Application of an analytical framework for multivariate mediation analysis of environmental data

Max T Aung,Yanyi Song,Lixia Zeng,John D Meeker,Subramaniam Pennathur,David E Cantonwine,Bhramar Mukherjee,Kelly K Ferguson,Thomas F Mcelrath

doi:10.1038/s41467-020-19335-2

Abstract

Diverse toxicological mechanisms may mediate the impact of environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. In this study, we introduce an analytical framework for multivariate mediation analysis to identify mediation pathways (q = 61 mediators) in the relationship between environmental toxicants (p = 38 analytes) and gestational age at delivery. Our analytical framework includes: (1) conducting pairwise mediation for unique exposure-mediator combinations, (2) exposure dimension reduction by estimating environmental risk scores, and (3) multivariate mediator analysis using either Bayesian shrinkage mediation analysis, population value decomposition, or mediation pathway penalization. Dimension reduction demonstrates that a one-unit increase in phthalate risk score is associated with a total effect of 1.07 lower gestational age (in weeks) at delivery (95% confidence interval: 0.48–1.67) and eicosanoids from the cytochrome p450 pathway mediated 26% of this effect (95% confidence interval: 4–63%). Eicosanoid products derived from the cytochrome p450 pathway may be important mediators of phthalate toxicity.

Highlights

Diverse toxicological mechanisms may mediate the impact of environmental toxicants on pregnancy outcomes
We showed that phthalates have been associated with increased risk for preterm delivery and reduced gestational age at delivery within the LIFECODES cohort[15,16]
Continuing to focus strictly on gestational age at delivery, we reduced the dimensionality of the exposure matrix by creating environmental risk scores for each exposure class: phthalates, phenols, metals, and polycyclic aromatic hydrocarbons

Summary

Introduction

Diverse toxicological mechanisms may mediate the impact of environmental toxicants (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. Polycyclic aromatic hydrocarbons commonly enter the environment through industrial and natural processes, such as the combustion of coal, fossil fuel, and organic debris[4] Additional anthropogenic activities such as natural resource extraction and electronic waste recycling can yield environmental contamination of heavy metals (e.g., lead, cadmium, mercury)[5]. We showed that phthalates have been associated with increased risk for preterm delivery and reduced gestational age at delivery within the LIFECODES cohort[15,16]. Based on these previous studies, there is circumstantial evidence of potential mediation between prenatal phthalate exposure and pregnancy outcomes through eicosanoids. These statistical methods have pushed the frontier of mediation analysis and created opportunities to make critical scientific discoveries using biomarkers from complex biological pathways

Methods

Results

Conclusion