Academic journal article Environmental Health Perspectives

Mediation of the Relationship between Maternal Phthalate Exposure and Preterm Birth by Oxidative Stress with Repeated Measurements across Pregnancy

Academic journal article Environmental Health Perspectives

Mediation of the Relationship between Maternal Phthalate Exposure and Preterm Birth by Oxidative Stress with Repeated Measurements across Pregnancy

Article excerpt

Introduction

Understanding causal mechanism in observational studies of environmental exposure and complex disease is challenging. A useful approach may be to screen human populations for biomarkers of exposures as well as mechanistic intermediates and assess relationships with mediation analyses to aid in establishing biological pathways. We recently observed that urinary concentrations of phthalate metabolites were associated with increased odds of preterm birth (Ferguson et al. 2014). Phthalate metabolites are indicative of exposure to phthalate diesters which are found ubiquitously in the environment in plastics, personal care products, and medications (ATSDR 2001, 2002). Exposure to these compounds during pregnancy has been linked to preterm birth in other previous studies as well, although some results are conflicting (Adibi et al. 2009; Meeker et al. 2009; Whyatt et al. 2009; Wolff et al. 2008). We hypothesized that this relationship may be mediated by phthalate-induced maternal oxidative stress. Our previous work circumstantially supports this hypothesis; we have established that urinary phthalate metabolites are associated with an increase in urinary 8-isoprostane, a biomarker of oxidative stress (Ferguson et al. 2015b), and that furthermore urinary 8-isoprostane is associated with an increased risk of preterm birth (Ferguson et al. 2015a). In the present analysis, we sought to quantify and test the role of 8-isoprostane in the relationship between maternal phthalate exposure during pregnancy and prematurity using a mediation analysis within a causal framework.

Mediation analysis has been used in social and epidemiological research for decades to understand causal pathways, biological mechanisms, and to design policy interventions (Pearl 2014). Its development originated in structural equation modeling, and with the work of Baron and Kenny (1986) became widely used in the context of linear models. Application of a counterfactual framework (Rubin 1974) has further provided a strong theoretical basis for causal inference from mediation analysis by precisely defining the necessary assumptions. This framework has also facilitated natural extension of mediation analysis to more complex models that include exposure-mediator interaction, nonlinear terms, and longitudinal data (Valeri and VanderWeele 2013; VanderWeele and Tchetgen Tchetgen 2014; VanderWeele and Vansteelandt 2010).

The use of mediation analysis in environmental and exposure epidemiology has been infrequent and more recent. For example, in the Normative Aging Study partial mediation of the relationship between black carbon particulate exposure and increased fibrinogen levels was observed through epigenetic modifications (Bind et al. 2014). The limited application of mediation analysis is surprising, because many studies in environmental epidemiology measure markers of intermediate biological changes (e.g., hormone levels, epigenetic modifications, and inflammatory cytokines) in addition to examining exposure and disease outcomes.

The goal of the present study was to examine causal mediation in an observational study of preterm birth. Specifically, we investigated mediation of the relationship between exposure to phthalates, as indicated by urinary phthalate metabolites, and preterm birth by oxidative stress, as indicated by urinary 8-isoprostane. Within the causal framework, we investigated the natural direct effect (NDE) and the natural indirect (i.e., mediated) effect (NIE), as illustrated in Figure 1. Statistically speaking, the NDE refers to the change in the odds of preterm birth (Y) in association with a defined change in the urinary phthalate concentration (A; e.g., from a to a*) while holding the urinary 8-isoprostane concentration (M) at the level it would have naturally been at with A set at the original level (e.g., a). The NIE refers to the change in the odds of preterm birth (Y) when urinary phthalate concentration is held at a specific level (e. …

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