PROJECT SUMMARY
The dramatic increase in the prevalence of childhood obesity in recent decades has made obesity one of the
greatest public health challenges of the modern world. It is estimated that by 2030, 33% and 50% of US
children ages 6-11 and 12-19 years, respectively, will be overweight or obese. Environmental exposures in
utero and during postnatal periods of heightened susceptibility may increase risk of obesity and adversely
impact cardiometabolic health. Organophosphate esters (OPEs) are additive flame retardants and plasticizers
that are extensively used worldwide after the phase-out of polybrominated diphenyl ethers (PBDEs). The
ubiquitous use of OPEs has resulted in almost all pregnant women having OPE exposures and children having
a higher body burden compared to adults. OPEs interfere with well-recognized biological pathways contributing
to the development of obesity and cardiometabolic health, including disruption of: 1) thyroid hormones; 2) sex
steroid hormones; and 3) peroxisome proliferator-activated receptors as well as inducing 4) chronic low-grade
inflammation. Toxicological studies indicate OPEs increase lipid accumulation, disrupt metabolic function, and
impair glucose tolerance, supporting their role as potential obesogenic and metabolism-disrupting chemicals.
Epidemiological studies report increased odds of being overweight and obese as well as higher waist
circumference, body mass index (BMI), total cholesterol, and triglycerides. However, no longitudinal study in
humans has examined repeated OPE measures in early life and their association with adiposity and
cardiometabolic health in adolescence, which is a significant data gap. This proposed application will capitalize
on resources of the Health Outcomes and Measures of the Environment (HOME) Study to be among the very
first to examine whether early life OPEs are associated with adiposity and cardiometabolic health measures in
adolescence, including BMI and waist circumference z-scores, fat-mass index, body fat %, blood pressure,
fasting glucose, serum lipids, adiponectin, and leptin, using a prospective study design. We will additionally
measure novel cardiometabolic intermediates, including high molecular weight adiponectin, glycoprotein
acetyls (GlycA), irisin, vaspin, and lipoprotein particles, as well as biomarkers of inflammation. We will use
Quantile g-computation (Q-gcomp) and Bayesian Kernel Machine Regression (BKMR) to examine complex
OPE mixtures to determine the individual and joint effects of OPEs on adiposity and cardiometabolic profiles in
adolescence. We will use data from the Maternal-Infant Research on Environmental Chemicals (MIREC)
Study, a pan-Canadian cohort, to validate findings from the HOME Study. We will generate novel findings on
whether early life OPEs are obesogenic and metabolism-disrupting chemicals during adolescence and identify
potential windows of susceptibility. Given the ubiquity of OPEs and the global burden of obesity and type 2
diabetes, the findings will be highly valuable for environmental policy making and exposure reduction.
