Metal mixtures, epigenome, adiposity and cardiometabolic risk across early life

ABSTRACT/PROJECT SUMMARY In this project, we will examine prospective associations of blood metal mixtures mineral and DNA methylation (DNAm) from the prenatal period to early childhood with adiposity and cardiometabolic risk across childhood and adolescence. We will leverage extant resources from four prospective cohorts: the TIGER Kids in Louisiana (N=342); the EPOCH (N=350) and Healthy Start (N=350) in Colorado; and the Generation R Study (N=500) in the Netherlands. The proposed study will include 1,542 children who are similar in age (4-16 years old) (discovery n=1042: TIGER Kids, EPOCH and Healthy Start; replication n=500: Generation R Study). Key elements of this proposal include directly-measured adiposity using gold standard methods (MRI and DXA), complementary information on a suite of cardiometabolic measures (fasting glucose, insulin, and lipids), and rich covariate data on lifestyle behaviors and Tanner staging. Additionally, the proposed study will generate new data on biomarkers of early-life exposure to blood metals (arsenic, lead, mercury, cadmium, selenium, magnesium, iron, and zinc) and DNAm at multiple time-points from birth through childhood for all four existing cohorts. In Aim 1, we will examine prospective associations of blood metal mixtures from the prenatal period to early childhood with adiposity and cardiometabolic risk across childhood and adolescence. In Aim 2, we will discover and validate prospective DNAm patterns at birth and in early childhood that mark the relationship of prior metal exposure with adiposity and cardiometabolic risk across childhood and adolescence. In Exploratory Aim 3, we will test whether potentially modifiable lifestyle behaviors (infant feeding mode, diet quality, consumption of specific foods/nutrients, activity level) mitigate the adverse effects of early-life metal exposure on adiposity and cardiometabolic risk. If successful, our findings will inform future research on policies and programs (e.g., systems-level changes to nutrition guidelines) to mitigate exposure to toxic metal mixtures and enhance intake of nutritious metals.