Early life exposure to metal mixtures: impacts on asthma and lungdevelopment

项目总结 儿童哮喘是儿童健康的主要负担，影响到7%的美国儿童(600万儿童) 每年一次。此外，儿童时期的肺功能对成人肺部发病率有很高的预测性。在子宫内和 儿童早期接触金属，既有必要的(有益于健康的)，也有非必要的(有害的)， 可能会影响呼吸道健康。毒理学证据表明，产前和儿童早期接触非 必需金属会引起氧化应激，从而扰乱正常的免疫系统发育并改变 表观基因组，免疫和肺发育的强大决定因素。母体和母体中金属的普遍存在 儿童环境及其在水、空气、饮食和住房中的可改变来源意味着潜在的大公共 对健康的影响。然而，现有的少数几项研究都有局限性：几乎所有的 单独分析金属，而不是将其作为混合物进行分析，并且只考虑暴露的单一时间点。这个 拟议的研究利用了Project Viva的数据，Project Viva是一个由2,128名母亲组成的大型、特征良好的产前队列。 1999年至2002年在马萨诸塞州东部招募的儿童对，以解决这些差距。建议数 研究将评估在怀孕前三个月和儿童早期接触金属混合物对：(1)血液 儿童早期过敏生物标志物总免疫球蛋白E和变应原特异性免疫球蛋白E的水平 致敏作用；(2)儿童中期普遍存在的哮喘，以及儿童早期对产前金属效应的调节 (3)儿童期中期的肺功能。拟议的研究通过以下方式克服了先前工作的局限性 联合分析14种金属，而不是单独分析，并区分早期金属暴露的贡献 妊娠VS儿童早期免疫系统和肺部病理。总体而言，这项研究将提供证据 用于干预措施，如饮食建议，以调节金属暴露，以促进呼吸 健康，并为这类干预措施提出最佳时间窗口。奖学金申请者的培训计划 是与赞助团队合作开发的，包括Alan Hubbard博士(赞助商)、John博士 Balmes(共同发起人)和Andres Cardenas博士(共同发起人)，并以因果推理能力为中心， 接触混合物的分析，以及儿童环境健康的学科领域知识，例如 毒理学、哮喘和围产期流行病学。这些领域的课程作业通过参加 会议、培训和研讨会。与个人赞助商和赞助商团队定期举行会议 整体而言，这将进一步促进培训。加州大学伯克利分校的环境非常支持 提供与环境领域不同的教职员工和研究合作的机会 流行病学，以及在统计计算、科学写作、职业发展、指导、 并提供建议。总体而言，培训计划和环境将确保申请者成熟为一个富有成效的 儿童环境健康领域的创新研究人员。

PROJECT SUMMARY Pediatric asthma is a major burden on child health, affecting 7% of American children (6 million children) annually. Additionally, lung function in childhood is highly predictive of adult pulmonary morbidity. In utero and early childhood exposure to metals, both essential (beneficial for health) and non-essential (harmful to health), may shape respiratory health. Toxicologic evidence suggests prenatal and early childhood exposure to non- essential metals causes oxidative stress, which disrupts normal immune system development and alters the epigenome, a strong determinant of immune and lung development. The ubiquity of metals in the maternal and child environments, and their modifiable sources in water, air, diet, and housing, imply potentially large public health impacts. However, the few existing studies examining these associations have limitations: almost all analyze metals individually rather than as a mixture, and consider only a single timepoint of exposure. The proposed research utilizes data from Project Viva, a large, well-characterized pre-birth cohort of 2,128 mother- child pairs recruited between 1999-2002 in eastern Massachusetts, to address these gaps. The proposed research will assess impacts of metal mixture exposure in the first trimester and early childhood on: (1) blood levels of total and allergen-specific immunoglobulin E (IgE) in early childhood, biomarkers of allergic sensitization; (2) prevalent asthma in mid-childhood, and mediation of prenatal metal effects by early childhood IgE; and (3) lung function in mid-childhood. The proposed research overcomes the limitations of prior work by analyzing 14 metals jointly rather than individually, and distinguishing contributions of metal exposure in early pregnancy vs. early childhood to immune system and lung pathology. Overall, this research will provide evidence for interventions, such as dietary recommendations, to modulate metal exposure in order to promote respiratory health, and suggest optimal time windows for such interventions. The training plan for the Fellowship applicant was developed in collaboration with the sponsorship team, including Dr. Alan Hubbard (sponsor), Dr. John Balmes (co-sponsor), and Dr. Andres Cardenas (co-sponsor), and centers on competency in causal inference, the analysis of exposure mixtures, and subject area knowledge in children’s environmental health, such as toxicology, asthma, and perinatal epidemiology. Coursework in these areas is enriched by attendance to conferences, trainings, and workshops. Regular meetings with individual sponsors and the sponsorship team as a whole will further facilitate training. The environment at the University of California, Berkeley is highly supportive of this training, providing access to a diverse array of faculty and research collaborations in environmental epidemiology, and abundant resources in statistical computing, scientific writing, career development, mentoring, and advising. Overall, the training plan and environment will ensure the applicant matures into a productive and innovative researcher in children’s environmental health.