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

早产和胎儿到儿童早期发育减慢是大量有害的晚年疾病和经济成本的根源。研究清楚地表明，怀孕期间的母体环境在这些结果的起源中发挥了作用，并有化学和非化学暴露的证据。然而，这一领域的一个主要缺点是只关注个体暴露，而没有考虑母亲在怀孕期间经历的同时应激源。在这项研究中，我们旨在研究怀孕期间邻苯二甲酸酯和应激生活事件作为重要的化学和非化学暴露与早产和减少胎儿到儿童早期生长的关系。重要的是，我们还将评估氧化应激作为这些联系的基础机制，并测试母亲膳食中补充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)调查在怀孕期间邻苯二甲酸盐和应激性生活事件暴露之间的关系中作为中介的氧化应激，以及从胎儿到儿童早期成长的轨迹；2)确定这些暴露对感兴趣的不良妊娠结局的相加或乘法影响；以及3)探索通过孕妇在怀孕期间补充omega-3脂肪酸来改变暴露、氧化应激和妊娠结局之间的关系的效果。这些研究问题将在婴儿发展和环境研究(DEDS)中进行调查，这是一个正在进行的多中心出生队列研究，于2010年启动，旨在调查怀孕早期接触邻苯二甲酸酯对婴儿生殖道发育的影响。关于怀孕前三个月孕妇尿邻苯二甲酸盐浓度的现有数据，以及关于怀孕期间三个时间点的应激性生活事件和膳食欧米茄-3脂肪酸补充的问卷调查，将与新的生物标记物测量和医疗记录摘要相结合，以有效和全面地调查这些新的研究问题。该项目将增进人们对怀孕期间邻苯二甲酸盐和母亲应激暴露如何与不良生育结局相互作用的理解，并提供对影响的机制和潜在补救措施的洞察。它还将对环境健康科学领域作出长期贡献，建立一个范例，在个人一级审查化学和非化学暴露的混合物与早产和胎儿至幼儿成长的关系。该项目很好地符合NIEHS的战略目标：1)包括调查综合环境暴露如何影响疾病的发病机制；2)提高对共同生物途径的了解，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是如何与儿童早期生命发育有关的一个关键的易感窗口。 过去几年的进展： 该项目于2016年启动。在整个项目过程中，我们测量了尿氧化应激生物标记物，提取了有关妊娠并发症和分娩方式的信息，并测量了在妊娠晚期收集的尿样中的邻苯二甲酸酯代谢物。在2020财年，我们发表了对这项研究中主要研究问题的分析结果，调查了怀孕期间邻苯二甲酸盐暴露和应激生活事件对早产的联合影响。此外，我们深入研究了研究中可用的胎儿和儿童生长数据，并开始进行分析，检查产前氧化应激与邻苯二甲酸盐代谢物浓度和纵向生长曲线之间的关系。

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 2020 we published our results from analysis of the primary research question in this study, examining the joint impact of phthalate exposure and stressful life events in pregnancy on preterm birth. Furthermore, we took a deep dive into fetal and childhood growth data available in the study, and began work on analyses examining associations between prenatal oxidative stress and phthalate metabolite concentrations and longitudinal growth profiles.