Pregnancy and postpartum as vulnerable exposure windows: phthalates and maternal cardiometabolic health

项目摘要/摘要 怀孕是一个变革性的时期，多个身体系统从根本上调整以保护和养育 发育中的胎儿。越来越多的证据表明，暴露在破坏新陈代谢的环境化学物质中 例如邻苯二甲酸盐，会扰乱身体适应怀孕需求的能力。 在横断面研究中，邻苯二甲酸酯破坏了多个核受体和激素介导的通路， 它们与肥胖、糖尿病、心血管疾病(CVD)和代谢综合征有关。我们的 对多胎妊娠队列的研究表明，某些邻苯二甲酸盐浓度的升高 代谢物与心脏代谢不良结局有关，包括妊娠体重超标。 体重增加、妊娠期糖尿病和糖耐量受损。在产后，母体生理学 必须重新调整到非怀孕状态，这可能是第二个关键期 更容易受到内分泌干扰。考虑到这段时间的监管失调尤其重要 有力的证据表明，未能适当地适应孕期和产后不断变化的需求 可能会增加未来患慢性病(如心血管疾病、2型糖尿病)的风险。关于这一点的总体假设 研究表明，怀孕和产后是邻苯二甲酸酯可能失调的敏感窗口。 母体生理学，导致长期的心脏代谢健康风险。我们建议全面的 出生后头四年心脏代谢健康的特征将为了解 产前和产后关键窗口期邻苯二甲酸盐暴露的影响。这项建议充分利用了 基础设施，丰富的数据和正在进行的两项怀孕队列研究的生物质谱库，Upside Moms (嗯；R01NR017602)和ERGO(R01ES026166)，它们是专门为研究母体心脏- 孕期和产后的代谢健康。这两组人的主要互补特征是怀孕初期 招募、跨孕期广泛收集生物样品和产后母体心脏代谢 评估。在联合UM-ERGO队列(n=500)中，我们评估母亲尿邻苯二甲酸酯代谢物 6个时间点(妊娠1-3个月；产后1-4年)的血药浓度和检查 产后1-4年与身体成分和心脏代谢生物标记物的关系。研究目标 包括：(1)确定怀孕和产后邻苯二甲酸酯浓度之间的关系以及 产后1-4年孕妇的身体组成；(2)检查怀孕和 产后1-4年邻苯二甲酸盐浓度和产妇心脏代谢情况； (3)使用创新的建模方法来确定邻苯二甲酸盐影响母体的敏感窗口 肥胖和心脏新陈代谢指标。我们的研究提供了一个独特的机会来检测邻苯二甲酸盐 孕期和产后早期暴露与产妇健康的关系超过4年的密集随访。

Project Summary/Abstract Pregnancy is a transformative period when multiple body systems radically adjust to protect and nurture the growing fetus. Increasingly, evidence shows that exposure to metabolism disrupting environmental chemicals such as phthalates, can dysregulate the body’s ability to adapt appropriately to the demands of pregnancy. Phthalates disrupt multiple nuclear receptor and hormone-mediated pathways and in cross-sectional research, they have been linked to obesity, diabetes, cardiovascular disease (CVD), and metabolic syndrome. Our research in multiple pregnancy cohorts demonstrates that elevated concentrations of certain phthalate metabolites are associated with adverse cardiometabolic outcomes including excessive gestational weight gain, gestational diabetes mellitus, and impaired glucose tolerance. In the postpartum, maternal physiology must readjust to the non-pregnant state, a physiological “reset” that may be a second critical period of heightened vulnerability to endocrine disruption. Dysregulation during this time is particularly important given the strong evidence that failure to appropriately adapt to the changing demands of pregnancy and postpartum may increase future risk of chronic disease (e.g. CVD, type 2 diabetes). The over-arching hypothesis of this research is that pregnancy and the postpartum are sensitive windows during which phthalates may dysregulate maternal physiology, leading to long-term cardiometabolic health risks. We propose that comprehensive characterization of cardiometabolic health in the first four years after childbirth will provide key insights into the effects of phthalate exposure during critical prenatal and postpartum windows. This proposal capitalizes on the infrastructure, rich data and biospecimen repositories of two ongoing pregnancy cohort studies, UPSIDE Moms (UM; R01NR017602) & ERGO (R01ES026166) that were specifically designed to study maternal cardio- metabolic health in pregnancy and postpartum. Key complementary features of the 2 cohorts are first trimester recruitment, extensive biospecimen collection across pregnancy, and postpartum maternal cardiometabolic assessments. In the combined UM-ERGO cohort (n=500) we evaluate maternal urinary phthalate metabolite concentrations at six time points (trimesters 1 & 3 in pregnancy; 1-4 years postpartum) and examine associations with body composition and cardiometabolic biomarkers from 1-4 years postpartum. Study aims include: (1) Determine associations between pregnancy and postpartum phthalate concentrations and maternal body composition at 1-4 years postpartum; (2) Examine associations between pregnancy and postpartum phthalate concentrations and maternal cardiometabolic profiles at 1-4 years postpartum; and (3) Employ innovative modeling approaches to identify sensitive windows in which phthalates affect maternal obesity and cardiometabolic measures. Our study presents a unique opportunity to examine phthalate exposure in pregnancy and early postpartum in relation to maternal health over 4 years of intensive follow-up.