Prenatal Exposures & Procarcinogenic Mutations

描述(由申请人提供)：分子和传统流行病学研究表明，宫内环境暴露与儿童癌症，特别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)前瞻性队列研究的新生儿中测量染色体畸变率，这是一个被证实的癌症风险的生物标记物。父母研究人群由不吸烟的母亲和居住在纽约市低收入少数族裔社区的新生儿组成，他们受到不同程度的环境暴露，包括多环芳烃(PAH)和有机磷农药，如毒死蜱。产前暴露已通过问卷调查、空气监测和生物标志物进行了评估。在一项初步研究中，我们检测了脐带血中一小部分染色体的频率和范围 用1-6号染色体全染色体涂染探针的荧光原位杂交(FISH)技术检测CCCEH人群。在调整了全基因组的等价物后，我们发现稳定的和总的染色体畸变率与多环芳烃和毒死蜱的暴露显著相关，这是在怀孕后期通过个人空气监测获得的空气样本中测量的。与预期相反，在研究人群中观察到的每条绘制的染色体的畸变数与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，我们的初步数据表明，婴儿及其母亲中某些代谢酶基因多态性(GSTPI/CyPlal)的存在预测了对产前暴露的反应，即婴儿脐带血中染色体畸变率的增加。其他研究表明，参与有机磷解毒的PON1基因的多态也可能影响染色体异常的发展。婴儿DNA修复能力(XPD/XRCC1)可能也在染色体损伤的持续性中起作用。因此，我们希望探讨胎儿和母亲的基因型别在调节环境暴露和胎儿染色体异常发展中的作用。我们建议扩大我们的初步研究，以包括CCCEH队列中的总共300名新生儿，以便更好地研究暴露于多环芳烃和家用杀虫剂与染色体畸变率之间的关系。我们以前已经证明，儿童白血病特有的染色体易位通常发生在出生前，可能是启动事件。为了更好地了解与白血病发生的第一步可能存在的联系，我们将检查从300名队列成员分娩时获得的样本，以及从两岁时相同儿童的子集获得的另外100份样本，以检查染色体异常的存在。作为一项试点举措，我们还将审查融合产品TEL-AMLI。我们之前已经发现，TEL-AML1被认为是儿童ALL发展的必要但不充分的步骤，在健康的新生儿中存在的频率是ALL发病率的100倍。这些最初的染色体易位的来源尚不清楚，但似乎与产前环境暴露有关。染色体异常，包括涉及特定的白血病易位和基因组其他区域的异常，可能提供有关白血病发生的病原体和/或对这些毒物敏感的染色体的有用信息。此外，在暴露于这些污染物不成比例高的少数群体中，还没有评估染色体异常异常用来衡量多环芳烃和农药暴露在子宫中造成的遗传损害。染色体畸变率的增加是癌症，特别是血液癌的一个公认的风险标志。因此，他们可能能够提供与多环芳烃和杀虫剂有关的癌症风险的信息。到目前为止，这些暴露与癌症风险之间的联系还没有在更易受影响的人群中进行充分的研究，例如胎儿或儿童暴露在高水平的常见城市污染物中。我们建议的研究也提供了一个独特的机会来探索染色体异常易感性的变化。这些数据可以帮助我们了解环境暴露的各种致癌风险，从而有助于制定政策，保护面临最大风险的人口。因此，本研究的最终目的是为预防未来儿童ALL做出贡献。

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.