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

项目总结/摘要 怀孕是一个转变时期，当多个身体系统从根本上调整，以保护和培养 胎儿发育越来越多的证据表明，暴露于代谢破坏环境化学品， 如邻苯二甲酸盐，会使身体适应怀孕要求的能力失调。 邻苯二甲酸酯破坏多个核受体和受体介导的通路，在横断面研究中， 它们与肥胖、糖尿病、心血管疾病（CVD）和代谢综合征有关。我们 多胎妊娠队列研究表明，某些邻苯二甲酸酯浓度升高 代谢产物与不良心脏代谢结果相关，包括妊娠期体重过重 妊娠期糖尿病和糖耐量受损。在产后，母亲的生理 必须重新调整到非怀孕状态，这是一种生理上的“重置”，可能是怀孕的第二个关键时期。 内分泌失调的脆弱性增加。在这段时间内的调节异常特别重要， 强有力的证据表明，未能适当地适应不断变化的需求，怀孕和产后 可能会增加未来患慢性疾病的风险（例如CVD，2型糖尿病）。这种过度假设 研究表明，怀孕和产后是邻苯二甲酸盐可能失调的敏感窗口 产妇生理，导致长期的心脏代谢健康风险。我们建议全面 分娩后前四年的心脏代谢健康特征将提供关键的见解， 在关键的产前和产后窗口期间邻苯二甲酸酯暴露的影响。该提案利用了 两项正在进行的妊娠队列研究的基础设施、丰富的数据和生物标本库，UPSIDE Moms (UM; R 01 NR 017602）和ERGO（R 01 ES 026166），专门设计用于研究母体心血管疾病。 怀孕和产后的代谢健康。2个队列的关键互补特征是妊娠早期 招募、妊娠期间广泛的生物样本采集和产后母体心脏代谢 评估。在合并的UM-ERGO队列（n=500）中，我们评估了母体尿邻苯二甲酸酯代谢产物 浓度在六个时间点（妊娠期1和3;产后1-4年），并检查 与产后1-4年的身体组成和心脏代谢生物标志物的相关性。研究旨在 包括：（1）确定妊娠和产后邻苯二甲酸酯浓度之间的关系， 产后1-4年的产妇身体成分;（2）检查妊娠与 产后邻苯二甲酸酯浓度和产后1-4年的母体心脏代谢特征;以及 (3)采用创新的建模方法来确定邻苯二甲酸酯影响母体的敏感窗口 肥胖和心脏代谢指标。我们的研究提供了一个独特的机会，检查邻苯二甲酸酯 在4年的密集随访中，研究了妊娠期和产后早期接触与孕产妇健康的关系。

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.