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

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 代谢物与不良的心脏代谢结果有关，包括妊娠体重增加过多， 妊娠期糖尿病和糖耐量受损。在产后，产妇的生理学必须 重新调整到非怀孕状态，这可能是第二个关键的增高期 易受内分泌干扰。在这段时间内的监管失调尤其重要，因为 未能适当适应孕期和产后不断变化的需求的证据可能会增加 未来罹患慢性病(如心血管疾病、2型糖尿病)的风险。这项研究的总体假设是 怀孕和产后是敏感的窗口，在此期间邻苯二甲酸酯可能会失调母体 生理学，导致长期的心脏新陈代谢健康风险。我们建议综合描述 出生后头四年的心脏代谢健康状况将为邻苯二甲酸盐的影响提供关键的见解 在产前和产后关键窗口期暴露。这项提议充分利用了基础设施，富有 两项正在进行的怀孕队列研究的数据和生物素资料库，向上的母亲 (嗯；R01NR017602)和ERGO(R01ES026166)，专门为研究母体心脏代谢健康而设计 在怀孕和产后。ERGO和UM有相同的资格标准，很早就招募了女性 怀孕和产后跟踪，并提供广泛的产前和产后生物标本 收集，加上产后产妇的心脏代谢评估。在建议的合并UM中- ERGO队列(n=500)我们利用更大的样本量来测量母亲的尿邻苯二甲酸盐 在6个时间点(怀孕1-3个月，产后1-3年)的血药浓度，并检查与身体的关系 产后1-4岁时的成分和心脏代谢生物标志物研究目标包括：(1)确定 孕期和产后邻苯二甲酸酯浓度与母体组成的关系 产后4年；2)检查怀孕和产后邻苯二甲酸酯浓度和 产后1-4年的母体心脏代谢情况；以及(3)使用新的建模方法来 确定邻苯二甲酸盐可能影响母体肥胖和心脏代谢指标的敏感窗口。我们的 研究是检查怀孕期间邻苯二甲酸盐暴露与产后早期的关系的独特机会 对孕产妇健康状况进行了4年多的密集随访。

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), specifically designed to study maternal cardiometabolic health in pregnancy and postpartum. ERGO and UM had identical eligibility criteria, recruiting women in early pregnancy and following them through the postpartum, with extensive prenatal and postpartum bio-specimen collection, coupled with postpartum maternal cardiometabolic assessments. In the proposed combined UM- ERGO cohort (n=500) we capitalize on a larger sample size to measure maternal urinary phthalate concentrations at 6 time points (1st and 3rd trimesters, 1-3 years postpartum) and examine associations with body composition and cardiometabolic biomarkers at 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 newer modeling approaches to identify sensitive windows in which phthalates may impact maternal obesity and cardiometabolic measures. Our study is a unique opportunity to examine phthalate exposure in pregnancy and the early postpartum in relation to maternal health over 4 years of intensive follow-up.