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

摘要 心血管疾病（CVD）是美国女性死亡的主要原因， 每三个女性死亡中就有一个。累积的证据已经确定了怀孕并发症以及生育能力 作为CVD的危险因素。然而，对环境影响的了解非常有限。 怀孕期间的暴露和短期和长期的产妇心血管和代谢健康。 具有潜在心脏代谢影响的环境化学品包括邻苯二甲酸盐和有机磷酸盐（OP） 阻燃剂，其广泛使用导致普遍存在的一般人群暴露。实验研究 证明了邻苯二甲酸酯和OP阻燃剂都能与人类过氧化物酶体增殖物激活的 受体（PPARs），一种参与脂质代谢调节的主核受体。在低生育力人群中， 在参加环境与生殖健康（EARTH）研究的妇女中，我们观察到更糟糕的妊娠 结果，包括活产率下降，妊娠丢失增加和血糖水平升高， 妊娠，尿中邻苯二甲酸酯和/或OP阻燃剂代谢物浓度增加。 然而，尚未研究妊娠期间邻苯二甲酸酯和OP阻燃剂暴露是否相关 长期（中年）孕产妇心血管和代谢健康。我们建议评估 孕前、妊娠和中年尿中邻苯二甲酸酯和OP阻燃剂代谢物浓度 （单独或混合）与长期心脏代谢健康（人体测量、血糖和血脂） 代谢、血压和炎症生物标志物）。我们还将确定最重要的窗口（S） 与心脏代谢健康相关的暴露，评估尿液的联合和交互作用 代谢物浓度和可改变的CVD生活方式风险因素（BMI、饮食、体力活动、吸烟） 与心脏代谢健康，并调查从怀孕到分娩的心血管健康结果的轨迹。 中年我们将我们的建议嵌入到地球研究（2004-2021）中，一组生育能力低下的夫妇参加了研究。 一个单一的生育中心，以确定生殖健康的环境预测因素。地球研究的优势 包括在怀孕前和怀孕期间收集尿液样本，以及其全面和丰富数据库 协变量。我们将联系并重新招募前女性地球参与者，他们将提供额外的尿液 样品包括邻苯二甲酸酯和OP阻燃剂代谢物的中期暴露窗口， 评估他们目前的健康状况。生育能力受损的女性患CVD的风险更高，因此， 该提案为探索女性心血管和代谢健康提供了一个难得的机会 到目前为止，在已经建立的地球研究中， 结果。从拟议的一系列调查结果将告知临床护理的妇女从 生殖年龄到中年，关于筛查和长期随访的CVD指南，以及未来 研究优先。

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.