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

摘要 心血管疾病(CVD)是美国女性的主要死亡原因，约占 每3例女性死亡中就有1例死亡。累积的证据已经确认了怀孕并发症和生育能力 措施，作为心血管疾病的危险因素。然而，关于环境影响的知识非常有限。 怀孕期间的暴露以及短期和长期的产妇心血管和代谢健康。 对心脏代谢有潜在影响的环境化学品包括邻苯二甲酸盐和有机磷(OP) 阻燃剂的广泛使用导致无处不在的普通人群暴露。实验研究 证明邻苯二甲酸酯和OP阻燃剂都能与人的过氧化物酶增殖物激活结合 受体(PPAR)，一种主要的核受体，参与脂类代谢调节。在亚生育力中 在参加环境与生殖健康(地球)研究的妇女中，我们观察到更糟糕的怀孕 结果，包括活产率下降，妊娠丢失增加和血糖水平升高 怀孕时，尿液中邻苯二甲酸盐和/或OP阻燃代谢物浓度增加。 然而，在怀孕期间接触邻苯二甲酸盐和OP阻燃剂是否相关，还没有研究。 长期(中年)孕妇的心血管和代谢健康。我们建议评估以下方面的关联 妊娠前期和中年尿邻苯二甲酸盐和OP阻燃代谢物浓度 (单独或混合)具有长期心脏代谢健康(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，评估尿液的联合和相互影响 CVD的代谢物浓度和可改变的生活方式危险因素(BMI、饮食、体力活动、吸烟) 心脏代谢健康，并调查从怀孕到 中年。我们将我们的建议嵌入了地球研究(2004-2021年)，这是一组参加 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 包括收集怀孕前和怀孕期间尿样及其全面和丰富的数据库 协变量。我们将联系并重新招募前地球女性参与者，她们将提供额外的尿液 包括邻苯二甲酸盐和OP阻燃代谢物的中年暴露窗口的样品和我们 将评估他们目前的健康状况。生育能力受损的女性患心血管疾病的风险更高，因此 该提案提供了一个探索女性心血管和代谢健康的绝佳机会 在久负盛名的地球研究中，到目前为止，该研究的重点是生育、怀孕和后代 结果。拟议的一系列调查的结果将为妇女的临床护理提供信息 生育年至中年，心血管疾病筛查和长期随访指南，以及未来 研究优先事项。

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.