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

摘要心血管疾病(CVD)是居住在美国的妇女的主要死亡原因 各州。在确定心血管疾病的可改变风险因素方面进展缓慢。越来越多的证据支持 怀孕可能是未来心血管疾病风险的压力测试，也是暴露于 内分泌干扰物(EDCs)与女性心血管疾病风险。我们的研究将解决以下关键需求 评估孕期和中年的EDC暴露以确定这些化学物质是否会增加心血管疾病的风险 在整个生殖生命过程中--心血管疾病风险因素发展的关键时期。我们将重点关注 接触全氟烷基物质和多氟烷基物质(PFAS)，这是一类普遍存在的持久性化学品。我们的 之前的研究和我们的初步数据表明，暴露于某些全氟辛烷磺酸的科学前提是强有力的 与妊娠和非妊娠妇女的心脏代谢不良结局有关。然而， 以前的研究没有前瞻性地评估怀孕到中期之间心血管疾病危险因素的发展。 生命或经检查的替代全氟辛烷磺酸化学品。这项研究的目的是确定 暴露于遗产和替代性全氟辛烷磺酸会改变妇女在其生殖生活中的心血管疾病风险。我们的 中心假设是，孕期和中年期间暴露于PFAS的较高水平会改变这一轨迹 心血管疾病风险，首先出现在妊娠高血压疾病(HDP)，随后 中年出现心血管危险因素(如肥胖、高血压、高血糖、血脂异常)。这 假说将使用来自Project Viva的数据通过3个AIMS进行验证，Project Viva是一项对1,563人进行的纵向队列研究 已有怀孕PFAS数据的孕妇，其中1198人目前正在参加20年 随访研究。在目标1中，我们将评估在以下情况下测量的传统全氟辛烷磺酸浓度之间的关联 妊娠早期与妊娠期间收缩压和舒张压的轨迹，以及HDP (即妊娠期高血压和先兆子痫)。在目标2中，我们将检查传统PFAS的关联 孕期血药浓度和孕期至中年全氟辛烷磺酸浓度变化与心血管疾病风险 因素(例如，体重指数、怀孕以来体重变化、中心性肥胖、空腹血糖、胰岛素、 血红蛋白A1c、高血糖、血压、高血压、血脂水平和血脂异常)。 (即怀孕后20年)。在目标3中，我们将评估遗留和替代PFAS之间的关联 在中年有心血管疾病危险因素的中年。在所有目标中，我们将检查个人对全氟化肥的风险敞口，并 他们的混合物使用了先进的统计技术。我们建议的创新方面包括：评估 将怀孕作为EDCS和妇女心血管疾病风险的易感窗口，检查下一代PFAS， 并使用了一个正在进行20年随访的大型、特征良好的队列。我们的发现将填补 关于环境化学品对未得到充分研究的时间段的影响的重要差距-- 怀孕和中年--对预防心血管疾病和降低风险的影响。

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.