率与多环芳烃和毒死蜱的暴露显着相关，这是在妊娠晚期通过个人空气监测获得的空气样本中测量到的。与预期相反，在本研究群体中每条染色染色体观察到的畸变数量与 DNA 含量不成正比，这表明某些染色体对某些化学试剂更敏感。此外，我们的试点数据表明，婴儿及其母亲中某些代谢酶多态性（GSTPI/CYPlal）的存在可以预测婴儿脐带血中染色体畸变增加对产前暴露的反应。其他研究表明，参与有机磷解毒的 PON1 基因的多态性也可能影响染色体畸变的发展。婴儿 DNA 修复能力 (XPD/XRCC1) 可能也在染色体损伤的持续性中发挥着作用。因此，我们希望探讨胎儿和母体基因型在环境暴露和胎儿染色体畸变的介导中的作用。我们建议扩大试点研究范围，纳入 CCCEH 队列中的总共 300 名新生儿，以便更好地研究 PAH 和家用杀虫剂暴露与染色体畸变水平之间的关系。我们之前已经表明，小儿白血病的染色体易位特征通常在产前出现，可能是起始事件。为了更好地了解与白血病发生的第一步之间可能存在的联系，我们将检查从 300 名队列成员分娩时获得的样本以及从同一儿童的两岁子集中获取的另外 100 个样本，以检查是否存在染色体畸变。作为一项试点计划，我们还将研究融合产品 TEL-AMLI。我们之前发现 TEL-AML1（被认为是儿童 ALL 发展的必要但非充分步骤）在健康新生儿中的存在频率是 ALL 发病率的 100 倍。这些最初染色体易位的起源尚不清楚，但似乎与产前环境暴露有关。染色体异常，包括特定的致白血病易位和基因组其他区域的染色体异常，可以提供有关涉及白血病发生的病因和/或对这些毒物敏感的染色体的有用信息。此外，尚未在接触这些污染物的比例过高的少数人群中评估染色体畸变的效用，以衡量多环芳烃和农药暴露在子宫内造成的遗传损害。染色体畸变的增加是癌症，特别是血液癌症的既定风险标志。因此，他们或许能够提供与多环芳烃和农药相关的癌症风险信息。迄今为止，尚未在更易受影响的人群（例如暴露于高水平常见城市污染物的胎儿或儿童）中充分研究这些暴露与癌症风险之间的联系。我们提出的研究还提供了一个独特的机会来探索染色体畸变易感性的变化。此类数据可以帮助我们了解环境暴露带来的全方位致癌风险，从而有助于制定保护面临最大风险的人群的政策。因此，这项研究的最终目标是为预防未来儿童 ALL 做出贡献。