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

心血管疾病（CVD）是美国妇女死亡的主要原因， States.在确定CVD的可改变的危险因素方面进展缓慢。越来越多的证据表明， 怀孕可能是未来CVD风险的压力测试，也是暴露于 内分泌干扰物（EDCs）与女性CVD风险我们的研究将解决迫切需要， 评估妊娠期和中年期EDC暴露，以确定这些化学物质是否会增加CVD风险 在整个生殖生命过程中，这是CVD危险因素发展的关键时期。我们将专注于 暴露于全氟烷基和多氟烷基物质（PFAS），这是一类普遍存在的持久性化学品。我们 科学前提是强有力的，因为先前的研究和我们的初步数据表明，暴露于某些PFAS是 与妊娠和非妊娠女性的不良心脏代谢结局相关。然而，在这方面， 以前的研究没有前瞻性地评估怀孕和中期之间心血管疾病危险因素的发展。 寿命或检查更换PFAS化学品。本研究的目的是确定是否 暴露于传统和替代PFAS会改变女性在整个生育期内的CVD风险。我们 中心假设是，在怀孕期间和中年期间，PFAS的较高暴露改变了轨迹 心血管疾病的风险，首先出现在怀孕的高血压疾病（HDP），随后 中年出现CVD风险因素（即肥胖、高血压、高血糖、血脂异常）。这 将使用来自Viva项目的数据通过3个目标对假设进行检验，Viva项目是一项纵向队列研究， 现有妊娠PFAS数据的孕妇，其中1198名目前正在参加一项为期20年的 跟踪研究。在目标1中，我们将评估在以下条件下测量的传统PFAS浓度之间的关联： 妊娠早期的收缩压和舒张压在整个妊娠期间的轨迹，以及HDP (i.e.妊娠高血压和先兆子痫）。在目标2中，我们将检查遗留PFAS的关联 妊娠期PFAS浓度以及从妊娠期到中年有CVD风险的PFAS浓度变化 因素（例如，体重指数，自指数妊娠以来的体重变化，中心性肥胖，空腹血糖，胰岛素， 血红蛋白A1 c、高血糖症、血压、高血压、血脂水平和血脂异常） (i.e.,怀孕20年后）。在目标3中，我们将评估遗留PFAS与置换PFAS的相关性 在中年有心血管疾病的危险因素。在所有目标中，我们将检查个人PFAS的暴露情况， 他们的混合物使用先进的统计技术。我们的提案的创新方面包括： 妊娠作为内分泌干扰物和女性心血管疾病风险的易感窗口，下一代PFAS的检查， 并使用了一个正在接受20年随访的大型、特征良好的队列。我们的发现将填补 关于环境化学品对一个未充分研究的时期的影响的重要差距， 怀孕和中年--对心血管疾病预防和降低风险的影响。

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.