Associations of phthalates, phthalate replacements, and their mixtures with eicosanoid biomarkers during pregnancy

Abstract

Humans are exposed to complex mixtures of phthalates. Gestational exposure to phthalates has been linked to preeclampsia and preterm birth through potential pathways such as endocrine disruption, oxidative stress, and inflammation. Eicosanoids are bioactive signaling lipids that are related to a variety of homeostatic and inflammatory processes. We investigated associations between urinary phthalates and their mixtures with plasma eicosanoid levels during pregnancy using the PROTECT cohort in Puerto Rico (N = 655). After adjusting for covariates, we estimated pair-wise associations between the geometric mean of individual phthalate metabolite concentrations across pregnancy and eicosanoid biomarkers using multivariable linear regression. We used bootstrapping of adaptive elastic net regression (adENET) to evaluate phthalate mixtures associated with eicosanoids and subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual. After adjusting for false-discovery, in single-pollutant analysis, 14 of 20 phthalate metabolites or parent compound indices showed significant and primarily negative associations with multiple eicosanoids. In our mixture analysis, associations with several metabolites of low molecular weight phthalates - DEP, DBP, and DIBP - became prominent. Additionally, MEHHTP and MECPTP, metabolites of a new phthalate replacement, DEHTP, were selected as important predictors for determining the concentrations of multiple eicosanoids from different pathway groups. A unit increase in phthalate ERS derived from bootstrapping of adENET was positively associated with several eicosanoids mainly from Cytochrome P450 pathway. For example, an increase in ERS was associated with 11(S)-HETE (β = 1.6, 95% CI: 0.020, 3.180), (±)11,12-DHET (β = 2.045, 95% CI: 0.250, 3.840), 20(S)-HETE (β = 0.813, 95% CI: 0.147, 1.479), and 9 s-HODE (β = 2.381, 95% CI: 0.657, 4.104). Gestational exposure to phthalates and phthalate mixtures were associated with eicosanoid levels during pregnancy. Results from the mixture analyses underscore the complexity of physiological impacts of phthalate exposure and call for further in-depth studies to examine these relationships.

Keywords: Eicosanoids; Mixture analysis; Phthalate replacements; Phthalates.

Figure 1.

Heat map of pair-wise associations between phthalate exposure analytes and eicosanoids biomarkers estimated using multiple linear regression (N=655). Both phthalate and eicosanoids were natural log-transformed. Models adjusted for maternal age, education, pre-pregnancy BMI, and specific gravity. P-values were adjusted for multiple comparisons (FDR q < 0.05).

Figure 2.

Heat map of multipollutant associations between phthalate exposure analytes and eicosanoids biomarkers selected by bootstrapping (B=100) of adaptive elastic net (≥ 50% selection) (N=530). Both phthalate and eicosanoids were natural log-transformed. Models adjusted for maternal age, education, pre-pregnancy BMI, and specific gravity.

Figure 3.

Associations and 95% confidence intervals between eicosanoid and ERS derived from 100 iterations of adaptive elastic net (N=530). Both phthalate and eicosanoids were natural log-transformed. Models adjusted for maternal age, education, pre-pregnancy BMI, and specific gravity.