Phthalate and stressful life event exposures and pregnancy outcomes: The role of oxidative stress

早产和减少胎儿到幼儿期的生长是广泛的不良晚年疾病和经济成本的根源。研究清楚地表明，怀孕期间的母亲环境在这些结果的起源中发挥了作用，并有证据表明化学和非化学暴露。然而，该领域的一个主要缺点是只关注个体暴露，而不考虑母亲在妊娠期间同时经历的压力源。在这项研究中，我们的目的是调查邻苯二甲酸酯酯和怀孕期间的压力生活事件，作为重要的化学和非化学暴露与早期分娩和减少胎儿到儿童早期生长有关。重要的是，我们还将评估氧化应激作为这些关联背后的机制，并测试母体膳食补充omega-3脂肪酸的潜在缓解作用。该项目的三个具体目标如下：1)研究氧化应激在邻苯二甲酸盐与妊娠早期分娩期间应激性生活事件暴露之间的关系以及从胎儿到儿童早期生长轨迹中的中介作用；2)确定这些暴露对相关不良妊娠结局的加性或乘性影响；3)探讨孕期孕妇膳食补充omega-3脂肪酸对暴露、氧化应激和妊娠结局之间关系的影响。这些研究问题将在婴儿发育与环境研究（TIDES）中进行调查，该研究是一项正在进行的多中心出生队列研究，于2010年启动，旨在调查妊娠早期接触邻苯二甲酸盐对婴儿生殖道发育的影响。妊娠前三个月母体尿邻苯二甲酸盐浓度的已有数据以及妊娠期间三个时间点的压力生活事件和膳食omega-3脂肪酸补充问卷的数据将与新的生物标志物测量和病历提取相结合，对这些新的研究问题进行有效和全面的调查。该项目将提高对孕期邻苯二甲酸盐和母亲应激暴露与不良分娩结局的相互作用的理解，并提供对影响的机制和潜在补救措施的见解。它还将为环境健康科学领域作出长期贡献，因为它建立了一种范式，在个人层面审查与早期分娩和胎儿至幼儿生长有关的化学品和非化学品接触混合物。本项目符合NIEHS的战略目标，包括：1)研究综合环境暴露对疾病发病机制的影响；2)提高对共同生物途径的理解，在这种情况下，氧化应激是这些暴露影响的基础；3)调查怀孕期间的暴露（易感的关键窗口）与儿童早期生活发展的关系。

Early delivery and reduced fetal to early childhood growth are the root of extensive adverse later-life diseases and economic costs. Research clearly indicates a role of the maternal environment during pregnancy in the origin of these outcomes, with evidence for both chemical and non-chemical exposures. However, a major shortcoming in this field is attention only to individual exposures without consideration for simultaneous stressors that mothers experience during gestation. In this study we aim to investigate phthalate diesters and stressful life events during pregnancy as important chemical and non-chemical exposures of interest in relation to early delivery and reduced fetal to early childhood growth. Importantly, we will also assess oxidative stress as a mechanism underlying these associations and test the potential mitigating role of maternal dietary omega-3 fatty acid supplementation. The three specific aims of the project are as follows: 1) Investigate oxidative stress as a mediator in the associations between phthalate and stressful life event exposures during pregnancy on early delivery and the trajectory from fetal to early childhood growth; 2) Determine the additive or multiplicative effects of these exposures on the adverse pregnancy outcomes of interest; and 3) Explore effect modification of the associations between exposures, oxidative stress, and pregnancy outcomes by maternal dietary supplementation with omega-3 fatty acids during pregnancy. These research questions will be investigated in The Infant Development and the Environment Study (TIDES), an ongoing multi-center birth cohort initiated in 2010 to investigate the impact of early pregnancy exposure to phthalates on infant reproductive tract development. Preexisting data on maternal urinary phthalate concentrations from the first trimester of pregnancy and from questionnaires on stressful life events and dietary omega-3 fatty acid supplementation at three time points during pregnancy will be combined with new biomarker measurement and medical record abstraction for efficient and comprehensive investigation of these novel research questions. This project will improve the understanding how phthalate and maternal stress exposures during pregnancy interact in the association with adverse birth outcomes, and provide insight into mechanism and potential remediation of effects. It will also make a long-term contribution to the field of environmental health sciences by establishing a paradigm for examining mixtures of chemical and non-chemical exposures at an individual level in relation to early delivery and fetal to early childhood growth. This project aligns well with the strategic goals of NIEHS by: 1) Including investigation of how combined environmental exposures impact disease pathogenesis; 2) Improving understanding of a shared biological pathway, in this case oxidative stress, underlying the impact of these exposures; and 3) Investigating how exposures during pregnancya critical window of susceptibilityrelate to the early life development of the child. Last years progress: This project was initiated in 2016. Throughout the course of this project, we have measured urinary oxidative stress biomarkers, abstracted information on pregnancy complications and mode of delivery, and measured urinary phthalate metabolites in urine samples collected in the third trimester. Over FY 2019 we rigorously examined 3rd trimester urinary oxidative stress biomarkers in our study. We asked, what factors are associated with higher oxidative stress levels? And observed associations with urinary phthalate metabolites, but not with psychosocial stress measures. We also asked, are oxidative stress levels associated with shorter time to delivery? And observed no associations in this study population. We additionally have investigated several tangential research questions using data collected as part of this project. Future will work will focus on the direct associations between urinary phthalate metabolites and outcomes in pregnancy.