Gestational PFAS Mixture Exposures, Longitudinal Metabolomic Profiles, and Adolescent Cardiometabolic Health

Project Abstract
Exposure to environmental chemical mixtures may increase the risk of cardiometabolic disease. Of particular
concern are prenatal exposure to perfluoroalkyl substances (PFAS), a class of chemicals used as processing
aids for oil/water repellant textiles, fluoropolymer manufacturing, food packaging, cleaning products, and
firefighting foams. PFAS exposure is ubiquitous, deriving from contaminated food and drinking water. Over 6
million people in the US have PFAS contaminated drinking water, and many more have low-level exposure.
Animal and human studies show that prenatal PFAS exposure may increase the risk of obesity, insulin
resistance, dyslipidemia, and hypertension – components of the cardiometabolic syndrome that markedly
increase the risk of adulthood cardiovascular diseases. However, few studies have investigated the health
effects of PFAS mixtures, and the biological pathways underlying these effects are poorly understood. Guided
by our preliminary studies and the hypothesis that biological pathways represented in the serum metabolome
are sensitive to early life PFAS mixture exposure and predictive of later life cardiometabolic health, we will use
non-targeted high-resolution metabolomics to quantify the associations between prenatal PFAS mixtures, the
metabolome, and cardiometabolic disease. Building upon two established and ongoing prospective cohorts of
pregnant women and their children from Canada (MIREC Study, n=500) and Cincinnati, Ohio (HOME Study,
n=250), we will measure >25,000 features of the serum metabolome at delivery and ages 3-5, and 7-12 years.
We will link these data to previously collected or to be measured prenatal PFAS biomarkers and
cardiometabolic outcomes at age 7-12 years. We will use sophisticated biostatistical techniques to reduce the
dimensionality of these data and discover metabolomic signatures associated with both prenatal PFAS
mixtures and cardiometabolic outcomes in MIREC, replicating our findings using HOME. Specifically, we will:
1) characterize trajectories of the serum metabolome in the first 12 years of life; 2) identify features of serum
metabolome trajectories in the first 12 years of life that predict adolescent cardiometabolic disease; 3)
determine if metabolome features mediate the association of prenatal exposure to PFAS mixtures with
adolescent cardiometabolic disease; and 4) determine the chemical identity of metabolome features
discovered in Aim 3. This interdisciplinary proposal that includes epidemiologists, clinicians, biostatisticians,
and chemists will efficiently leverage two ongoing cohort studies to address these timely aims. Ultimately, the
proposed studies will have substantial impact by improving our knowledge of the health effects of PFAS,
identifying novel metabolic alterations associated with PFAS mixtures and adolescent health, and improving
our understanding of biological pathways affecting cardiometabolic disease. These results are critical to
ongoing evaluations of PFAS toxicity and may help identify exposed populations at risk of cardiometabolic
disease and potentially ameliorate the effects of PFAS exposure.

Grant Number: 3R01ES032836-04S1
NIH Institute/Center: NIH
Principal Investigator: Joseph Braun