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

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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.