Exposure to phthalates and OP flame retardants and long-term maternal cardiovascular and metabolic health

ABSTRACT
Cardiovascular disease (CVD) is the leading cause of death among U.S. women, accounting for approximately
1 of every 3 female deaths. Cumulative evidence has identified pregnancy complications as well as fertility
measures, as CVD risk factors. However, there is very limited knowledge on the impact of environmental
exposures during pregnancy and both short and long-term maternal cardiovascular and metabolic health.
Environmental chemicals with potential cardiometabolic impact include phthalates and organophosphate (OP)
flame retardants, which widespread use leads to ubiquitous general population exposure. Experimental studies
demonstrated that both phthalates and OP flame retardants bind to human peroxisome proliferator-activated
receptors (PPARs), a master nuclear receptor that is involved in lipid metabolism regulation. Among subfertile
women enrolled in the Environment and Reproductive Health (EARTH) Study, we observed worse pregnancy
outcomes, including decreased live birth rates, increased pregnancy loss and elevated glucose levels during
pregnancy, with increasing urinary concentrations of phthalate and/or OP flame retardant metabolites.
However, it is unstudied whether phthalate and OP flame retardant exposure during pregnancy is associated
with long-term (midlife) maternal cardiovascular and metabolic health. We propose to evaluate associations of
preconception, pregnancy and midlife urinary phthalate and OP flame retardant metabolite concentrations
(individually and as a mixture) with long-term cardiometabolic health (anthropometry, glucose and lipid
metabolism, blood pressure and inflammatory biomarkers). We will also identify the most important window(s)
of exposure associated with cardiometabolic health, evaluate the joint and interactive effects of urinary
metabolite concentrations and modifiable lifestyle risk factors for CVD (BMI, diet, physical activity, smoking)
with cardiometabolic health, and investigate trajectories of cardiovascular health outcomes from pregnancy to
midlife. We embed our proposal within the EARTH Study (2004-2021), a cohort of subfertile couples attending
a single fertility center to identify environmental predictors of reproductive health. Strengths of EARTH Study
include collection of urine samples both before and during pregnancy and its comprehensive and rich database
of covariates. We will contact and re-enroll former female EARTH participants who will provide additional urine
samples comprising the midlife window of exposure for phthalate and OP flame retardant metabolites and we
will assess their current health status. Women with impaired fertility are at higher risk of CVD, thus this
proposal provides an exceptional opportunity to explore cardiovascular and metabolic health among women
within the well-established EARTH Study, which so far, has focused on fertility, pregnancy and offspring
outcomes. Results from the proposed series of investigations will inform clinical care for women from the
reproductive years through midlife, CVD guidelines regarding screening and long-term follow-up, and future
research priorities.

Grant Number: 5R01ES033651-05
NIH Institute/Center: NIH
Principal Investigator: BRENDA BIRMANN