Circulating levels of Persistent Organic Pollutants and Subclinical Atherosclerosis progression in Postmenopausal women

ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in women in the US and globally. Menopausal transition poses remarkably elevated risk of CVD making postmenopausal women a population of special attention. There is an increasing concern about the exposure to environmental chemicals, particularly persistent organic pollutants (POPs), that disrupt human endocrine milieu and adversely affect cardiovascular health. The bioaccumulation of POPs over lifetime induces significant long-term health impact, especially among older population. However, the long-term effect of POPs on subclinical atherosclerosis progression, an early pathological feature of CVD, has not been studied well in postmenopausal women. In addition, the effect of POPs on atherosclerosis progression has not been evaluated in the US population. To our knowledge, no longitudinal study has been conducted to investigate the effects of POP mixtures and atherosclerosis progression. The only longitudinal study reporting an adverse effect of a specific class of POPs, per- and polyfluoroalkyl substances (PFASs), on increased carotid intima-media thickness (IMT, ultrasound) over 10 years was from a Swedish senior cohort. To fill the gaps in our understanding, we will investigate the long-term associations of plasma POPs concentrations and atherosclerosis progression in postmenopausal women in a unique cohort; Early vs Late Intervention Trial with Estradiol (ELITE) with 5-year longitudinal measurements of subclinical carotid atherosclerosis including gold-standard ultrasound measures (IMT, echogenicity, and stiffness) and frozen plasma samples to analyze absolute concentrations of 60 POPs from four main classes (polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), organochlorinated pesticides (OCPs), and (PFASs). ELITE is a randomized clinical trial including 596 early (<6years since menopause) and late (≥10years since menopause) postmenopausal women comparing rates of atherosclerosis progression over 5 years between women randomized to hormone therapy (HT) and placebo. Beyond the goal of investigating the effect of POP mixtures on atherosclerosis progression, we will investigate the impact of POP mixtures on risk factors of atherosclerosis including metabolic (lipids, glucose, HbA1c, and insulin resistance) and inflammatory biomarkers. Important covariates including the design factors (HT and placebo, early and late-postmenopausal groups), obesity, smoking, diet, and physical activity will be adjusted for in the analysis. To assess the generalizability of the adverse effect of POP exposure across various subgroups of postmenopausal women, we will evaluate POPs’ associations with atherosclerosis progression in subgroups of women randomized to HT and placebo, as well as early and late postmenopausal groups. This study will provide important evidence on long- term effect of POP mixtures on atherosclerosis progression and related metabolic and inflammatory pathophysiology among postmenopausal women who are at high risk of CVD. Findings from this study will help identify key individual and subgroups of POPs as targets for regulations, remediations, and CVD prevention.