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

项目摘要 儿童哮喘是儿童健康的主要负担，影响7%的美国儿童（600万儿童） 每年。此外，儿童期肺功能高度预测成人期肺部发病率。在子宫内和 幼儿期接触金属，包括基本金属（有益健康）和非基本金属（有害健康）， 可能影响呼吸系统健康。毒理学证据表明，产前和幼儿期接触非- 必需金属会引起氧化应激，破坏正常的免疫系统发育， 表观基因组，免疫和肺发育的强决定因素。金属在母体中的普遍存在， 儿童环境及其在水、空气、饮食和住房等方面的可改变来源，意味着潜在的大规模公共 健康影响。然而，现有的少数研究检查这些协会有局限性：几乎所有 单独分析金属，而不是作为混合物，并只考虑单一的暴露时间点。的 拟议的研究利用了来自Viva项目的数据，Viva项目是一个由2,128名母亲组成的大型、特征良好的出生前队列， 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。拟议 研究将评估在头三个月和幼儿期接触金属混合物对以下方面的影响：（1）血液 儿童早期总免疫球蛋白E和过敏原特异性免疫球蛋白E（IgE）水平，过敏性疾病的生物标志物 致敏;（2）在儿童中期流行哮喘，并通过幼儿期调解产前金属效应 IgE;（3）儿童中期肺功能。拟议的研究克服了先前工作的局限性， 共同分析14种金属，而不是单独分析，并区分早期金属暴露的贡献， 妊娠与幼儿期对免疫系统和肺部病理的影响。总的来说，这项研究将提供证据， 干预措施，如饮食建议，以调节金属暴露，以促进呼吸系统 健康，并建议这种干预措施的最佳时间窗口。研究金申请人的培训计划 是与赞助团队合作开发的，包括Alan Hubbard博士（赞助商），John 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，如 毒理学哮喘和围产期流行病学在这些领域的课程是丰富的出席， 会议、培训和研讨会。定期与个别赞助商和赞助团队举行会议， 一个整体将进一步促进培训。在加州大学伯克利分校的环境是高度支持 这种培训，提供获得环境的教师和研究合作的多样化 流行病学，以及统计计算，科学写作，职业发展，指导， 和建议。总的来说，培训计划和环境将确保申请人成熟成为一个富有成效的， 儿童环境健康创新研究者。

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.