Environmental Toxicants and Cardiovascular Health Trajectories Across Childhood and Adolescence

About This Grant

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the United States. Its precursors, including high body mass index, elevated blood pressure, and dyslipidemia, emerge as early as age 3 years and strongly pre- dict adult CVD events and mortality. These findings underscore the urgent need for primordial prevention, a core priority of NHLBI, which focuses on promoting and preserving cardiovascular health (CVH) before disease onset. The American Heart Association’s Life’s Essential 8 construct provides a validated framework for as- sessing CVH across the lifespan using eight behavioral and biological parameters. This construct is also a strong indicator of future CVD events, whereby higher (better) CVH scores confers lower risk of adult CVD. Emerging evidence, including findings from our preliminary work, suggests that early-life exposure to environ- mental toxicants such as toxic metals (e.g., cadmium, lead), per- and polyfluoroalkyl substances, and air pollu- tion, may accelerate CVH decline through shared metabolic pathways including oxidative stress, endothelial dysfunction, and lipid dysregulation. However, the extent to which these toxicants influence CVH trajectories in children remains poorly understood. This R01 proposal will leverage data from 1,332 mother-child pairs in Pro- ject Viva, a well-characterized NIH-funded prospective pre-birth cohort in eastern Massachusetts with over two decades of follow-up. The study will: 1) investigate associations between prenatal toxicant exposures and CVH trajectories from childhood to adolescence, and assess effect modification by maternal lifestyle factors (Aim 1); 2) examine associations between postnatal toxicant exposures and CVH trajectories, and evaluate effect modi- fication by both maternal and child lifestyle factors (Aim 2); and 3) identify metabolomic signatures underlying CVH decline and assess their potential as biomarkers of toxicant exposure (Aim 3). Innovative features of this proposal include assessment of toxicant mixtures during sensitive developmental windows (i.e., pregnancy and childhood), advanced modeling of CVH trajectories from childhood to adolescence using modern analytical methods, and integration of untargeted metabolomics to uncover novel pathophysiologic mechanisms. Find- ings from this R01 will directly advance NHLBI’s Strategic Vision by identifying modifiable environmental fac- tors and molecular mechanisms that contribute to CVH decline. We anticipate our results will inform early-life interventions and therapeutic strategies to preserve CVH and reduce lifelong CVD risk, particularly in vulnera- ble pediatric populations.