Prenatal Exposures & Procarcinogenic Mutations

产前暴露

• 批准号: 7089849
• 负责人: Manuela A Orjuela
• 金额: $ 34.51万
• 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/7089849
• 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，子宫环境暴露与儿童期癌症的风险增加，尤其是急性白血病之间可能存在关系。我们建议评估可能增加儿童时期风险的出生前环境暴露。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癌症风险的验证生物标志物染色体畸变。父母研究人群由居住在纽约市低收入少数民族社区中的非吸烟母亲和新生儿组成，他们受到不同水平的环境暴露，包括多环芳族碳氢化合物（PAH）和有机磷酸盐农药，例如毒性磷酸盐。已经通过问卷，空气监测和生物标志物评估了产前暴露。在一项试点研究中，我们检查了一小部分中脐带血中染色体畸变的频率和范围 使用荧光原位杂交（FISH）的CCCEH种群与1-6染色体的整个染色体涂料探针。调整了整个基因组当量，我们发现，稳定和总染色体畸变的频率与暴露于PAH和毒性狼疮的暴露显着相关，这是通过在妊娠三年中通过个人空气监测获得的空气过时测量的。与预期相反，在这项研究人群中观察到的每个彩绘染色体的畸变数与DNA含量不成比例，这表明某些染色体对某些化学剂更敏感。此外，我们的试验数据表明，婴儿及其母亲在婴儿脐带血中的染色体像差增加方面，存在某些代谢酶多态性（GSTPI/cyplal）及其母亲，可以预测对产前暴露的反应。其他研究表明，参与有机磷酸盐排毒的PON1基因中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）也可能在染色体损伤的持续性中起作用。因此，我们希望探索胎儿和母体基因型在环境暴露的介导以及胎儿中染色体畸变的发展中的作用。我们建议将我们的试点研究扩展，以包括来自CCCEH队列的总共300名新生儿，以便更好地检查PAH与家用农药的暴露与染色体畸变水平之间的关系。我们以前已经表明，小儿白血病的染色体易位特征通常是在本应纳特原状出现的，这可能是作为启动事件。为了更好地理解白血病的第一步的可能联系，我们将研究从300个队列成员分娩时获得的样品，并在二岁时从同一儿童的一个子集中获得另外100个样本，以存在染色体像差。作为试点计划，我们还将检查融合产品Tel-AMLI。我们以前已经找到了Tel-AML1，这被认为是童年的发展是必要但不足的一步，它以100倍的频率存在于健康的新生儿中。这些初始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，包括涉及特定白血病易位的染色体异常和基因组其他区域的染色体异常，可能会提供有关涉及白血病发生的病因和/或染色体易受毒物的有用信息。此外，在少数族裔人群中，尚未评估染色体畸变对子宫和农药暴露造成的遗传损害的效用，而这些污染物暴露于这些污染物的少数族裔人群中尚未评估。染色体畸变的增加是癌症，尤其是血液学癌症的既定风险标志。因此，他们可能能够提供有关与PAH和农药关系的癌症风险的信息。到目前为止，在更易感的人群中，例如胎儿或暴露于高水平的普通城市污染物的儿童中，这些暴露与癌症风险之间的联系尚未得到充分的研究。我们提出的研究还提供了一个独特的机会，可以探索染色体畸变易感性的变化。这样的数据可以帮助我们告知环境暴露的各种致癌风险，从而有助于制定将保护人口最大风险的政策。因此，这项研究的最终目标是为预防未来的童年做出贡献。