Per- and Polyfluoroalkyl substances mixtures and maternal cardiovascular disease risk across the reproductive life course

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ABSTRACT Cardiovascular disease (CVD) is the leading cause of death among women living in the United States. Progress in identifying modifiable risk factors of CVD has been slow. Growing evidence supports the idea that pregnancy may be a stress test for future CVD risk and also a sensitive window of exposure for endocrine disrupting chemicals (EDCs) and women’s CVD risk. Our study will address the critical need to evaluate EDC exposures in pregnancy and midlife to determine whether these chemicals increase CVD risk across the reproductive life course—a key time period of CVD risk factor development. We will focus on exposure to per- and polyfluoroalkyl substances (PFAS), a class of ubiquitous, persistent chemicals. Our scientific premise is strong as prior studies and our preliminary data suggest that exposure to certain PFAS are associated with adverse cardiometabolic outcomes in both pregnant and non-pregnant women. However, previous studies have not prospectively evaluated CVD risk factor development between pregnancy and mid- life or examined replacement PFAS chemicals. The objective of this study is to determine whether exposures to legacy and replacement PFAS alter CVD risk in women across their reproductive lives. Our central hypothesis is that higher exposure to PFAS during pregnancy and through midlife alters the trajectory of CVD risk, first emerging in pregnancy as hypertension disorders of pregnancy (HDP), with subsequent emergence of CVD risk factors (i.e. obesity, hypertension, hyperglycemia, dyslipidemia) in midlife. This hypothesis will be tested through 3 aims using data from Project Viva, a longitudinal cohort study of 1,563 pregnant women with existing pregnancy PFAS data, of which 1198 are currently participating in a 20 year follow up study. In Aim 1, we will evaluate the association between legacy PFAS concentrations measured at 1st trimester of pregnancy with trajectories of systolic and diastolic blood pressure across pregnancy, and HDP (i.e. gestational hypertension and preeclampsia). In Aim 2, we will examine associations of legacy PFAS concentrations in pregnancy and the change in PFAS concentrations from pregnancy to midlife with CVD risk factors (e.g., body mass index, weight change since index pregnancy, central obesity, fasting glucose, insulin, hemoglobin A1c, hyperglycemia, blood pressure, hypertension, lipid levels, and dyslipidemia) during midlife (i.e.,20 years following pregnancy). In Aim 3, we will assess the association of legacy and replacement PFAS in mid-life with CVD risk factors in midlife. Across all aims, we will examine exposure to individual PFAS and their mixtures using advanced statistical techniques. The innovative aspects of our proposal include: evaluation of pregnancy as a susceptible window for EDCs and women’s CVD risk, examination of next-generation PFAS, and use of a large, well-characterized cohort that is undergoing 20 year follow up. Our findings will fill an important gap about the impact of environmental chemicals on an understudied time period—between pregnancy and midlife—with implications for CVD prevention and risk reduction.