The relationship between phthalate risk score and gestational age at delivery is mediated by cytochrome p450 derived eicosanoids: application of a novel analytical pipeline for high-dimensional multivariate mediation analysis

Abstract

Background: There are diverse toxicological mechanisms that may mediate the impact of several toxicant classes (phthalates, phenols, polycyclic aromatic hydrocarbons, and metals) on pregnancy outcomes. However, there is a critical knowledge gap for the assessment of high-dimensional mediation with biomarkers of inflammation, oxidative stress, and lipid metabolism pathways (cytochrome p450, lipoxygenases, cyclooxygenases). The objective of this study is to introduce an analytical pipeline that implements high-dimensional mediation analysis through dimension reduction of exposures analytes and endogenous mediator biomarkers.Methods: We implemented a high-dimensional mediation analysis pipeline in the LIFECODES prospective birth cohort (n=161), focusing on identifying mediation pathways using endogenous signaling molecules (q=63 biomarkers of intermediate effect) in the relationship between multiple environmental toxicants (p=38 exposure biomarkers) and gestational age at delivery. Our analytical pipeline included: (1) pairwise mediation with every possible unique combination of biomarkers of exposure and intermediate effect, (2) mediator shrinkage using Bayesian shrinkage mediation analysis and dimension reduction using population value decomposition, and (3) combining exposure dimension reduction by estimating environmental risk scores for each toxicant class. Results: Pairwise mediation yielded subtle natural indirect effects with no significant total or direct effects. Mediator and exposure dimension reduction demonstrated that one unit increase in the phthalate risk score was associated with a total effect of a 1.09 week reduction in gestational age at delivery (95% confidence interval: 1.78 - 0.36 weeks) and that 24.5% of this effect was mediated by the cytochrome p450 pathway.Conclusions: Although sparse effects are observed for individual exposure biomarkers, especially in underpowered samples, our findings for the cumulative effect of phthalates underline the importance of investigating these toxicants as mixtures. Endogenous eicosanoidproducts of the cytochrome p450 pathway may be important mediators for the toxic effects of phthalates during pregnancy.