Project 2 - Identifying In Utero Exposures that are Risk Factors for Childhood Leukemia

摘要 项目2 -确定儿童白血病的危险因素 虽然关于急性淋巴细胞白血病（ALL）可能的危险因素的重要发现已经被发现， 由CIRCLE和其他儿童白血病（CL）研究人员，时间和机制， 报告的化学物质导致儿童ALL仅部分特征，CL的其他风险因素包括 可能会被不断发展的“组学”技术发现。 因为儿童白血病通常出现在生命的前5年， 应该是儿童白血病病因学研究的一个主要焦点。我们假设 “胎儿疾病组”（代表所有胎儿暴露）影响儿童白血病的因果途径。使用 从加州的存档新生儿血斑（ANBS），我们建议测量代表胎儿的化学物质 来自两项流行病学研究的400例ALL病例和800例匹配对照的暴露， 加州儿童白血病研究（CCLS）和加州母子出生队列（CA出生队列）。 分析将采用液相色谱-高分辨率质谱法（LC-HRMS）进行 小分子和反应性亲电试剂与人血清白蛋白（HSA）的加合物的非靶向组学， 34位的半胱氨酸氨基酸（“Cys 34加合物”）。这种数据驱动的设计将使我们能够描述 怀孕期间母体/胎儿从不同来源（包括污染）接受的广泛类别的暴露， 饮食、药物和内源性过程。通过比较儿童白血病病例和 对照组，我们将在ANBS中找到区别性的化学特征，这些特征将被注释并与数据一起使用， 项目1和3调查因果路径。在一个单独的分析中，我们将比较小 分子和Cys 34加合物与那些匹配的母血，收集在怀孕期间， 200例ALL病例和400例对照，并将测试母亲暴露与儿童期之间的关联。 所有.最后，在进行小分子和加合物的组学分析时，我们将针对特定的 感兴趣的生物标志物，包括苯（一种已知的人类白血病原）、咖啡、吸烟、酒精 消耗和活性氧（ROS）。 由于缺乏关于胎儿和母亲在怀孕期间接触的现有数据， 这是一个探索儿童白血病早期病因的绝佳机会， 与ANBS一起实现这些目标的方法。由于其他国家为研究目的维持ANBS， 该项目的成功结果将为开发、维护和利用 美国所有儿童疾病调查的ANBS储存库

ABSTRACT Project 2 – Identifying In Utero Exposures that are Risk Factors for Childhood Leukemia Though important findings regarding possible risk factors of acute lymphoblastic leukemia (ALL) have been made by CIRCLE and other childhood leukemia (CL) investigators, the timing and mechanisms by which the reported chemicals cause childhood ALL are only partially characterized, and additional risk factors of CL are likely to be discovered using evolving “omics” technology. Because children generally present with childhood leukemia during the first 5 years of life, in utero exposures should be a major focus of investigations regarding the etiology of childhood leukemia. We hypothesize that the ‘fetal exposome’ (representing all fetal exposures) affects causal pathways in childhood leukemia. Using archived neonatal blood spots (ANBS) from California, we propose to measure chemicals representing fetal exposures from 400 ALL cases and 800 matched controls combined from two epidemiologic studies, the California Childhood Leukemia Study (CCLS) and the California Mother-Child Birth Cohort (CA Birth Cohort). Analyses will employ liquid chromatography-high resolution mass spectrometry (LC-HRMS) to perform untargeted omics of small molecules and adducts of reactive electrophiles with human serum albumin (HSA) at cysteine amino acid at position 34 (‘Cys34 adductomics’). This data-driven design will allow us to characterize broad classes of maternal/fetal exposures received during gestation from diverse sources including pollution, diet, drugs and endogenous processes. By comparing omic profiles between childhood leukemia cases and controls, we will find discriminating chemical features in ANBS that will be annotated and used with data in Projects 1 and 3 to investigate causal pathways. In a separate analysis we will compare profiles of small molecules and Cys34 adducts in ANBS with those matched to maternal blood, collected during pregnancy from 200 ALL cases and 400 controls, and will test for associations between maternal exposures and childhood ALL. Finally, while conducting omics analyses of small molecules and adducts, we will target particular biomarkers of interest, including benzene (a known human leukemogen), coffee, smoking, alcohol consumption and reactive oxygen species (ROS). Given the dearth of existing data regarding fetal and maternal exposures during pregnancy, this project offers an exceptional opportunity to explore early-life causes of childhood leukemia and to validate our untargeted methods for pursuing these aims with ANBS. Since other States maintain ANBS for research purposes, a successful outcome from this project would provide important impetus to develop, maintain and exploit repositories of ANBS for investigations of all childhood diseases in the U.S.