Project 1 - In Utero Chemical Exposures, Immune Status, and Childhood Leukemia

摘要 项目1 -室内化学品暴露、免疫状态和儿童白血病 急性淋巴细胞白血病（ALL）是儿童最常见的恶性肿瘤。有令人信服的证据 儿童ALL通常在子宫内开始，并且ALL风险受新生儿免疫状态的影响。的儿童 发展成ALL的人在出生后的第一年往往有更多的暴发性感染，尽管他们在出生后的第一年中 比对照组更频繁地暴露于常见感染。对于这种明显的免疫现象， 发生ALL的儿童中的失调是免疫系统在子宫内编程的异常。有 有几条证据支持这一假设首先，我们观察到， 在出生时，IL-10（一种免疫抑制细胞因子）的水平较低。第二，产妇 怀孕期间的感染和出生后母亲免疫球蛋白E（IgE）水平较高是积极的 与ALL风险相关，提示母体调节胎儿免疫发育在 确定所有风险。最后，我们已经确定了与儿童ALL风险增加相关的化学物质， 其中一些是免疫状态的潜在修饰剂，包括多氯联苯、多溴联苯、 二苯醚、多环芳烃和烟草烟雾。本拟议项目的目标 是首次评估子宫内化学品暴露与婴儿免疫状态之间的相互作用， 母亲和孩子都在童年的发展中。我们假设子宫内的特异性 化学品暴露将影响母亲和新生儿的免疫状态， 所有儿童的风险。为了验证这一假设，我们将利用两个现有的特殊资源， NIH资助的研究（通过核心A）：出生时采集的新生儿干血点（新生儿血点）， 加州儿童白血病研究（CCLS），一项基于人群的病例对照研究， 来自加州母子出生队列的新生儿血斑和孕中期母体血清。在 在这两个群体中，我们将（1）通过测量免疫调节细胞因子来表征免疫状态， 生物标本，（2）检查子宫内化学品暴露（项目2中确定）是否影响免疫 状态，和（3）评估宫内化学品暴露与儿童ALL风险的关系， 考虑到免疫状态。在CCLS人群中，家庭灰尘测量和自我报告的化学物质 暴露将用于进一步描述子宫内化学品暴露的特征，以及母体感染的数据 将用于帮助表征母体免疫状态。一种基因工程小鼠模型， 儿童ALL将用于阐明子宫内化学品暴露的机制， 母亲/新生儿免疫状态相互作用，启动ALL（通过核心C）。此外，关于 母亲/新生儿免疫状态将纳入DNA甲基化分析（项目3）。我们 拟议的项目将填补儿童ALL病因学的重要知识空白，并进一步 了解子宫内化学品暴露的免疫调节作用。

ABSTRACT Project 1 – In Utero Chemical Exposures, Immune Status, and Childhood Leukemia Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. There is compelling evidence that childhood ALL is often initiated in utero and ALL risk is affected by neonatal immune status. Children who developed ALL tend to have had more fulminant infections during the first year of life, despite having had less frequent exposure to common infections than controls. One plausible explanation for this apparent immune dysregulation in children who develop ALL is aberrant in utero programming of the immune system. There are several lines of evidence that support this hypothesis. First, we have observed that children who develop ALL later in life had lower levels of IL-10, an immunosuppressive cytokine, at birth. Second, both maternal infections during pregnancy and higher maternal immunoglobulin E (IgE) levels after birth are positively associated with ALL risk, suggesting a role for maternal modulation of fetal immune development in determining ALL risk. Finally, we have identified chemicals associated with increased risk of childhood ALL, some of which are potential modifiers of immune status, including polychlorinated biphenyls, polybrominated diphenyl ethers, polycyclic aromatic hydrocarbons, and tobacco smoke. The objective of this proposed project is to assess, for the first time, the interplay between in utero chemical exposures and the immune status of both the mother and the child in the development of childhood ALL. We hypothesize that specific in utero chemical exposures will impact maternal and neonatal immune status and the altered immune status increases the risk of childhood ALL. To test this hypothesis, we will leverage exceptional resources from two existing NIH-funded studies (through Core A): neonatal dried blood spots collected at birth (neonatal blood spots) from the California Childhood Leukemia Study (CCLS), a population-based case-control study, and paired samples of neonatal blood spots and second trimester maternal serum from the California Mother-Child Birth Cohort. In both populations, we will (1) characterize immune status by measuring immunomodulatory cytokines in biospecimens, (2) examine whether in utero chemical exposures (identified in Project 2) influence immune status, and (3) assess the relation of in utero chemical exposures to the risk of childhood ALL, while accounting for immune status. In the CCLS population, home dust measurements and self-reported chemical exposures will be used to further characterize in utero chemical exposures, and data on maternal infections during pregnancy will be used to help characterize maternal immune status. An engineered mouse model of childhood ALL will be used to elucidate mechanisms by which in utero chemical exposures and maternal/neonatal immune status interact to initiate ALL (through Core C). In addition, data on maternal/neonatal immune status will be incorporated in the analysis of DNA methylation (Project 3). Our proposed project will fill important knowledge gaps in the etiology of childhood ALL, and further the understanding of immunomodulatory effects of in utero chemical exposures.