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

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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.